synthesis and antituberculous activity of quinoline isosteres of isoniazid

Pharmaceutical Chemistry Journal, Vol. 45, No. 4, July, 2011 (Russian Original Vol. 45, No. 4, April, 2011)

SYNTHESIS AND ANTITUBERCULOUS ACTIVITY OF QUINOLINE ISOSTERES OF ISONIAZID A. V. Zimichev,1 M. N. Zemtsova,1 A. G. Kashaev,1 and Yu. N. Klimochkin1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 45, No. 4, pp. 21 – 23, April, 2011. Original article submitted June 7, 2010.

We present an evaluation of the antimycobacterial activity of a series of 2-aryl(heteryl)-4-quinolinecarboxylic acids. Compounds with potential value against Mycobacterium tuberculosis H37Rv were found. Key words: 2-R-6-R¢-4-Quinolinecarboxylic acids, 2-R-6-R¢-4-quinolinecarboxylic acid hydrazides, tuberculosis.

The directed search for organic compounds acting specifically on Mycobacterium tuberculosis has been widely pursued in recent years because of the appearance of strains resistant to agents such as isoniazid and rifampicin. Annual mortality due to tuberculosis amounts to about two million people [1]. Recent publications indicate that the most promising isoniazid analogs are among the compounds of the quinoline series [2, 3] with substituents in different positions of the ring. 1

We have undertaken further modeling of new analogs with the pharmacophore groups of known antimycobacterial compounds by chemical optimization, taking cognizance of the observation that substitution of the carboxyl group by an amide group and introduction of a nitro group are associated with significant levels of retention of and sometimes increases in biological activity. We performed chemical optimization on the basis of 2-phenyl-4-quinolinecarboxylic acid with substitution of the phenyl ring with substituted phenyl, heteryl, or substituted heteryl fragments (compounds II – IX) or substitution of the carboxyl group with carbohydrazide groups (compounds

State Higher Professional Educational Institution “Samara State Technical University,” Samara, Russia; e-mail: [email protected].

H2NHN

O

H N

O

C

COOH

R2

C R3

N

I – XI

R

N

R

N

R1

XXI – XXXVI

XII – XX S H N

O C

N

N

R2

R1

XXXVII – LIV

217 0091-150X/11/4504-0217 © 2011 Springer Science+Business Media, Inc.

218

A. V. Zimichev et al.

TABLE 1. Substituted Quinolinecarboxylic Acids. Compound

I II III IV V VI VII

Ph 2-thienyl 5-nitro-2-thienyl 2,2¢-bithienyl-5-yl 2-thienylvinyl 5-nitro-2-thienylvinyl 5¢-nitro-2,2¢-bithienyl-5-yl

VIII 5¢-nitro-2,2¢-bithienyl-5-ylvinyl IX 4-nitrophenyl X 4-aminophenyl XI 4-bromophenyl

an

Compound

% inhibition MIC, mg/ml

R

XII – XX) or XXI – LIV).

TABLE 2. Substituted Quinolinecarboxylic Acid Hydrazides.

arylamide

3 3 8 2

> 6.25 > 6.25 > 6.25 > 6.25

5 95 12

> 6.25 3.125 6.25

15

6.25

7 5 11

6.25 6.25 6.25

fragment

XII XIII XIV XV XVI XVII

% inhibition MIC, mg/ml

R

Ph 2-thienyl 5-nitro-2-thienyl 5-nitro-2-thienylvinyl 2-thienylvinyl

2,2¢-bithienyl-5-yl XVIII 5¢-nitro-2,2¢-bithienyl-5-yl XIX 2,2¢-bithienyl-5-vinyl XX

5¢-nitro-2,2¢-bithienyl-5-ylvinyl Isoniazid

3 5 73 95 58 8

> 6.25 > 6.25 1.56 1.56 3.125 > 6.25

14

6.25

12

> 6.25

22

3.125

98

0.78

zene or dichloroethane was added, along with a solution of 0.005 mol of the corresponding amine in 10 ml of benzene or dichloroethane and 3 – 5 drops of DMF. The reaction mix was boiled for 3 h. The precipitate forming on cooling was collected by filtration, washed with water, and dried. Amide yields were from 73% to 98%.

(compounds

EXPERIMENTAL CHEMICAL SECTION 2-R-4-quinolinecarboxylic acids I – XI were prepared using the Pfitzinger reaction, as described previously [4]. 2-R-quinolinecarbohydrazides XII – XX were prepared using a method based on the corresponding esters of 2-R-quinolinecarboxylic acids [4, 5]. 2-R-4-quinolinecarboxamides XXI – LIV were prepared using a general method [5]. General method. Thionyl chloride (8 ml) was added to a suspension of 0.005 mol of 2-R-4-quinolinecarboxylic acid (I – XI) in 50 ml of dry benzene and the mixture was boiled for 3 h. The solvent was evaporated and 50 ml of dry ben-

EXPERIMENTAL BIOLOGICAL SECTION Antituberculous activity against M. Tuberculosis H37Rv was initially determined by spot tests in microplates at a concentration of 6.25 mg/ml. Fluorescing compounds were subsequently tested using the BAC-TEC 460 radiometric system [6]. Compounds with MIC ? 90% were re-tested by sowing in liquid growth medium at decreasing concentrations: 3.25 and 1.5625 mg/ml [7].

TABLE 3. Substituted Quinolinecarboxylic Acid Amides. R1

Compound

R2

R3

% inhibition

MIC, mg/ml

H H H H H

2 2 5 0 0

> 6.25 > 6.25 > 6.25 > 6.25 > 6.25 > 6.25

XXI XXII XXIII XXIV XXV

Ph 2-thienyl 5-nitro-2-thienyl 2-thienylvinyl 2,2¢-bithienyl

Ph Ph Ph Ph Ph

XXVI

5¢-nitro-2,2¢-bithienyl-5-yl

Ph

H

3

XXVII

2,2¢-bithienyl-5-ylvinyl

Ph

H

0

> 6.25

5¢-nitro-2,2¢-bithienyl-5-ylvinyl Ph 2-thienyl 5-nitro-2-thienyl 2-thienylvinyl

Ph

H

8

> 6.25

2,2¢-bithienyl

4-CH3Ph 4-CH3Ph 4-CH3Ph 4-CH3Ph 4-CH3Ph

CH3 CH3 CH3 CH3 CH3

2 2 7 0 0

> 6.25 > 6.25 > 6.25 > 6.25 > 6.25

XXVIII XXIX XXX XXXI XXXII XXXIII XXXIV


4-CH3Ph

CH3

5

> 6.25

XXXV

2,2¢-bithienyl-5-ylvinyl

4-CH3Ph

CH3

2

> 6.25

XXXVI

5¢-nitro-2,2¢-bithienyl-5-ylvinyl

4-CH3Ph

CH3

7

> 6.25

Synthesis and Antituberculous Activity

219

TABLE 4. Substituted Quinolinecarboxylic Acid Heterylamides. Compound

XXXVII XXXVIII XXXIX XL XLI XLII XLIII XLIV XLV XLVI XLVII XLVIII XLIX L LI LII LIII LIV

R1

Ph 2-thienyl 5-nitro-2-thienyl 5-nitro-2-thienyl@Z_TBL_CELL_END = 5-nitro-2-thienylvinyl 5¢-nitro-2,2¢-bithienyl-5-yl Ph 2-thienyl 5-nitro-2-thienyl 5-nitro-2-thienylvinyl 5¢-nitro-2,2¢-bithienyl-5-yl

MIC, mg/ml

R2

% Inhibition

Ph Ph Ph Ph Ph Ph

8 13 87 96 58 60

> 6.25 > 6.25 6.25 3.125 3.125 6.25

2-thienyl 2-thienyl 2-thienyl 2-thienyl 2-thienyl

18 27 82 98 38

> 6.25 > 6.25 6.25 3.125 6.25

2-thienyl

46

6.25


5-bromo-2-thienyl 5-bromo-2-thienyl 5-bromo-2-thienyl 5-bromo-2-thienyl 5-bromo-2-thienyl

12 14 22 64 38

> 6.25 > 6.25 > 6.25 6.25 6.25


5-bromo-2-thienyl

40

6.25

5¢-nitro-2,2¢-bithienyl-5-ylvinyl Ph 2-thienyl 5-nitro-2-thienyl 5-nitro-2-thienylvinyl

Among the study compounds, high levels of antituberculous activity were observed with compounds VI, XIV, XV, XL, XLI, and XLVI (Tables 1 – 4). REFERENCES 1. R. Jain, B. Vaitilingam, A. Nayyar, and P. B. Palde, Bioorg. Med. Chem. Lett., 13, 1051 – 1054 (2003). 2. V. Monga, B. Nayyar, B. Vaitilingam, et al., Bioorg. Med. Chem. Lett., 12, 6465 – 6472 (2004).

3. A. Libienkampt, J. Mao, B. Wan, et al., J. Med. Chem., 52, 2109 – 2118 (2009). 4. M. N. Zemtsova, P. L. Trantenberg, A. V. Zimichev, et al., 2-Substituted Quinolines and their Vinylogs [in Russian], Samara State Technical University, Samara (2005). 5. A. G. Kashaev, A. V. Zimichev, and M. N. Zemtsova, Izv. Vuzov Khimiya Khim. Tekhnol., 52(10), 3 – 10 (2009). 6. S. Eswaran, A. V. Adhikari, and R. A. Kumar, Eur. J. Med. Chem., 45, 957 – 966 (2010). 7. L. Collins, S. G. Franzblay, Antimicrob. Chemother., 41, 1004 (1997).