Synthesis and Regioselective Reaction of Some Unsymmetrical

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Dec 10, 2015 - heterocycles [4] and synthesis of the heterocyclic chalcone in ... An authentic reaction was done, when the acid 2 was submitted to react with.

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Synthesis and Regioselective Reaction of Some Unsymmetrical Heterocyclic Chalcone Derivatives and Spiro Heterocyclic Compounds as Antibacterial Agents Maher A. El-Hashash, Sameh A. Rizk * and Saad R. Atta-Allah Received: 19 October 2015 ; Accepted: 3 December 2015 ; Published: 10 December 2015 Academic Editor: Philippe Belmont Chemistry Department, Science Faculty, Ain-Shams University, Abassia, Cairo 11566, Egypt; [email protected] (M.A.E.-H.); [email protected] (S.R.A.-A.) * Correspondence: [email protected] or [email protected]; Tel.: +20-106-482-7759

Abstract: A number of novel heterocyclic chalcone derivatives can be synthesized by thermal and microwave tools. Treatment of 4-(4-Acetylamino- and/or 4-bromo-phenyl)-4-oxobut-2-enoic acids with hydrogen peroxide in alkaline medium were afforded oxirane derivatives 2. Reaction of the epoxide 2 with 2-amino-5-aryl-1,3,4-thiadiazole derivatives yielded chalcone of imidazo[2,1-b]thiadiazole derivative 4 via two thermal routes. In one pot reaction of 4-bromoacetophenone, diethyloxalate, and 2-amino-5-aryl-1,3,4-thiadiazole derivatives in MW irradiation (W 250 and T 150 ˝ C) under eco-friendly conditions afforded an unsuitable yield of the desired chalcone 4d. The chalcone derivatives 4 were used as a key starting material to synthesize some new spiroheterocyclic compounds via Michael and aza-Michael adducts. The chalcone 4f was similar to the aryl-oxo-vinylamide derivatives for the inhibition of tyrosine kinase and cancer cell growth. The electron-withdrawing substituents, such as halogens, and 2-amino-1,3,4-thiadiazole moeity decreasing the electron density, thereby decreasing the energy of HOMO, and the presence of imidazothiadiazole moiety should improve the antibacterial activity. Thus, the newly synthesized compounds were evaluated for their anti-bacterial activity against (ATCC 25923), (ATCC 10987), (ATCC 274,) and (SM514). The structure of the newly synthesized compounds was confirmed by elemental analysis and spectroscopic data. Keywords: 4-aryl-4-oxo-but-2-enoic acid; spiropyrazole; spiroisoxazole; spiropyrane

oxirane;

chalcone;

imidazo[2,1-b]thiadiazole;

1. Introduction The anti-proliferative activity of (E)-4-aryl-4-oxo-2-butenoic acid amides was shown against three human tumor cell lines [1], in addition to a multitude of biological activities [2]. Chalcone derivatives are one of the major classes of natural products with widespread distribution in fruits, vegetables, spices, tea and soy based foodstuff. Recently, they have been a subject of great interest for their interesting pharmacological activities [3]. A series of chalcone derivatives bearing heterocycles [4] and synthesis of the heterocyclic chalcone in combination with antibiotics [5] were recorded. Most of the chalcones are highly biologically active with a number of pharmacological and medicinal applications [6]. Spiroindoline [7] and imidazoline derivatives [8] can be evaluated for their binding affinities and antagonistic activities at the neuropeptide YY5 receptor, as well as their good brain penetration. Also, spironolactone [9,10] is effective in treating mild hypertension without inducing hypokalemia or increased secretion of Aldosterone and Ephlerenone. Notably,

Molecules 2015, 20, 22069–22083; doi:10.3390/molecules201219827

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ketoconazole [11,12] has been successful as an antifungal agent. If the spiroimidazole derivatives [13] antibacterial agents it may beciprofloxacin), observed that antagonistic results are combined with(vancomycin, antibacterial ciprofloxacin), agents (vancomycin, it may be activity observed that from the competitive binding of the medicinal molecules into bacteria cells’ receptor. On the other antagonistic activity results from the competitive binding of the medicinal molecules into bacteria hand, the isoxazolines are evaluated their in vitro [14,15] antifungal and their proliferative cells’ receptor. On [14,15] the other hand, theforisoxazolines are activity evaluated for their in vitro response toactivity humanand mononuclear peripheral blood to cells. Imidazo-oxazole [16] can be antifungal their proliferative response human mononuclear derivatives peripheral blood cells. synthesized via treatment of imidazole derivatives with oxirane, and they have been tested for Imidazo-oxazole derivatives [16] can be synthesized via treatment of imidazole derivatives with anti-mycobacterial activity. (E)-4-aryl-4-oxo-2-butenoic acids are convenient poly electrophilic oxirane, and they have beenThe tested for anti-mycobacterial activity. The (E)-4-aryl-4-oxo-2-butenoic reagents for the addition reaction of nucleophiles; e.g., carbon, nitrogen, and sulfur occure.g., exclusively acids are convenient poly electrophilic reagents for the addition reaction of nucleophiles; carbon, at the α-carbon electrophilic center of the carboxy precursors used for the synthesis of relevant nitrogen, and sulfur occur exclusively at the α-carbon electrophilic center of the carboxy heterocyclicused compounds [17–22]. The authors have reportedcompounds [19,23] that[17–22]. the behavior of 4-(4-acetyl precursors for the synthesis of relevant heterocyclic The authors have amino/bromo phenyl)-4-oxo-but-2-enoic acids (1) toward the hydrogen peroxide in the presence of reported [19,23] that the behavior of 4-(4-acetyl amino/bromo phenyl)-4-oxo-but-2-enoic acids (1) 8% sodium hydroxide/methanol afforded the epoxide products of (E)-1-(4-acetylaminobenzoyl)-2toward the hydrogen peroxide in the presence of 8% sodium hydroxide/methanol afforded the oxirane carboxylic acids (2). Among them, imidazo[2,1-b]1,3,4-thiadiazole is an(2). attractive arylthem, unit epoxide products of (E)-1-(4-acetylaminobenzoyl)-2-oxirane carboxylic acids Among that causes a decrease in electron density (low HOMO) of the synthesized chalcones, which increases imidazo[2,1-b]1,3,4-thiadiazole is an attractive aryl unit that causes a decrease in electron density its antibacterial [24]. (low HOMO) ofactivity the synthesized chalcones, which increases its antibacterial activity [24]. 2. Results Resultsand andDiscussion Discussion 2.1. Chemistry 2.1. Chemistry The regioselective reaction reactionof of (E)-1-(aroyl)-2-oxirane carboxylic (2) 2-amino-5-arylwith 2-aminoThe regioselective (E)-1-(aroyl)-2-oxirane carboxylic acidsacids (2) with 5-aryl-1,3,4-thiadiazole in the presence of boiling ethanol afforded imidazo[2,1-b]thiadiazole 1,3,4-thiadiazole in the presence of boiling ethanol afforded imidazo[2,1-b]thiadiazole derivatives derivatives [18,19], via the N-alkylation of aminomoieties thiadiazole added to αtheposition activated 3 [18,19], via3the N-alkylation of amino thiadiazole that moieties added tothat the activated of αposition ofheterocycle 3-membered heterocycle [25] of the carboxylic acids (Scheme 1). Refluxing adducts 3-membered [25] of the carboxylic acids 2 (Scheme 1). 2Refluxing adducts 3 with drops 3ofwith drops of triethylamine [TEA] in boiling ethanol chalcone derivatives 4 in good triethylamine [TEA] in boiling ethanol afforded theafforded chalconethe derivatives 4 in good yield. The 1 1 1 yield. The geometrical of the compounds 4 can be detected only in H-NMR The geometrical isomerism isomerism of the compounds 4 can be detected only in H-NMR spectra. Thespectra. H-NMR of 1 H-NMR of the compound 4a in DMSO reveals δ ppm at 2.54 (s, CH ) corresponding to CH CONH 3 3 the compound 4a in DMSO reveals δ ppm at 2.54 (s, CH3) corresponding to CH3CONH precursor, precursor, by 7.48–7.86 corresponding to the aromatic the proton of arylidine has multipliedmultiplied by 7.48–7.86 corresponding to the aromatic protons;protons; the proton of arylidine has two two chemical shift values 7.72, 1H, s,arylidine, CH=, arylidine, to the E-configuration, (high chemical shift values at 7.72,at1H, s, CH=, referringreferring to the E-configuration, 82% (high 82% integrated 1 H-NMR reflects stability of E-isomer), and at 7.78, 1H, s, CH=, arylidine, 1 integrated value (%) in value (%) in H-NMR reflects stability of E-isomer), and at 7.78, 1H, s, CH=, arylidine, 18% in the 18% form of a Z-configuration. δ ppm ofproton the arylidine proton of the form in of the a Z-configuration. The chemical The shift chemical δ ppm of shift the arylidine of the Z-configuration Z-configuration was due of to the the carbonyl field effect of the moiety of at the imidazole, was increased due to increased the field effect moiety ofcarbonyl the imidazole, and 13.2, s, acidic and NH at 13.2, s, acidic NH proton was exchangeable with D O. 2 proton was exchangeable with D2O.

Scheme 1. Synthetic Synthetic routes compounds (i) Reaction the oxirane derivative 2 Scheme 1. routes for for compounds 2–4.2–4. (i) Reaction of the ofoxirane derivative 2 within within 2-amino-1,3,4-thiadiazole in boiling ethanol afforded α-hydroxy ketone 3; (ii) Refluxing the 2-amino-1,3,4-thiadiazole in boiling ethanol afforded α-hydroxy ketone 3; (ii) Refluxing the derivatives derivatives 3 in boiling afforded ethanol/TEA, afforded chalcone derivatives 4 in good 3 in boiling ethanol/TEA, chalcone derivatives 4 in good yield 60%–71%; (iii)yield Direct60%–71%; synthesis (iii) Direct synthesis of the chalcone derivatives54h,inbut butanol/reflux h, 35%–40%. but in poor yield of 35%–40%. of the chalcone derivatives 4 in butanol/reflux in poor yield5of

An authentic reaction was done, when the acid 2 was submitted to react with 2-amino-5-aryl1,3,4-thiadiazole in boiling butanol, which led to spontaneous dehydration of the adduct 3 to afford 22070 2

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An authentic reaction was done, when the acid 2 was submitted to react with Molecules 2015, 20, page–page 2-amino-5-aryl-1,3,4-thiadiazole in boiling butanol, which led to spontaneous dehydration of the adduct 3 to afford the more thermodynamically stable 4 chalcone (Scheme product 1). The new 4, the the more thermodynamically stable 4 (Scheme 1). The new 4, thechalcone thermallyproduct labile acid 2 thermally labile acid 2 and/or substituted aminothiazoles were very sensitive to higher temperatures. and/or substituted aminothiazoles were very sensitive to higher temperatures. The classical synthesis The classical innot Schemes 1 and 2 wasthe not suitable because the prolonged (4–6 (Route iii) insynthesis Schemes 1(Route and 2iii) was suitable because prolonged (4–6 h) heating (110–120 °C)h) ˝ heating (110–120 C) led to butanol yields lower than 40% whichThe tended tochalcone decrease.derivative The novel led to butanol yields lower than 40% and which tended to and decrease. novel chalcone derivative 4 can also be synthesized in one pot reaction, fusing the 2-aminothiadiazole, 4 can also be synthesized in one pot reaction, fusing the 2-aminothiadiazole, diethyloxalate and diethyloxalate and 4-bromoacetophenone in apellet with small (useless amount organic of water 4-bromoacetophenone derivatives in pelletderivatives KOH, with smallKOH, amount ofawater (useless in MW irradiation (W 250 T 150in˝ C) forwith 15 min, in line with eco-friendly solvent)organic in MW solvent) irradiation (W 250 and T 150 °C) forand 15 min, line eco-friendly environmental environmental chemistry, affordedderivative the chalcone derivative also, with it wasa formed with poor chemistry, afforded the chalcone 4d, but also, it 4d, wasbut formed poor yield of a40%. yield of 40%. Scheme 2 outlinesofthe of the derivative novel chalcone derivative 4d. Attempts Scheme 2 outlines the synthesis thesynthesis novel chalcone 4d. Attempts to have favourableto have access to the desired chalcone using suitable base triethylamine [TEA] led to of the accessfavourable to the desired chalcone using suitable base triethylamine [TEA] led to the decomposition decomposition of the reactive chalcone 4, when the authors used strong basic medium. the reactive chalcone 4, when the authors used strong basic medium. O

O

O

H

H

COOH

COOH

O

H

Br

H

S

H2N N

Br

(i)

Ph

H

N

HO

N

S N

Ph N

O

(ii)

Br O

O

H

H

COOH

H O

COOH

H

Br

S

H2N N

(iii)

Ph

O

Br

N

Br

N

S N

(iv)

4d

Ph N

O

O

O

O

O O

+

O +

S

H2N N

N

O

Ph

N

O

N

S Ph N

Br Br

Scheme 2. 2. Synthetic and Conditions: (i) ethanol/reflux 3 h, 74%; (ii) Scheme Synthetic route routefor forcompound compound4d. 4d.Reagents Reagents and Conditions: (i) ethanol/reflux 3 h, 74%; ethanol/TEA/reflux 5 h, good yield 60%–71%; (iii) Butanol/reflux 5 h, with a poor yield of 35%–40%; (ii) ethanol/TEA/reflux 5 h, good yield 60%–71%; (iii) Butanol/reflux 5 h, with a poor yield of (iv) MW irradiation (W 250 and(W T 150 15 min, with poorwith yieldaof 35%–45%. ˝ C) for 35%–40%; (iv) MW irradiation 250 °C) andfor T 150 15amin, poor yield of 35%–45%.

Chalcone bears a very good synthon so that varieties of novel heterocycles with good Chalcone very good synthon so interesting that varieties of of novel heterocycles with good pharmaceuticalbears profilea can be designed [4–6]. An feature this structure is a pincer-like pharmaceutical can be designed An between interesting feature structure a pincer-like conformation ofprofile the molecule [26], and a[4–6]. reaction isatin and of thethis α-amino acidisafforded the conformation of the molecule [26], and a reaction between isatin and the α-amino acid afforded the azomethine ylide, with regioselective addition to the C=C bond of aroylacrylic acid or chalcone. The azomethine with addition to the C=C bond bi-nucleophiles, of aroylacrylic acid chalcone. electrophilicylide, centers in regioselective 4 can be allowed to react with simply e.g., or hydrazine The electrophilic centers in 4 can be allowed to react with simply bi-nucleophiles, e.g., hydrazine derivatives and hydroxyl amine, to afford important spiro heterocyclic compounds [19]. Treatment derivatives and4b, hydroxyl amine, to afford important spiro heterocyclic compounds [19]. Treatment of the isomers 4d, 4e and 4f with hydrazine hydrate and/or hydroxylamine (Scheme 3) affordedof the isomers 4b, 4d,compounds 4e and 4f with hydrate hydroxylamine (Scheme 3) afforded spiro heterocyclic 5 andhydrazine 6 via formation ofand/or the hydrazone and oxime intermediates 5i spiro heterocyclic compounds 5 and 6 via formation of the hydrazone and oxime intermediates and 6i, respectively [19]. Moreover, when the chalcone derivatives 4 were allowed to react with the 5i and 6i, respectively [19]. Moreover, when the chalcone derivatives were allowed to react with cyclopentanone in the presence of sodium hydroxide, this afforded 50% 4adducts 7 [27]. Treatment of the in theanhydride presence ofafforded sodium spiro-pyrane hydroxide, this afforded 850% adducts 7 [27]. Treatment thecyclopentanone adduct 7 with acetic derivative instead of formation of the of the adduct 7 with acetic anhydride afforded spiro-pyrane 8 instead of reactivity formationofofthe the furo[3,2-d]1,3,4-thiadiazole[3,2-a]imidazole [19]. These reactionsderivative can be reflected in the furo[3,2-d]1,3,4-thiadiazole[3,2-a]imidazole [19]. These reactions can begroup reflected in the reactivity carbonyl group of the aroyl moiety which is greater than the carbonyl of imidazole moiety.of the of the moiety which is greater carbonyl imidazole moiety. Thecarbonyl authors group reported thataroyl the product 8 can be changedthan andthe returned to 7group after of approximately one The reported that can be changed returned 7 after day.authors The lower stability of the the product 8 allowed the ring and to open again to and returnapproximately to the productone 7 2 day. The stabilityspiro of the product 8 that allowed thesurrounded ring to open andatoms. return to the product 7 due to thelower bridgehead carbon atom can be byagain four sp due toThe theprocedure bridgehead spiro include carbon atom can reaction be surrounded by four sp2 atoms. would arrestthat of the at the cycloalkane level and restart with different carbon nucleophiles. The authors expected that in at thethe case of electron level withdrawing groups The procedure would include arrest of the reaction cycloalkane and restart with in the pyrane structures, the best were attained byinthe procedure. As it is shown, the different carbon nucleophiles. Theyields authors expected that thedirect case of electron withdrawing groups best yield in spiro-pyrane derivative 8 were achieved for the derivative 8a, which subsequently its chalcone 4a was the most commonly used in the continued research. 22071 3

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in the pyrane structures, the best yields were attained by the direct procedure. As it is shown, the best yield in spiro-pyrane derivative 8 were achieved for the derivative 8a, which subsequently itsMolecules chalcone the most commonly used in the continued research. 2015,4a 20,was page–page Molecules 2015, 20, page–page (i)

O N N

O Ar O Ar O

N

N N NS

4

N

(i)

Ar

-

Ar

O

(ii)

S

4

O

(ii)

(iii)

NOH Ar

O

O

Ar O

N

NOH N

O

OAr

N

Ar

(iii) O

NNH2 N NNH2

-

N

7N

-

Ar

N N NS

-

Ar

(iv)

-

Ar

Ar

5i S

N N

6i

N

H N

O

H N

O

Ar

-

Ar NS

Ar

-

Ar S

N

6i

O

N

Ar-

4b, Ar Ar == C C6H H (4NHCOCH ), = C H (4Cl) 4a, 6 44(4NHCOCH33), Ar = C66H54 -

- = C H (2Cl) 4c, Ar = C H (4NHCOCH ), Ar 4b, Ar = C66H44(4NHCOCH33), Ar = C66H44(4Cl)

O

6N

-

N

N

N

4d,ArAr= =CCH 6 H 4 (4Br), Ar = C6 H5 4c, 6 4 (4NHCOCH3 ), Ar = C6 H4 (2Cl) 4e, Ar = C6 H4 (4Br), Ar- = C6 H4 (4Cl) 4d, Ar = C6 H 4 (4Br), Ar = C6 H5 - = C H (2Cl) 4f, Ar = C6 H4 (4Br), Ar 6 4 4e, Ar = C6 H 4 (4Br), Ar = C6 H4 (4Cl)

-

Ar

N S

N

-

Ar

S

-

4f, Ar = C6 H4 (4Br), Ar = C6 H4 (2Cl)

6

N

N

4a, Ar = C6 H4 (4NHCOCH3 ), Ar = C6 H5

O

O

O

-

-

Ar

S

O

N

O

-

Ar

N S

N

N

5 N

N

N

5N

Ar

5i

O Ar

7

N

Ar

(iv)

S

-

N N NS

Ar

Ar

N

-

Ar

N S

N

8N

-

Ar

S

8 Scheme 3. Synthetic route for compounds 5–8. Reagents and Conditions: (i) NH2NH2/ethanol/reflux 6 h, Scheme 3. Synthetic route for compounds 5–8. Reagents and Conditions: (i) NH2 NH2 / 60%–65%; (ii) NH 2OH/pyridine/reflux 5 h, 55%–70%; (iii) Cyclopentanone/ethanol/NaOH(50%)/Stir, Scheme 3. Synthetic route for compounds 5–8. Reagents and Conditions: (i) NH2NH 6 h, ethanol/reflux 6 h, 60%–65%; (ii) NH2 OH/pyridine/reflux 5 h, 55%–70%; (iii)2/ethanol/reflux Cyclopentanone/ 65%–74%; (ii) (iv) NH Acetic anhydride/ reflux51h, h, 55%–70%; 35%–45%. (iii) Cyclopentanone/ethanol/NaOH(50%)/Stir, 60%–65%; 2OH/pyridine/reflux ethanol/NaOH(50%)/Stir, 65%–74%; (iv) Acetic anhydride/reflux 1 h, 35%–45%. 65%–74%; (iv) Acetic anhydride/ reflux 1 h, 35%–45%. Ar

So, when the chalcone 4a was allowed to react with different carbon acids, e.g., ethylacetoacetate, So, when the chalcone 4a was allowed to react with carbon acids, e.g., ethylacetoacetate, ethylcyanoacetate, diethylmalonate, acetylacetone, and different malononitrile. The reaction can proceed with So, when the chalcone 4a was allowed to react with different carbon acids, e.g., ethylacetoacetate, ethylcyanoacetate, diethylmalonate, acetylacetone, and malononitrile. The reaction can proceed with ethylacetoacetate through the intermediate 9a followed ring closure The via the tetrahedral mechanism ethylcyanoacetate, diethylmalonate, acetylacetone, and by malononitrile. reaction can proceed with ethylacetoacetate through the intermediate 9a followed by ring closure via the tetrahedral mechanism to afford the regioselective product 10 that9a can be confirmed the lower stability of themechanism product 11 ethylacetoacetate through the intermediate followed by ringby closure via the tetrahedral to(Scheme afford the regioselective product 10 that can be confirmed by the lower stability of the product 11 authors assumed this wouldby similarly work with ethylcyanoacetate to afford 4). theThe regioselective product 10 one-pot that canreaction be confirmed the lower stability of the product 11 (Scheme 4). The authors assumed this one-pot reaction would similarly work with ethylcyanoacetate and diethylmalonate that confirmed this factreaction through the cyclization of the intermediates 9b–c. (Scheme 4). The authors assumed this one-pot would similarly work with ethylcyanoacetate 1 and and diethylmalonate that confirmed this fact through the cyclization of the intermediates 9b–c. In the same manner, the spiro-pyrane derivative 11 was alternatively substituted with R R2 and diethylmalonate that confirmed this fact through the cyclization of the intermediates 9b–c. 1 2 InIn the the derivative 11 substituted with R R and 1 and groups, theymanner, were synthesized in good yields from acetylacetone and/or malononitrile (the same thesame same manner, the spiro-pyrane spiro-pyrane derivative 11 was was alternatively alternatively substituted with RR2 groups, they synthesized in from and/or malononitrile (thesame same bi-functional carbon acids). According the proposed pathway, the use ofmalononitrile a controlled sequential groups, they were were synthesized in good goodtoyields yields from acetylacetone acetylacetone and/or (the bi-functional carbon acids). According to the the proposed proposed pathway, the the use of aagive controlled sequential procedure for the preparation of spiro-pyrone 10 and spiro-pyrane 11use should access sequential to a wider bi-functional carbon acids). According to pathway, of controlled 1, and Rgive 2. procedure for the preparation of spiro-pyrone 10 and spiro-pyrane 11 should access to wider series of spiro compounds 10 and 11, having different substituents R, R procedure for the preparation of spiro-pyrone 10 and spiro-pyrane 11 should give access to aawider 1 , and R2 . series of spiro compounds 10 and 11, having different substituents R, R series of spiro compounds 10 and 11, having different substituents R, R1, and R2. R

O

O O

N N NS

Ar Ar

N

N

O O

N 4a S

Ph Ph

4a

Ar = C6H4(4NHCOCH3) Ar = C6H4(4NHCOCH3)

XCH 2 Y NaOHY XCH 2 NaOH

y O y

x x

O

Ar

O O N

N

N N NS

Ar

O

N

S

Ph

Fusion

O Ar

Ph

Fusion

Ar

9 9a, X = COCH 9 3, Y = COOEt O

O R

N

O

N N

N Ph

N S

Ph

10N MajorS

+10 Major + 1

R

1

R

R

R O

10a, 55% 10b, 45% 10a, 55% 10c, 85% 10b, 45% 10c, 85%

R = COCH3 R = CN R = COCH3 R = COOEt R = CN R = COOEt

2

2

O

O

N

N N

9b, X = CN, Y = COOEt N N S 9a, X = COCH3, Y = COOEt O 9c, X = Y = COOEt Ar 9b, = COOEt 11NMinor S 9d,XX==CN, Y =YCOCH 9c, X = Y = COOEt3 Ar 9e, X = Y = CN 11 Minor 9d, X = Y = COCH3 9e, X = Y = CN Scheme 4. Synthetic route for compounds 9–11.

1

2

11a, 23% R = CH 3, R = COOEt 11b, 25% R = NH , R = COOEt Ph 11a, 23% R 11= CH 2, R 22= COOEt 11c, 44% R = CH3 , R = COCH 11b, 25% R 1= NH 3, R 2 = COOEt3 Ph 11d, 40% R1 = NH2 , R2 = CN 11c, 44% R 11= CH 32, R 22= COCH 3 11d, 40% R 1 = NH 2, R 2 = CN

Scheme 4. Synthetic route for compounds 9–11.

Scheme 4. Synthetic route for compounds 9–11. 2.2. Antibacterial Activity Evaluation

2.2. Antibacterial Activity Evaluation Agar Diffusion Method AgarThe Diffusion Method obtained new compounds were screened in vitro for their antibacterial activities against Gram positive bacteria aureus (ATCCin 25923) Bacillus cereus (ATCC 10987)), Gram The obtained new (Staphylococcus compounds were screened vitro and for their antibacterial activities against negative bacteria (Serratia marcesens aureus (ATCC(ATCC 274) and Proteus mirabiliscereus (SM514)), theGram agar Gram positive bacteria (Staphylococcus 25923) and Bacillus (ATCCusing 10987)), diffusion technique. The results of the antibacterial activity tests are shown in Table 1. negative bacteria (Serratia marcesens (ATCC 274) and Proteus mirabilis (SM514)), using the agar 22072 diffusion technique. The results of the antibacterial activity tests are shown in Table 1.

Molecules 2015, 20, 22069–22083

2.2. Antibacterial Activity Evaluation Agar Diffusion Method The obtained new compounds were screened in vitro for their antibacterial activities against Gram positive bacteria (Staphylococcus aureus (ATCC 25923) and Bacillus cereus (ATCC 10987)), Gram negative bacteria (Serratia marcesens (ATCC 274) and Proteus mirabilis (SM514)), using the agar diffusion technique. The results of the antibacterial activity tests are shown in Table 1. Table 1. Antibacterial activity of the synthesized compounds: Agar diffusion method. Compound No. 4a 4b 4c 4d 4e 4f 6a 6b 7a 7b 8a 8b 9a 9b 10a 10b Chloramphenicolr Ampicillinr

Gram Positive Staphylococcus aureus Bacillus cereus +++ +++ +++ +++ ++ +++ ++ ++ ++ ++ ´ + ++ ++ + + +++ +++

++ ++ +++ ++ + +++ ++ ++ ++ ++ + + ++ +++ + + +++ +++

Gram Negative Serratia marcesens Proteus mirabilis +++ ++ +++ ++ + ++ ++ ++ +++ +++ ´ + +++ +++ + + +++ +++

++ ++ ++ ++ + +++ + + + + ´ + +++ ++ + + +++ +++

The width of the zone of inhibition indicates the potency of antibacterial activity; (´) no antibacterial activity (0%–25%); (+) mild activity with the diameter of the zones equal to 0.5–0.8 cm (25dehydroascorbate 40%); (++) moderate activity with the diameter of the zones equal to 1.1–1.2 cm (55%–65%); (+++) marked high activity with the diameter of the zones equal to 1.8–2.0 cm (85%–100%).

Most of the synthesized compounds were found to possess some antibacterial activity towards all the microorganisms used. Compounds 4, 6, 7, 9 possess the highest antibacterial activities because they have been 65%–95% inhibition zone for antibacterial activity for both gram positive and gram negative bacteria. The generated QSAR model [24] indicates that a minimum HOMO energy of more than 30 chalcone derivatives contributes positively to the antibacterial activity. Electron-withdrawing substituents are lower the HOMO energy, such as halogens, due to the inductive effect of halogen which results in the decrease in electron density from the σ space of benzene ring, particularly o-chloro derivatives, thereby decreasing the energy of HOMO [28]. Designing chalcone derivatives with a high degree of bonding linearity (κ2 index) with groups that increase molecular weight (high value of ADME Weight) represents a positive contribution to the antibacterial activity [24]. P-glycoprotein (P-gp) is an ATP-dependent multidrug resistance efflux transporter that plays an important role in anticancer drug resistance and in the pharmacokinetics of medicines [29]. The bio-isostere of aroyl vinylamide and the new synthetic compound 4 indicated antitumor activities, as well as tyrosine kinase inhibition [30]. So, the authors wanted to synthesize unsymmetrical heterocyclic chalcone derivatives possessing imidazo-thiadiazole moiety, considered as antibacterial agents [16], with high molecular weight and electron withdrawing groups (low HOMO values); e.g., o-halo aryl and 2-amino-1,3,4-thiazole precursors and the characteristic linearity of bonding patterns (high κ2) that exhibit high antibacterial activity, c.f. Tables 1 and 2 and Figures 1 and 2. The authors explained that the strongest activities of the synthetic compounds 4c

22073

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and 4f (Table 1) were due to the inductive effect of the 2-chloro derivatives that decreases the electron density (decreased HOMO values), as shown in Figure 1B,D and increases the antibacterial activity. But the 4-chloro derivatives have electromeric effects that increase the electron density (increased Molecules 2015, 20, page–page HOMO) and decrease activity, as shown in Figure 1A,C. Also, the results are shown in Table 2, screen the Minimum Inhibitory Concentration (MIC) and calculated values of ADME, HOMO, and κ2 that are used to generate the QSAR model. The effect of amino-1,3,4-thiazole precursors were stronger than pyridyl and nitrophenyl precursors [24] that outlined the strong antibacterial activity of the synthesized compounds (Table 2). Molecules 2015, 20, page–page

(A)

(C)

(B) (A)

(B)

(C)

(D)

(D)

Figure 1. Outlines the electron distribution in HOMO for 4e (A); 4f (B); 4b (C) and 4c (D) compounds, Figure theare electron distribution in HOMO HOMOdensity for 4e 4eis(A); (A); (B); and 4c Figure 1. 1. Outlines Outlines the electron in for 4f (B); 4b 4b (C) and derivatives 4c (D) (D) compounds, compounds, respectively, outlined,distribution confirming that electron low4f among the (C) o-chloro respectively, are outlined, confirming that electron density is low among the o-chloro (decreased HOMO and increased activity). Electron deficient at the center of molecule means increase respectively, are outlined, confirming that electron density is low among the o-chloro derivatives derivatives antibacterial as the compounds 4f (B) and 4c (D). at the center of molecule means increase (decreasedthe HOMO and activity increased activity). Electron deficient

(decreased HOMO and increased activity). Electron deficient at the center of molecule means increase the the antibacterial antibacterial activity activity as as the the compounds compounds 4f 4f (B) (B) and and 4c 4c (D). (D).

Figure 2. Outlines the ring B in a blue circle that contains three electronegative nitrogen atoms, a carbonyl group and a halogen atom. These elements decrease the HOMO value and increase activity. Red circle outline aryl vinyl amide structure isostere for synthesized chalcones 4.

On the other hand, the resistance mechanism to penicillin antibiotics in these bacteria is the expression of beta-Lactamase enzyme. In order to use the penicillin antibiotics which are still effective Figure 2. Outlines the ring B in a blue circle that contains three electronegative nitrogen atoms, a Figureagainst 2. Outlines the ring B in blueevaluated circle that contains three electronegative nitrogen them, Jaramillo et al. [31]a had many chalcones as inhibitors of this enzyme. Theatoms, group and atom. These elements decrease HOMO value activity. chalcone derivatives 4 exhibit high antibacterial activity due the to presence of and activated double acarbonyl carbonyl group andaahalogen halogen atom. These elements decrease thethe HOMO value and increase increase activity. Red circle outline aryl vinyl amide structure isostere for synthesized chalcones 4. bondoutline as capping the enzyme, means the chalcones as a possible drug (enzyme inhibitor). Red circle arylagent vinylfor amide structure isostere for synthesized chalcones 4. Also, the spiro compounds 6 exhibit high antibacterial activity [32–34] as compared with compounds

On the other hand, the resistance mechanism to penicillin antibiotics in these bacteria is the 6 expression of beta-Lactamase enzyme. In order to use the penicillin antibiotics which are still effective 22074 against them, Jaramillo et al. [31] had evaluated many chalcones as inhibitors of this enzyme. The chalcone derivatives 4 exhibit high antibacterial activity due to the presence of activated double bond as capping agent for the enzyme, means the chalcones as a possible drug (enzyme inhibitor).

Molecules 2015, 20, 22069–22083

On the other hand, the resistance mechanism to penicillin antibiotics in these bacteria is the expression of beta-Lactamase enzyme. In order to use the penicillin antibiotics which are still effective against them, Jaramillo et al. [31] had evaluated many chalcones as inhibitors of this enzyme. The chalcone derivatives 4 exhibit high antibacterial activity due to the presence of activated double bond as capping agent for the enzyme, means the chalcones as a possible drug (enzyme Molecules 2015, 2015, 20, 20, page–page page–page Molecules 2015, 20, Molecules 2015, 20, page–page Molecules Molecules 2015,Also, 20, page–page page–page inhibitor). the spiro compounds 6 exhibit high antibacterial activity [32–34] as compared with Molecules 2015, 20, page–page compounds 5 and of the spiro five membered rings is near to structure penicillincore core 5 and and 10, 10, because because10, ofbecause the spiro spiro five membered rings is is near near to structure structure of of penicillin core and 10, because of the spiro five membered rings is near to structure of penicillin and 10, because of the spiro five membered rings is near to structure of penicillin core 55 of five membered rings to of penicillin core and 10, 10, because because ring) of the the spiro five membered rings is near to structure of penicillin core 555(β-lactam-thiazole and of the spiro five membered rings is near to structure of penicillin core andso sothey theycan canbe bematching matchingwith withthe theenzyme enzymemore morethan thancompounds compounds10. 10. (β-lactam-thiazole ring) ring) and and so they can be matching with the enzyme more than compounds 10. (β-lactam-thiazole ring) and (β-lactam-thiazole ring) and so they can be matching with the enzyme more than compounds 10. (β-lactam-thiazole so they can with the more than 10. (β-lactam-thiazole ring) and so NH theygroup can be beofmatching matching with the enzyme enzyme more than compounds compounds 10. (β-lactam-thiazole ring) and so they can be matching with the enzyme more than compounds 10. Compounds 5 have an acidic pyrazole precursor and so they have less fitting with Compounds 5555 have have an an acidic acidic NH NH group group of of pyrazole pyrazole precursor precursor and and so so they they have have less less fitting fitting with with Compounds have an NH group precursor and so less with Compounds have an acidic NH group of pyrazole precursor and so they have less fitting with Compounds Compounds 5the have an acidic acidic NH compounds group of of pyrazole pyrazole precursor andantibacterial so they they have haveactivity less fitting fitting with enzyme. On other hand, the 7, and 9 exhibit high due to the enzyme. On the other hand, the compounds 7, and 9 exhibit high antibacterial activity due to the enzyme. On the other hand, the compounds 7, and exhibit high antibacterial activity due to the enzyme. On the other hand, the compounds 7, and exhibit high antibacterial activity due to the enzyme. On the other hand, the compounds 7, and 99999 exhibit high antibacterial activity due to the enzyme. On the other hand, the compounds 7, and exhibit high antibacterial activity due to the enzyme. On the other hand, the compounds 7, and exhibit high antibacterial activity due to the presenceof ofthe thecarbonyl carbonylgroups groupsthat thatcondensed condensedwith withNH NH22-E -E(enzymatic (enzymaticinhibitor). inhibitor). 2-E presence of the carbonyl groups that condensed with NH (enzymatic inhibitor). presence presence of the carbonyl groups that condensed with NH -E (enzymatic inhibitor). presence presence of of the the carbonyl carbonyl groups groups that that condensed condensed with with NH NH2222-E -E (enzymatic (enzymatic inhibitor). inhibitor). Table 2. Rationalization of the synthesized Chalcones 4 as antibacterial agents using quantum Table 2. 2. Rationalization Rationalization of of the the synthesized synthesized Chalcones Chalcones 4444 as as antibacterial antibacterial agents agents using using quantum quantum Table 2. of as antibacterial agents using quantum Table 2. Rationalization of the synthesized Chalcones as antibacterial agents using quantum Table Table 2. Rationalization Rationalization of the the synthesized synthesized Chalcones Chalcones 44 as as antibacterial antibacterial agents agents using using quantum quantum Table 2. Rationalization the synthesized Chalcones chemical computation. of chemical computation. chemical computation. chemical computation. chemical chemical computation. computation. chemical computation. b bb MICa aaaaaa ADME Comp. Substituent Substituent Substituent Substituent MIC Comp. Substituent Substituent ADME MIC b Comp. Substituent Substituent ADME b bb κ2 Index b bb MIC Comp. Substituent Substituent ADME MIC Comp. ADME MIC Comp. Substituent Substituent ADME bbb HOMO MIC HOMO κ2 Index Index bbbb Comp. Substituent Substituent ADME b HOMO κ2 Index HOMO κ2 Index Ref. Ring A Ring B (ug/mL) HOMO Weight HOMO bbb κ2 κ2 Index Index Ref. Ring A A Ring B B Weight HOMO κ2 /mL) Weight Ref. Ring Ring ((ug/mL)

Ref. Ref. Ref. 4a 4a 4a 4a 4a 4a 4a

Ring A Ring Ring A A NHCOCH NHCOCH 33 NHCOCH NHCOCH NHCOCH NHCOCH3333 3 NHCOCH

4b 4b 4b 4b 4b 4b 4b

NHCOCH 33 NHCOCH NHCOCH NHCOCH 333 3 NHCOCH NHCOCH 3 NHCOCH

4c 4c 4c 4c 4c 4c 4c

NHCOCH 33 NHCOCH NHCOCH NHCOCH 333 3 NHCOCH NHCOCH 3 NHCOCH

4d 4d 4d 4d 4d 4d

Br Br Br Br Br Br

4e 4e 4e 4e 4e 4e

Br Br Br Br Br Br

4f 4f 4f 4f 4f 4f 4f

Br Br Br Br Br Br Br

6 [24] [24] [24] 66 [24] 6 [24] 666 [24] [24]

H H H H HH H

9 [24] [24] [24] 99 [24] 9 [24] 999 [24] [24]

H H H H HH H

aa aaa a

ug /mL) ((((ug ug/mL) /mL) ug /mL)

Ring B Ring Ring B B

N N N NN N N NN N N SS N N SS S N N S N N N N N N N NN N NN NN N SS S N S S N N NN S Cl Cl N Cl Cl Cl N Cl N N NN N N N N N N S N S S N S N SS N N N N N N N NN N N NN N N SS N N SS S N N S N N N N N N NN N N NN N N SS N S N S S N N S N N Cl Cl N Cl Cl Cl N Cl N N NN N N NN N N SS N S N SS N N S N N N

N N N N N N

Cl Cl Cl Cl Cl Cl

Cl Cl Cl Cl Cl Cl

NO22 NO NO NO NO2222 NO

600 600 600 600 600

600 600

Weight Weight Weight 320.3 320.3 320.3 320.3 320.3 320.3 320.3

−11.864 ´11.864 −11.864 −11.864 −11.864

−11.864 −11.864

8.762 8.762 8.762 8.762 8.762

700 700 700 700 700

700 700

253.6 253.6 253.6 253.6 253.6

253.6 253.6

−10.282 −10.282 ´10.282 −10.282 −10.282

−10.282 −10.282

9.163 9.163 9.163 9.163 9.163

500 500 500 500 500 500 500

393.1 393.1 393.1 393.1 393.1 393.1 393.1

−13.409 −13.409 ´13.409 −13.409 −13.409 −13.409 −13.409

9.718 9.718 9.718 9.718 9.718 9.718

600 600 600 600 600 600

314.3 314.3 314.3 314.3 314.3 314.3

−11.940 −11.940 −11.940 ´11.940 −11.940 −11.940

7.415 7.415 7.415 7.415 7.415 7.415

700 700 700 700 700 700

225.2 225.2 225.2 225.2 225.2 225.2

−11.322 −11.322 −11.322 −11.322 ´11.322 −11.322

7.505 7.505 7.505 7.505 7.505 7.505

500 500 500 500 500

500 500

275.3 275.3 275.3 275.3 275.3

275.3 275.3

−13.918 −13.918 ´13.918 −13.918 −13.918

−13.918 −13.918

8.914 8.914 8.914 8.914 8.914

600 600 600 600 600

600 600

321.3 321.3 321.3 321.3 321.3

321.3 321.3

−9.752 −9.752 −9.752 ´9.752 −9.752

−9.752 −9.752

8.590 8.590 8.590 8.590 8.590

700 700

277.29 277.29 277.29 277.29 277.29

277.29 277.29

−9.509 −9.509 −9.509 ´9.509 −9.509

−9.509 −9.509

7.513 7.513 7.513 7.513 7.513

700 700 700 700 700

8.762 8.762 9.163 9.163 9.718

8.914 8.914

8.590 8.590 7.513 7.513

Minimum Inhibitory Inhibitory Concentration; Concentration; bbbbb Calculated Calculated values values used used to to generate generate QSAR QSAR models. models. Minimum Inhibitory Concentration; Calculated values used to generate QSAR models. Minimum Inhibitory Concentration; Calculated values used to generate QSAR models. Minimum b Calculated a Minimum b Calculatedvalues Minimum Inhibitory Concentration; Calculated values usedtoto togenerate generate QSAR models. Minimum Inhibitory Concentration; used generate QSAR models. Inhibitory Concentration; values used QSAR models.

3. Experimental Experimental Section Section 3. Section 3. Experimental Section 3. 3.3.Experimental Experimental ExperimentalSection Section 3.1. General General Information Information 3.1. General Information 3.1. General Information 3.1. 3.1. General Information 3.1.General GeneralInformation Information 3.1. All melting points are are corrected corrected and and determined determined on on aaaa stuart stuart electric electric melting melting point point apparatus apparatus All melting points are corrected and determined on stuart electric melting point apparatus All melting points are corrected and determined on stuart electric melting point apparatus All All melting points are corrected and determined on stuart electric melting point apparatus Allmelting meltingpoints pointsare arecorrected correctedand anddetermined determinedon onaaastuart stuartelectric electricmelting meltingpoint pointapparatus apparatus All melting points (Microanalytical centre, centre, ainshams ainshams university, university, Cairo, Cairo, Egypt). Egypt). Elemental Elemental analyses analyses were were carried carried out out by by (Microanalytical centre, ainshams university, Cairo, Egypt). Elemental analyses were carried out by (Microanalytical centre, ainshams university, Cairo, Egypt). Elemental analyses were carried out by (Microanalytical (Microanalytical centre, ainshams university, Cairo, Egypt). Elemental analyses were carried out by (Microanalyticalcentre, centre,ainshams ainshamsuniversity, university,Cairo, Cairo,Egypt). Egypt).Elemental Elementalanalyses analyseswere werecarried carriedout outby by (Microanalytical Elementar Viro El-Microanalysis at the Micro-analytical Center, National Research Center, Egypt. IR Elementar Viro El-Microanalysis at the Micro-analytical Center, National Research Center, Egypt. IR Elementar Viro El-Microanalysis at the Micro-analytical Center, National Research Center, Egypt. IR Elementar the Micro-analytical Center, National Research Center, Egypt. IR Elementar Viro El-Microanalysis atat thethe Micro-analytical Center, National Research Center, Egypt. IR ElementarViro ViroEl-Microanalysis El-Microanalysisat Micro-analytical Center, National Research Center, Egypt. spectra (KBr) (KBr) were were recorded recorded on on infrared infrared spectrometer spectrometer FT-IR FT-IR 400D 400D (New (New York, York, NY, NY, USA) USA) using using spectra (KBr) were recorded on infrared spectrometer FT-IR 400D (New York, NY, USA) using spectra (KBr) were recorded on infrared spectrometer FT-IR 400D (New York, NY, USA) using spectra spectra (KBr) were recorded on on infrared spectrometer FT-IR 400D (New York, NY, USA) using IR spectra (KBr) were recorded infrared spectrometer FT-IR 400D (New York,NY, NY,USA) USA)using using spectra (KBr) were recorded on infrared spectrometer FT-IR 400D (New York, −1 1 −1 1 OMNIC program program and and are are reported reported frequency frequency of of absorption absorption in in terms terms of of cm cm´ and 1111H-NMR H-NMR spectra −1 OMNIC program and are reported frequency of absorption in terms of cm and H-NMR spectra 1H-NMR OMNIC program and are reported frequency of absorption in terms of cm and H-NMR spectra −11and OMNIC −1 cm−1 OMNIC program and are reported frequency of absorption absorption in in terms terms of of cm and spectra OMNICprogram programand andare arereported reported frequency frequency of and H-NMR H-NMRspectra spectra OMNIC and spectra recorded on on aaaa Bruker Bruker spectrophotometer spectrophotometer (Rheinstetten, (Rheinstetten, Germany) Germany) at at 400 400 MHz MHz using using TMS TMS as as internal internal recorded on Bruker spectrophotometer (Rheinstetten, Germany) at 400 MHz using TMS as internal recorded on Bruker spectrophotometer (Rheinstetten, Germany) at 400 MHz using TMS as internal recorded recorded on Bruker spectrophotometer (Rheinstetten, Germany) at 400 MHz using TMS as internal recordedon onaaaBruker Brukerspectrophotometer spectrophotometer(Rheinstetten, (Rheinstetten,Germany) Germany)at at400 400MHz MHzusing usingTMS TMSas asinternal internal recorded standard and with residual signals of the deuterated solvent δ = 7.26 ppm for CDCl 3 and δ 2.51 ppm standard and with residual signals of the deuterated solvent 7.26 ppm for CDCl 3 and 2.51 ppm standard and with residual signals of the deuterated solvent δδδ======7.26 7.26 ppm for CDCl and δδδ2.51 2.51 ppm standard residual signals of the deuterated solvent δδ ppm for CDCl 333 and δδ ppm standard and with residual signals of the deuterated solvent 7.26 ppm for CDCl and 2.51 ppm standardand andwith with residual signals of the deuterated solvent 7.26 ppm for CDCl and 2.51 ppm standard and with residual signals of the deuterated solvent δ 7.26 ppm for CDCl 3 3and δ 2.51 ppm 13 13 for DMSO-d DMSO-d6666.... 13 C-NMR spectra were were recorded recorded on on the the same same spectrometer spectrometer (Rheinstetten, (Rheinstetten, Germany) Germany) 13 for DMSO-d C-NMR spectra were recorded on same spectrometer (Rheinstetten, Germany) 13 C-NMR for C-NMR spectra the 13C-NMR for spectra for DMSO-d C-NMR spectra were recorded ononthe the same spectrometer (Rheinstetten, Germany) forDMSO-d DMSO-d66.6 .13 spectrawere wererecorded recordedon thesame samespectrometer spectrometer(Rheinstetten, (Rheinstetten,Germany) Germany) at 100 100 MHz MHz and and referenced referenced to to solvent solvent signals signals δδδδ ==== 77 77 ppm ppm for for CDCl CDCl3333 and and δδδδ 39.50 39.50 ppm ppm for for DMSO-d DMSO-d6666.... at 100 MHz and referenced to solvent signals 77 ppm for CDCl and 39.50 ppm for DMSO-d at 100 MHz and referenced to solvent signals 77 ppm for CDCl and 39.50 ppm for DMSO-d at atat100 100 MHz and referenced to solvent signals 77 ppm for CDCl and 39.50 ppm for DMSO-d 100MHz MHzand andreferenced referencedto tosolvent solventsignals signalsδδδ===77 77ppm ppmfor forCDCl CDCl333and andδδδ39.50 39.50ppm ppmfor forDMSO-d DMSO-d66.6. . at DEPT 135 135 NMR NMR spectroscopy spectroscopy were were used used where where appropriate appropriate to to aid aid the the assignment assignment of of signals signals in in the the DEPT 135 NMR spectroscopy were used where appropriate to aid the assignment of signals in the DEPT 135 NMR spectroscopy were used where appropriate to aid the assignment of signals in the DEPT DEPT 135 NMR spectroscopy were used where appropriate to aid the assignment of signals in the DEPT 135 NMR spectroscopy were used where appropriate to aid the assignment of signals inthe the DEPT 135 NMR spectroscopy were used where appropriate to aid the assignment of signals in 13C-NMR spectra. The mass spectra were recorded on Shimadzu GCMS-QP-1000 EX mass 11H13 Hand 13 and C-NMR spectra. The mass spectra were recorded on Shimadzu GCMS-QP-1000 EX mass 111H13 1 H-and and C-NMR spectra. The mass spectra were recorded on Shimadzu GCMS-QP-1000 EX mass 1313 C-NMR mass spectra 1 HHand C-NMR spectra. The mass spectra were recorded on Shimadzu GCMS-QP-1000 EX mass and13 C-NMRspectra. spectra.The The mass spectrawere wererecorded recordedon onShimadzu ShimadzuGCMS-QP-1000 GCMS-QP-1000EX EXmass mass spectrometer (Kyoto, (Kyoto, Japan) Japan) used used the the electron electron ionization ionization technique technique at at 70 70 e.v. e.v. Homogeneity Homogeneity of of all all spectrometer (Kyoto, Japan) used the electron ionization technique at 70 e.v. Homogeneity of all spectrometer (Kyoto, Japan) used the electron ionization technique at 70 e.v. Homogeneity of all spectrometer spectrometer (Kyoto, (Kyoto, Japan) Japan) used used the the electron electron ionization ionization technique technique at at 70 70 e.v. e.v. Homogeneity Homogeneity of of all all spectrometer synthesized compounds compounds was was checked checked by by TLC. TLC. synthesized compounds was checked by TLC. synthesized compounds was checked by TLC. synthesized synthesized compounds compounds was was checked checked by by TLC. TLC. 22075 synthesized 3.2. General General Procedure Procedure for for Synthesis Synthesis of of the the Compounds Compounds 2, 2, 3, 3, 5a 5a and and 5c 5c are are in in the the literature literature [19] [19] 3.2. General Procedure for Synthesis of the Compounds 2, 3, 5a and 5c are in the literature [19] 3.2. General Procedure for Synthesis of the Compounds 2, 3, 5a and 5c are in the literature [19] 3.2. 3.2. General General Procedure Procedure for for Synthesis Synthesis of of the the Compounds Compounds 2, 2, 3, 3, 5a 5a and and 5c 5c are are in in the the literature literature [19] [19] 3.2. 3.3. General General Procedure Procedure for for Synthesis Synthesis of of the the Compounds Compounds 4a–f 4a–f 3.3.

Molecules 2015, 20, 22069–22083

spectrometer (Kyoto, Japan) used the electron ionization technique at 70 e.v. Homogeneity of all synthesized compounds was checked by TLC. 3.2. General Procedure for Synthesis of the Compounds 2, 3, 5a and 5c are in the Literature [19] 3.3. General Procedure for Synthesis of the Compounds 4a–f Fuse the compounds 3a–f (0.01 mol) and 3–5 drops triethyl amine (TEA) in oil bath for 5 min, then refluxing in 50 mL of boiling aqueous ethanol for 5 h. The solid was separated after cooling and the pH of the solution was 6.5. The crude products were filtered, washed by petroleum ether (b.p. 40–60 ˝ C), dried and then recrystallized from dioxane. (E)-N-(4-(2-(5-Oxo-2-Phenylimidazo[2,1-b]1,3,4-thiadiazol-6(5H)ylidine)acetyl)phenyl)acetamide (4a). Yield 2.35 g (60%), light yellow finely crystalline, m.p. 176–178 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH), 3055 (CH), 1706, 1670, 1650 (CO), 1613 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 2.54 (3H, s, CH3 ), 7.72 (1H, s, CH=, arylidine, 82% in form of E-configuration), 7.78 (1H, s, CH=, arylidine, 18% in form of Z-configuration), 7.48–7.86 (9ArH, m, aromatic protons), 13.2 (1H, s, acidic NH proton which exchanged in D2 O), 13 C-NMR δ, 40.0 (CH3 CO), 105.4 (C2,6 Ph), 110.6 (C3,5 Ph), 125.5 (C4 Ar), 142.3 (C3,5 Ar), 144.8 (CH=), 147.4 (C2 Ar), 148 (C6 Ar), 148.5 (C4 Ph), 150.2 (C=CH), 152.4 (C1 Ph), 154.5 (C1 Ar), 156.0 (CNS), 162.2 (CN2 S), 165.1 (CO imidaz.), 168.0 (CO amide), 190.2 (CO ketone), and found, %: C 61.50, H 3.59, N 14.30, S 8.19 for C20 H14 N4 O3 S. Calculated, %: C 61.53, H 3.61, N 14.35, S 8.21; MS: m/z 346 [M+ ´ CH2 =C=O], 141 [imidazole thiadiazole moiety]. (E)-N-(4-(2-(2-(4-Chlorophenyl-5-oxo-imidazo[2,1-b]1,3,4-thiadiazol-6(5H)ylidine)acetyl)phenyl)acetamide (4b). Yield 2.85 g (67%), yellow finely crystalline, m.p. 210–212 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH), 1710, 1691, 1655 (CO); 1630 (C=N); 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 2.06 (3H, s, CH3 ), 7.73 (1H, s, CH=, arylidine, 78% in form of E-configuration), 7.81 (1H, s, CH=, arylidine, 22% in form of Z-configuration), 7.44–7.83 (8ArH, m, aromatic protons), 12.6 (1H, s, acidic NH proton which exchanged in D2 O); 13 C-NMR δ 22.5 (CH3 CO), 121.2 (C2,6 Ph), 128.8 (C3,5 Ph), 129.5 (C4 Ar), 131.5 (C4 PhCl), 132.3 (C3,5 Ar), 134.6 (CH=), 137.1 (C2 Ar); 138.3 (C6 Ar), 140.2 (C=CH), 142.0 (C Ph), 142.4 (C1 Ar), 160.3 (CNS), 161.4 (CN2 S), 166.5 (CO imidaz), 167.4 (CO amide), 191.0 (CO ketone) and found, %: C 56.53; H 3.06; N 13.16, Cl 8.30, S 7.53 for C20 H13 N4 O3 SCl. Calculated, %: C 56.54, H 3.08, N 13.19, Cl 8.34, S 7.55. (E)-N-(4-(2-(2-(2-Chlorophenyl-5-oxo-imidazo[2,1-b]1,3,4-thiadiazol-6(5H)ylidine)acetyl)phenyl)acetamide (4c). Yield 2.68 g (63%), yellow finely crystalline, m.p. 198–200 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH); 1710, 1691, 1655 (CO); 1630 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 2.06 (s, 3H, CH3 ), 7.69 (1H, s, CH=, arylidine, 80% in form of E-configuration), 7.77 (1H, s, CH=, arylidine, 20% in form of Z-configuration), 7.44–7.83 (8ArH, m, aromatic protons), 12.4 (1H, s, acidic NH proton which exchanged in D2 O), and found, %: C 56.50, H 3.02, N 13.11, Cl 8.30, S 7.51 for C20 H13 N4 SO3 Cl. Calculated, %: C 56.54, H 3.08, N 13.19, Cl 8.34, S 7.55; MS: m/z 389 [M+ ´ Cl], 347 [389 ´ CH2 CO]. (E)-6-(4-Bromophenyl)-2-oxoethylidine)-2-phenylimidazo[2,1-b]1,3,4-thiadiazol-5(6H)-one (4d). Yield 2.72 g (66%), yellow powder, m.p. 152–154 ˝ C. IR (KBr), υ, cm´1 : 1694, 1672 (CO); 1613 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 7.70 (1H, s, CH=, arylidine, 86% in form of E-configuration), 7.79 (1H, s, CH=, arylidine, 14% in form of Z-configuration), 7.44–7.73 (9ArH, m, aromatic protons). 13 C-NMR δ 119.6 (C2,6 Ph), 127.6 (C3,5 Ph), 130.5 (C4 Ph), 132.7 (C3,5 Ar), 135.3 (C2,6 Ar), 137.6 (C1 Ph), 139 (CH=), 141.2 (C4 Ar), 142.1 (C1 Ar), 145.5 (C=), 149.7 (CNS), 155.3 (CN2 S), 166.8 (CO imidaz.), 179.2 (CO) and found, %: C 52.50; H 2.35; N 10.15. C18 H10 N3 O2 BrS. Calculated, %: C 52.42, H 2.42, N 10.19. MS: m/z 378 [M+ ´ CO], 335 [M+ ´ Ph], 263 [M+ ´ Ph(Br)], 138 [imidazolothiadiazole moiety]. (E)-6-(4-Bromophenyl)-2-oxoethylidine)-2-(4-chlorophenyl)imidazo[2,1-b]1,3,4-thiadiazol-5(6H)-one (4e). Yield 3.17 g (71%), yellow finely crystalline, m.p. 168–170 ˝ C. IR (KBr), υ, cm´1 : 1710, 1691 (CO), 1630 (C=N); 1 H-NMR (DMSO-d6 ), δ, ppm (J, Hz): 7.70 ( 1H, s, CH=, arylidine, 78% in form of

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E-configuration), 7.80 (1H, s, CH=, arylidine, 22% in form of Z-configuration), 7.60–7.83 (8ArH, m, aromatic protons), and found, %: C 48.30, H 2.10, N 9.33. C18 H9 N3 O2 BrClS. Calculated, %: C 48.37, H 2.15, N 9.40. (E)-6-(4-Bromophenyl)-2-oxoethylidine)-2-(2-chlorophenyl)imidazo[2,1-b]1,3,4-thiadiazol-5(6H)-one (4f). Yield 3.04 g (68%), yellow finely crystalline, m.p. 180–182 ˝ C. IR (KBr), υ, cm´1 : 1708, 1684 (CO); 1630 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 7.73 (1H, s, CH=, arylidine, 73% in form of E-configuration), 7.84 (1H, s, CH=, arylidine, 27% in form of Z-configuration), 7.72–7.86 (8ArH, m, aromatic protons), and found, %: C 48.35, H 2.15, N 9.35 for C18 H9 N3 O2 BrClS. Calculated, %: C 48.37; H 2.15; N 9.40. 3.4. General Procedure for Synthesis of the Compounds 5b, 5d, and 5e A mixture of chalcone derivatives 4b, 4d and 4e (5 mmol) and hydrazine hydrate (0.5 mL, 0.01 mol) in boiling ethanol (50 mL) was heated under reflux for 5 h. The reaction mixture was allowed to cool and the product was filtered, dried, and recrystallized from the benzene and/or ethanol. N-(4-(2-(2-Chlorophenyl)-5-oxo)-21 ,41 -dihydro-5H-spiro[imidazo[2,1-b]1,3,4-thiadiazol-6,31 -pyrazol]-51 yl) phenyl)acetamide (5b). Yield 1.43 g (65%), off white crystal, m.p. 164–166 ˝ C. IR (KBr), υ, cm´1 : 3420 (NH); 1671, 1640 (CO); 1 H-NMR (DMSO-d6 ), δ, ppm (J, Hz): 1.2 (d, 2H, CH2 , J = 5.4); 2.5 (3H, s, CH3 ); 5.8 (1H, br. s, NH); 7.0–7.81 (8H, m, Ar-H); 12.40 (1H, br. s, NH of acetamide moiety), 13 C-NMR δ, 22.3 (CH3 CO); 69.6 (CH2 C=N); 122.4 (C4 Ph), 126.8 (C3,5 Ph), 129.1 (C Spiro), 131.5 (C3 Ar), 131.8 (C5 Ar), 132.6 (C2,6 Ph), 137.4 (C2 Ar), 138 (C6 Ar), 140.2 (C4 Ar), 144.5 (C1 Ar), 145.1 (C1 Ph), 158.0 (C=N), 161.3 (CNS), 163.2 (CN2 S), 165.3 (CO imidaz.), 167.8 (CO amide), and found, %: C 54.70, H 3.42, N 19.10, Cl 8.02, S 7.27 for C20 H15 N6 O2 ClS. Calculated, %: C 54.73, H 3.45, N 19.15, Cl 8.08, S 7.30. 51 -(4-Bromophenyl)-2-phenyl-21 ,41 -dihydro-5H-spiro[imidazo[2,1-b]1,3,4-thiadiazol-6,31 -pyrazol]-5-one (5d). Yield 1.28 g (60%), White finely crystalline, m.p. 138–140 ˝ C. IR (KBr), υ, cm´1 : 3423, 3151 (NH), 1671, 1640 (CO), 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 1.2 (2H, d, CH2 , J = 5.5), 2.5 (3H, s, CH3), 5.4 (1H, s, NH), 7.0–7.81 (9H, m, Ar-H); 13 C-NMR δ, 69.4 (CH2 C=N), 122.1 (C4 Ph), 125.9 (C3,5 Ph), 127.1 (C Spiro), 131.4 (C3 Ar), 131.8 (C5 Ar), 132.5 (C2,6 Ph), 136.8 (C2 Ar), 137.4 (C6 Ar), 140.2 (C4 Ar), 144.5 (C1 Ar); 145.1 (C1 Ph), 158.0 (C=N), 161.3 (CNS), 163.2 (CN2 S); 165.3 (CO imidaz.), and found, %: C 50.70, H 2.81, N 16.40, Br 18.71, S 7.50 for C18 H12 N5 OBrS. Calculated, %: C 50.72, H 2.84, N 16.43, Br 18.74, S 7.52. 51 -(4-Bromophenyl)-(2-(4-chlorophenyl)-21 ,41 -dihydro-5H-spiro[imidazo[2,1-b]1,3,4-thiadiazol-6,31 -pyrazol]5-one (5e). Obtained similarly to compound 5a from compound 4f (2.23 g, 5 mmol). Yield 1.50 g (65%), white finely crystalline, m.p. 150–152 ˝ C. IR (KBr), υ, cm´1 : 3423, 3333 (NH); 1680, 1648 (CO); 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz); 1.4 (2H, d, CH2 , J = 5.4), 2.5 (3H, s, CH3), 5.4 (1H, s, NH), 7.0–7.81 (8H, m, Ar-H); found, %: C 46.89, H 2.40, N 15.20, Br 17.32, Cl 7.67, S 6.92 for C18 H11 N5 OBrClS. Calculated, %: C 46.92, H 2.41, N 15.20, Br 17.34, Cl 7.69, S 6.95; MS: m/z 464 [M+ + 2]; 461 [M+ ]; 418 [M+ ´ CH2 =C=O]; 194 [spiro moiety]. 3.5. General Procedure for Synthesis of the Compounds 6a–d A mixture of 4a, 4b, 4d and/or 4f (5 mmol) and hydroxyl amine hydrochloride (0.52 g; 7.5 mmol) in boiling pyridine (25 mL) was heated under reflux for 6 h. The reaction mixture was allowed to cool, poured into ice/HCl until pH of the solution is 6.5, and the product was filtered, dried, and recrystallized from ethanol. N-(4-(5-Oxo-2-phenyl-21 ,41 -dihydro-5H-spiro[imidazo[2,1-b]1,3,4-thiadiazol-6,51 -isoxazol]-31 yl)phenyl) acetamide (6a). Yield 1.11g (55%), white finely crystalline. m.p. 197–200 ˝ C. IR (KBr), υ, cm´1 : 3425 (NH), 1647 (CO), 1630 (C=N); 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 2.5 (3H, s, CH3 ), 3.59 (2H, d,

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CH2 , J = 5.7), 7.53–7.96 (10H, m, Ar-H), and found, %: C 59.30, H 3.65, N 17.24. C20 H15 N5 O3 S. Calculated, %: C 59.26, H 3.70, N 17.28. N-(4-(2-(4-Chlorophenyl-5-oxo-21 ,41 -dihydro-5H-spiro[imidazo[2,1-b]1,3,4-thiadiazol-6,51 -isoxazol]-51 yl)phenyl) acetamide (6b). Yield 1.47 g (67%), white finely crystalline powder, m.p. 192–195 ˝ C. IR (KBr) υ, cm´1 : 3271 (NH), 1660 (CO), 1631 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 2.3 (3H, s, CH3 ), 3.20 (2H, d, CH2, J = 5.7), 7.53–7.96 (10H, m, Ar-H); 13 C-NMR (DMSO), δ, ppm, 21.7 (CH3 CO), 66.6 (CH2 C=N), 119.7 (C spiro), 126.8 (C3,5 Ar), 128.3 (C3,5 PhCl), 130.5 (C2,6 PhCl), 134.5 (C2,6 Ar), 136.9 (C4 PhCl), 138.2 (C4 Ar), 140.2 (C1 Ar), 143.5 (C1 PhCl), 147.1 (C=N), 161.3 (CNS), 164.0 (CN2 S), 166.4 (CO imidaz.), 168.0 (CO amide), and found, %: C 54.58, H 3.19, N 15.88, Cl 8.02, S 7.27 for C20 H14 N5 O3 ClS. Calculated, %: C 54.61, H 3.21, N 15.92, Cl 8.06, S 7.29. 31 -(4-Bromophenyl)-2-phenyl-41 H,5H-spiro[imidazo[2,1-b]1,3,4-thiadiazol-6,51 -isoxazol]-5-one (6c). Yield 1.56 g (70%), white finely crystalline, m.p. 197–200 ˝ C. IR (KBr) υ, cm´1 : 3425 (NH); 1630 (C=N). 1 H-NMR (DMSO-d ), δ, ppm, (J, Hz): 3.99 (2H, s, CH ), 7.53–7.96 (10H, m, Ar-H). 13 C-NMR (DMSO), 6 2 δ, ppm, 65.8 (CH2 C=N); 111.2 (C spiro); 116.2 (C3,5 Ar); 120.9 (C3,5 Ph); 124.6 (C2,6 Ar); 132.7 (C2,6 Ph); 134.3 (C4 Ph); 136.3 (C4 PhBr), 139.2 (C1, PhBr); 140.6 (C1 , Ph); 153.0 (C=N); 157.2 (CNS); 162.3 (CN2 S); 166.0 (CO imidaz.) and found, %: C 50.60, H 2.58, N 13.12, Br 18.68, S 7.48 for C18 H11 N4 O2 BrS. Calculated, %: C 50.60, H 2.60, N 13.11, Br 18.70, S 7.50. 31 -(4-Bromophenyl)-2-(2-chlorophenyl)-41 H,5H-spiro[imidazo[2,1-b]1,3,4-thiadiazol-6,51 -isoxazol]-5-one (6d). Yield 1.39 g (58%), white finely crystalline powder, m.p. 192–195 ˝ C. IR (KBr) υ, cm´1 : 3271 (NH), 1680 (CO), 1631 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 3.49 (2H, br. s, CH2 ), 7.53–7.96 (10H, m, Ar-H), found %: C 46.85, H 2.16, N 12.11, Br 17.29, Cl 7.65, S 6.92 for C18 H10 N4 O2 BrClS. Calculated, %: C 46.82, H 2.18, N 12.13, Br 17.31, Cl 7.68, S 6.94. 3.6. General Procedure for Synthesis of the Compounds 7a–c A mixture of 4a, 4b and/or 4d (5 mmol), cyclopentanone (0.45 mL, 5 mmol), (50%) NaOH (5 mL) and ethanol (25 mL) was refluxed for 3 h, and left overnight for 3 days. The reaction mixture was poured into ice/HCl, until pH of the solution becomes 6.5. The crude product was filtered, washed by petroleum ether (b.p. 40–60 ˝ C), and then crystalized from benzene. N-(4-(2-(5-Oxo-6-(3-oxocyclopentyl)-2-phenyl-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-6-yl)acetyl)phenyl) acetamide (7a). Yield 1.57 g (65%), white finely crystalline powder, m.p. 176–178 ˝ C. IR (KBr) υ, cm´1 : 3245 (NH); 1685, 1670, 1650 (CO), 1613 (C=N); 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 1.12 (6H, m, 3CH2 ), 2.02 (1H, dd, H-cyclopent.); 2.36 (3H, s, CH3 ); 2.50 (2H, s, CH2 CO); 7.44–7.73 (9ArH, m, aromatic protons); 13.2 (1H, s, acidic NH proton which exchanged in D2 O) and found, %: C 63.25; H 4.65, N 11.79, S 6.77 for C25 H22 N4 SO4 . Calculated, %: C 63.28, H 4.67, N 11.81, S 6.76. MS: m/z 474; 432 [M+ ´ CH2=C=O]; 141 [imidazolothiadiazole moiety]. N-(4-(2-(2-(4-Chlorophenyl)-5-oxo-6-(3-oxocyclopentyl)-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-6-yl)acetyl) phenyl)acetamide (7b). Yield 1.88 g (74%), white finely crystalline. m.p. 210–212 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH); 1710, 1691, 1655 (CO); 1630 (C=N); 1 H-NMR (DMSO-d6 ), δ, ppm (J, Hz): 1.2 (6H, m, 3CH2 ), 2.02 (1H, dd, H-cyclopent.); 2.47 (3H, s, CH3 ); 2.51(2H, s, CH2 CO); 7.44–7.83 (8ArH, m, aromatic protons; 8.2 (1H, s, acidic NH proton which exchanged in D2 O); 13 C-NMR (DMSO), δ, ppm, 22.4 (CH3 CO); 31.8 (C3,4 cyclopent); 57.2 (C5 cyclopent); 67.8 (CH2 CO spiro); 109.3 (C2 , CH, cyclopent); 119.6 (C3,5 Ar´ ); 122.2 (C spiro); 124.3 (C3,5 Ar); 131.7 (C2,6 Ar´ ); 135.5 (C2,6 Ar); 141.5 (C4 Ar´ ), 143.4 (C4 Ar), 144.1 (C1 Ar´ ), 152.6 (C1 Ar), 161.0 (CNS), 164.0 (CN2 S), 167.0 (CO imidaz), 168.0 (CO amide), 190.2 (CO ketone) 192.0 (CO cyclopent) and found, %: C 59.05, H 4.15, N 11.03, Cl 6.94, S 6.28 for C25 H21 N4 O4 ClS. Calculated, %: C 59.00, H 4.16, N 11.01, Cl 6.96, S 6.30. 6-(2-(4-Bromophenyl)-2-oxoethyl)-2-(4-chlorophenyl)-6-(3-oxocyclopentyl)imidazo[2,1-b][1,3,4]thiadiazol-5 (6H)-one (7c). Yield 1.83 g (70%), white finely crystalline. m.p. 196–198 ˝ C. IR (KBr), υ, cm´1 :

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3245 (NH); 1710, 1691, 1655 (CO); 1630 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 1.2 (6H, m, 3CH2 ), 2.08 (1H, dd, H-cyclohex.), 2.32 (3H, s, CH3 ), 2.53 (2H, s, CH2 CO), 7.62–7.83 (8ArH, m, aromatic protons), 8.2 (1H, s, acidic NH proton which exchanged in D2 O); And found, %: C 52.05; H 3.25; N 7.93, Br 15.03, Cl 6.66, S 6.00 for C23 H17 N3 O3 BrClS. Calculated, %: C 52.04, H 3.23; N 7.92, Br 15.05, Cl 6.68, S 6.03; MS: m/z 531 [M+ + 2], 529 [M+ ] 170; 139. 3.7. General Procedure for Synthesis of the Compounds 8a–c A mixture of 7a (1.2 g, 2.5 mmol) and acetic anhydride (5 mL, 50 mmol) was refluxed in water bath for 2 h. The excess acetic anhydride was removed by fraction distillation and the separated product was filtered, dried and recrystallized from a mixture of toluene–ethanol. N-(4-(51 -Oxo-21 -phenyl-6,7-dihydro-5H,51 H-spiro[cyclopenta[b]pyran-4,61 -imidazo[2,1-b][1,3,4]thiadiazol]2-yl)phenyl)acetamide (8a). Yield 502 mg (45%), white powder. m.p. 140–142 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH); 1646, 1668 (CO); 1613 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm (J, Hz): 1.43 (6H, m, 3CH2 ), 2.5 (3H, s, CH3 ), 6.7 (1H, s, pyrane-H), 7.44–7.73 (9ArH, m, aromatic protons); 13.2 (1H, s, acidic NH proton which exchanged in D2 O), and found, %: C 65.75, H 4.40, N 12.25, S 7.00 for C25 H20 N4 O3 S. Calculated, %: C 65.77, H 4.42, N 12.27, S 7.02; MS: m/z 456 [M+ ], 337 [M+ ´ PhNCO], 141 [imidazolothiadiazole moiety]. N-(4-(21 -(4-Chlorophenyl)-51 -oxo-6,7-dihydro-5H,51 H-spiro[cyclopenta[b]pyran-4,61 -imidazo[2,1-b][1,3,4] thiadiazol]-2-yl)phenyl)acetamide (8b). Yield 516 mg (39%), white powder. m.p. 172–174 ˝ C. IR (KBr) υ, cm´1 : 1630 (C=N), 1645, 1670 (CO), 3245 (NH). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 1.37 (6H, m, 3CH2 ); 2.06 (3H, s, CH3 ), 6.6–6.7 (s,1H, pyrane), 7.44–7.83 (8ArH, m, aromatic protons), 8.2 (1H, s, acidic NH proton which exchanged in D2 O), found, %: C 61.13, H 3.88, N 11.43, Cl 7.20, S 6.50 for C25 H19 N4 O3 ClS. Calculated, %: C 61.16, H 3.90, N 11.41, Cl 7.22, S 6.53; MS: m/z 490 [M+ ], 377 [M+ ´ PhCl], 170, 140. 2-(4-Bromophenyl)-21 -(4-chlorophenyl)-51 -oxo-6,7-dihydro-5H,51 H-spiro[cyclopenta[b]pyran-4,61 -imidazo [2,1-b][1,3,4]thiadiazol]-51 -one (8c). Yield 420 mg (35%), white, finely crystalline powder; m.p. 236–238 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH), 1672 (CO), 1630 (C=N); 1 H-NMR (DMSO-d6 ), δ, ppm (J, Hz): 1.28 (8H, m, 4CH2 ), 6.6–6.7 (1H, s, pyrane), 7.44–7.83 (8ArH , m, aromatic protons), and found, %: C 53.85, H 2.95; N 8.19, Br 15.56, Cl 6.90, S 6.23 for C23 H15 N3 O2 BrClS. Calculated, %: C 53.87, H 2.95, N 8.19, Br 15.58, Cl 6.91, S 6.26; MS: m/z 511 [M+ ]. 3.8. General Procedure for Synthesis of the Compounds 9a–c A mixture of 4a (3.91 g, 0.01mol), and carbon acids e.g. ethylacetoacetate, ethylcyanoacetate, diethylmalonate, acetylacetone, malononitrile (0.01 mol), (50%) NaOH (8 mL) and ethanol (50 mL), was made and left overnight for 3 days. The reaction mixture was poured into ice/HCl, the crude product was filtered and washed by petroleum ether (b.p. 40–60 ˝ C), and then crystallized from ethanol. Ethyl 2-(6-(2-(4-acetamidophenyl)-2-oxoethyl)-5-oxo-2-phenyl-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-6yl)-3-oxobutanoate (9a). Yield 2.08 g (40%), white finely crystalline, m.p. 180–182 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH), 1742, 1671, 1655 (CO), 1630 (C=N). 1 HNMR (DMSO-d6 ), δ, ppm, (J, Hz): 1.21 (3H, t, CH3 ), 2.32–2.34 (6H, s, 2CH3 ), 2.47 (2H, s, CH2 CO), 4.23 (2H, q, CH2 CO), 5.3 (1H, s, methine), 7.62–7.83 (9ArH, m, aromatic protons), 11.2 (1H, s, acidic NH proton which exchanged in D2 O); and found, %: C 59.93, H 4.62, N 10.72, S 6.14 for C26 H24 N4 O6 S. Calculated, %: C 59.99, H 4.65, N 10.76, S 6.16; MS: m/z 520 [M+ ], 170, 139. Ethyl 2-(6-(2-(4-acetamidophenyl)-2-oxoethyl)-5-oxo-2-phenyl-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-6yl)-2-cyanoacetate (9b). Yield 1.87 g (37%), white finely crystalline, m.p. 164–166 ˝ C. IR (KBr), υ, cm´1 : 3331, 3245 (NH), 1734, 1670, 1645 (CO), 1630 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 1.23 (3H, t, CH3 ), 2.32 (3H, s, CH3 ), 2.47 (2H, s, CH2 CO), 4.09 (2H, q, CH2 CO), 5.1 (1H, s, methine), 22079

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7.35–7.72 (9ArH, m, aromatic protons), 12.1 (1H, s, acidic NH proton which exchanged in D2 O), found, %: C 59.60, H 4.17, N 13.88, S 6.35 for C25 H21 N5 O5 S. Calculated, %: C 59.63, H 4.20, N 13.91, S 6.37; MS: m/z 503 [M+ ], 430 [M+ ´ COOEt], 170, 140. Diethyl 2-(6-(2-(4-acetamidophenyl)-2-oxoethyl)-5-oxo-2-phenyl-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-6 -yl)malonate (9c). Yield 3.86 g (70%), white finely crystalline. m.p. 144–146 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH), 1671, 1742 (CO), 1630 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 1.22 (6H, t, 2CH3 ), 2.32–2.35 (6H, s, 2CH3 ), 2.47 (2H, s, CH2 CO), 4.45 (4H, q, CH2 CO), 5.6 (1H, s, methine), 7.62–7.83 (9ArH, m, aromatic protons), 11.2 (1H, s, acidic NH proton which exchanged in D2 O). 13 C-NMR (DMSO), δ, 14.5 (2CH3 CH2 ), 22.4 (CH3 CO Ar), 60.5 (2CH3 CH2 CO), 64.7 (CH2 CO spiro), 92.6 (CH(CO)2 ), 114.6 (C4 Ph), 122.1 (C3,5 Ph), 127.5 (C spiro), 128.2 (C3,5 Ar), 129.6 (C2,6 Ph), 131.6 (C2,6 Ar), 134.2 (C4 Ar), 137.9 (C1 Ph), 140.2 (C1 Ar), 149.5 (CNS), 154.1 (CN2 S), 163.4 (CO imidaz), 168.3 (CO amide), 176.6 (2CO ester), 193.0 (CO ketone), and found, %: C 58.86; H 4.72; N 10.15, S 5.79 for C27 H26 N4 O7 S. Calculated, %: C 58.90, H 4.76, N 10.18, S 5.82; MS: m/z 550 [M+ ], 170, 139. N-(4-(2-(6-(2,4-Dioxopentan-3-yl)-5-oxo-2-phenyl-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-6-yl)acetyl) phenyl)acetamide (9d). Obtained similarly to compound 9a, from compound 4a (3.91 g, 0.01 mol) and acetylacetone (1.05 mL, 0.01 mol). Crystalised from benz-ethanol. Yield 2.94 g (60%), white powder. m.p. 158–160 ˝ C. IR (KBr) υ, cm´1 : 3245 (NH); 1670, 1645 (CO), 1630 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm (J, Hz): 2.32–2.46 (9H, br. s, 3CH3 ), 2.47 (2H, s, CH2 CO), 5.2 (1H, s, methine), 7.35–7.72 (9ArH, m, aromatic protons), 12.1 (1H, s, acidic NH proton which exchanged in D2 O), and found, %: C 61.22, H 4.49, N 11.40, S 6.52 for C25 H22 N4 O5 S. Calculated, %: C 61.21; H 4.52; N 11.42, S 6.54; MS: m/z 490 [M+ ]; 447 [M+ ´ COCH3 ], 170, 140. N-(4-(2-(6-(Dicyanomethyl)-5-oxo-2-phenyl-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-6-yl)acetyl)phenyl) acetamide (9e). Crystalized from ethanol. Yield 3.29 g (72%), white powder, m.p. 122–124 ˝ C. IR (KBr), υ, cm´1 : 3320 (NH); 1655 (CO); 1630 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 2.32 (3H, s, CH3 ), 2.47 (2H, s, CH2 CO), 5.0(1H, s, methine), 7.35–7.72 (9ArH, m, aromatic protons), 12.1 (1H, s, acidic NH proton which exchanged in D2 O). 13 C-NMR, δ, 21.8 (CH3 CO Ar), 62.5 (CH2 CO spiro), 95.1 (CH(CN)2 ), 112.6 (C4 Ph), 119.3 (C3,5 Ph), 124.5 (C spiro), 125.4 (C3,5 Ar), 128.6 (C2,6 Ph), 131.2 (C2,6 Ar), 133.4 (C4 Ar), 135.6 (C1 Ph), 139.2 (C1 Ar), 147.7 (CNS), 152.1 (CN2 S), 163.2 (CO imidaz), 167.3 (CO amide), 170.6 (2CN), 189.4 (CO ketone); found, %: C 60.49, H 3.50, N 18.38, S 7.00 for C23 H16 N6 O3 S: C 60.52, H 3.53, N 18.41, S 7.02; and MS: m/z 456 [M+ ], 380 [M+ ´ Ph], 170, 140. 3.9. General Procedure for Synthesis of the Compounds 10a–c and 11a–d The adduct 9 (1.9 mmol) was fused in oil bath for 1 h. The reaction mixture was poured into ice, the crude product filtered and washed by petroleum ether (b.p. 40–60 ˝ C), and then crystalized. N-(4-(31 -Acetyl-21 ,5-dioxo-2-phenyl-21 ,31 -dihydro-5H-spiro[imidazo[2,1-b][1,3,4]thiadiazole-6,41 -pyran]-61 yl)phenyl)acetamide (10a). Crystalized from dioxane. Yield 495 mg (55%), white finely crystalline, m.p. 210–212 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH), 1743, 1685, 1670, 1650 (CO), 1613 (C=N); 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 2.36 (6H, s, 2CH3 ), 4.50 (1H, s, CH(CO)2 ), 6.2 (1H, s, PyH), 7.44–7.73 (9ArH, m, aromatic protons), 13.2 (1H, s, acidic NH proton which exchanged in D2 O); found: %: C 60.70, H 3.79, N 11.75, S 6.76 for C24 H18 N4 O5 S. Calculated, %: C 60.75, H 3.82, N 11.81, S 6.76; MS: m/z 474 [M+ ], 141 [imidazolothiadiazole moiety]. N-(4-(31 -Cyano-21 ,5-dioxo-2-phenyl-21 ,31 -dihydro-5H-spiro[imidazo[2,1-b][1,3,4]thiadiazole-6,41 -pyran]-61 yl)phenyl)acetamide (10b). Crystalized from ethanol. Yield 409 mg (45%), white finely crystalline, m.p. 198–200 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH), 2220 (CN), 1740, 1691, 1672, 1655, (CO), 1630 (C=N); 1 H-NMR (DMSO-d ), δ, ppm, (J, Hz): 2.47 (3H, s, CH ), 4.51 (1H, s, CH(CO)(CN)), 6.1 (1H, s, PyH), 6 3 7.44–7.83 (9ArH, m, aromatic protons), 8.2 (1H, s, acidic NH); found, %: C 60.35, H 3.28, N 15.31, S 7.00 for C23 H15 N5 O4 S. Calculated, %: C 60.39; H 3.31; N 15.31, S 7.01.

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Ethyl 61 -(4-acetamidophenyl)-21 ,5-dioxo-2-phenyl-21 ,31 -dihydro-5H-spiro[imidazo[2,1-b][1,3,4] thiadiazole6,41 -pyran]-31 -carboxylate (10c). Yield 1.17 g (85%), white finely crystalline, m.p. 162–164 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH), 1752, 1738, 1670, 1650 (CO), 1613 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm (J, Hz): 1.2 (2H, t, CH2 ), 2.5 (3H, s, CH3 ), 4.11 (2H, q, CH2 O), 4.4 (1H, s, CH(CO)2 ), 6.2(1H, s, PyH), 7.44–7.73 (9ArH, m, aromatic protons); 13.2 (1H, s, acidic NH proton which exchanged in D2 O); found, %: C 59.50, H 3.95, N 11.08, S 6.32 for C25 H20 N4 O6 S. Calculated, %: C 59.52, H 4.00, N 11.11, S 6.35; MS: m/z 504 [M+ ], 462 [M+ ´ CH2=C=O], 141. Ethyl 61 -(4-acetamidophenyl)-21 -methyl-5-oxo-2-phenyl-5H-spiro[imidazo[2,1-b][1,3,4]thiadiazole-6,41 -pyran] -31 -carboxylate (11a). Crystalized from benzene. Yield 219 mg (23%), white powder, m.p. 180–182 ˝ C. IR (KBr), υ, cm´1 : 3245 (NH), 1742, 1671, 1655, (CO), 1630 (C=N); 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 1.21 (3H, t, CH3 ), 2.32 (6H, s, 2CH3 ), 4.23 (2H, q, CH2 CO), 6.3 (s, 1H, PyH), 7.62–7.83 (9ArH, m, aromatic protons), 11.2 (1H, s, acidic NH proton which exchanged in D2 O); found, %: C 62.15, H 4.38, N 11.13, S 6.35 for C26 H22 N4 O5 S. Calculated, %: C 62.14, H 4.41, N 11.15, S 6.38; MS: m/z 502 [M+ ], 170, 139. Ethyl 61 -(4-acetamidophenyl)-21 -amino-5-oxo-2-phenyl-5H-spiro[imidazo[2,1-b][1,3,4]thiadiazole-6,41 -pyran]31 -carboxylate (11b). Crystalized from benzene. Yield 249 mg (25%), white powder, m.p. 164–166 ˝ C. IR (KBr), υ, cm´1 : 3331, 3245 (NH), 1734, 1670, 1645 (CO), 1630 (C=N); 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 1.23 (3H, t, CH3 ), 2.32 (6H, s, 2CH3 ), 4.09 (2H, q, CH2 CO), 5.2(2H, br. s, NH2 ), 6.1 (1H, s, PyH), 7.35–7.72 (9ArH, m, aromatic protons), 12.1 (1H, s, acidic NH proton which exchanged in D2 O), and found, %: C 59.60, H 4.18, N 13.90, S 6.35 for C25 H21 N5 O5 S. Calculated, %: C 59.63, H 4.20, N 13.91, S 6.37; MS: m/z 503 [M+ ], 430 [M+ ´ COOEt]; 170. N-(4-(31 -Acetyl-21 -methyl-5-oxo-2-phenyl-5H-spiro[imidazo[2,1-b][1,3,4]thiadiazole-6,41 -pyran]-61 -yl)phenyl) acetamide (11c). Yield 810 mg (64%), white powder; m.p. 194–196 ˝ C. IR (KBr), υ, cm´1 : 3245(NH), 1687, 1670, 1650, (CO), 1613 (C=N). 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 2.52 (9H, br. s, 3CH3 ), 6.3 (1H, s, PyH), 7.35–7.80 (9ArH, m, aromatic protons), 11.6 (1H, s, acidic NH proton which exchanged in D2 O); found, %: C 63.52, H 4.25, N 11.85, S 6.75 for C25 H20 N4 O4 S. Calculated, %: C 63.55, H 4.27, N 11.86, S 6.78; MS: m/z 472 [M+ ], 353 [M+ ´ PhN=C=O], 141 [imidazolothiadiazole moiety]. N-(4-(21 -Amino-31 -cyano-5-oxo-2-phenyl-5H-spiro[imidazo[2,1-b][1,3,4]thiadiazole-6,41 -pyran]-61 -yl)phenyl) acetamide (11d). Yield 600 mg (60%), white finely crystalline, m.p. 222–224 ˝ C. IR (KBr), υ, cm´1 : 3285, 3245 (NH), 2220 (CN), 1672, 1655 (CO), 1630 (C=N); 1 H-NMR (DMSO-d6 ), δ, ppm, (J, Hz): 2.46 (3H, s, CH3 ), 5.2 (2H, br. s, NH2 ), 6.3 (1H, s, PyH), 7.25–7.66 (9ArH, m, aromatic protons), 11.3 (1H, s, acidic NH proton which exchanged in D2 O); found, %: C 60.50; H 3.51; N 18.40, S 7.00 for C23 H16 N6 O3 S. Calculated, %: C 60.52, H 3.53, N 18.41, S 7.02. MS: m/z 456 [M+ ]. 4. Conclusions In the present work, a series of novel chalcone and the spiro heterocyclic derivatives 4–11 were synthesized using 4-Aryl-4-oxo-2-butenoic acids 1a–b as starting materials. The structures of the new compounds were elucidated using IR, 1 H-NMR, 13 C-NMR and mass spectroscopy. Some of the newly synthesized compounds were screened against bacterial strains and most of them showed high antibacterial activities that were confirmed by QSAR study. Electron-withdrawing substituents are lower the HOMO energy, and increase (κ2 index) represents a positive contribution to the antibacterial activity. Acknowledgments: The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at EPRI, Cairo and Ain Shams Universities for their cooperation in this research. Author Contributions: The listed authors contributed to this work as described in the following. Maher A. El-Hashash established the concepts of the work, and interpreted the results, Sameh A. Rizk, carried out the synthetic work, interpreted the results and prepared the manuscript, and Saad R. Atta-Allah carried out the synthetic work, and cooperated in the preparation of the manuscript. All authors read and approved the final manuscript.

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Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are available from the authors. © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).

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