Crystal structure and molecular docking studies of octahydrocycloocta[b]pyridine-3-carbonitriles as potential inhibitors against Mycobacterium tuberculosis

RA Nagalakshmi; J Suresh; S Maharani; R Ranjith Kumar

Crystal structure and molecular docking studies of octahydrocycloocta[b]pyridine-3-carbonitriles as potential inhibitors against Mycobacterium tuberculosis

RA Nagalakshmi, J Suresh, S Maharani, R Ranjith Kumar

Abstract

The compounds 1-benzyl-2-imino-4-p-tolyl-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carbonitrile (Ia) and 1-benzyl-2-imino-(4-methoxyphenyl-1,2,5,6,7,8,9,10-octahydrocycloocta {b]pyridine-3-carbonitrile (Ib) were synthesized. The crystal structures of the compounds were determined by single crystal X ray diffraction. The compounds C₂₆ H₂₇ N₃ (Ia) and C₂₆ H₂₇ N₃O (Ib) crystallize in the triclinic system (a = 10.2304(4) Å, b = 10.5655(4) Å, c = 11.8271(4) Å, α = 101.755(2) °, β = 106.934(2) °, γ = 114.071(2) ° and Z = 2 for I(a) and a = 10.2738(4) Å, b = 11.1654(5) Å, c = 11.4162(4) Å α = 98.549(2) °, β = 106.183(2) °, γ = 117.070(2) ° and Z = 2 for I(b)). In both compounds (Ia) and (Ib) the pyridine ring adopts a planar conformation and the cyclooctane ring adopts a twisted boat chair conformation. The synthesized compounds were screened for their antibacterial activities against the enzyme enoyl acyl carrier protein reductase, which is involved in the fatty acid biosynthesis of the mycobacterial cell wall. Both compounds showed good antibacterial activities. The synthesis of the compounds, their structure determination, their conformation, their intra- and intermolecular interactions and docking study results are given.

Keywords

Conformation; Ring motif; Anti mycotuberculosis activity; Molecular docking; Inha

References

Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, Collins D, de Lisle G & Jacobs WR Jr 1994 inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263 227-230

Besra GS & Chatteriee D 1994 Lipids and carbohydrate of Mycobacterium tuberculosis. In Tuberculosis: Pathogenesis, Protection, and Control, pp 285-306. Eds BR Blood. Washington, DC: ASM Press

Bernstein J, Lott WA, Steinberg BA & Yale HL 1952 Chemotherapy of experimental tuberculosis. Am RevTuberc 65 357-374

Bernstein J, Davis RE, Shimoni L & Chang NL 1995 Patterns in Hydrogen Bonding: Functionality and Graph Set Analysis in Crystals. Angew Chem Int Ed Engl 34 1555-1573

Blanchard JS 1995 Enzymatic characterization of the target for isoniazid in Mycobaterium tuberculosis. Biochemistry 34 8235-8241

Bruker 2004 APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA

Cohn DL, Bustreo F & Raviglione MC 1997 Drug-resistant tuberculosis: review of the worldwide situation and the WHO/IUATLD global surveillance project. Clin Infect Dis 24 S121-S130

Dandia A, Sehgal V & Singh P 1993 Synthesis of fluorine containing 2-aryl-3-pyrazolyl/pyranyl/isoxazolinyl-indole derivatives as antifungal and antibacterial agents. Indian J Chem 32 1288-1291

Dessen A, Quemard A, Blanchard JS, Jacobs WR & Sacchettini JC 1995 Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science 267 1638-1641

Dietrich J & Doherty TM 2009 Interaction of Mycobacterium tuberculosis with the host: consequences for vaccine development APMIS 117 440-457

Lavie A, Vetter IR, Konrad M, Goody RS, Reinstein J & Schlichting I 1997 Structure of thymidylate kinase reveals the cause behind the limiting step in AZT activation. Nat Struct Biol 4 601-604

Lewandowicz A, Tyler PC, Evans GB, Furneaux RH & Schramm VL 2003 Achieving the ultimate physiological goal in transition state analogue inhibitors for purine nucleoside phosphorylase. J Biol Chem 278 31465-31468

Goodsell DS, Morris GM & Olson AJ 1998 Automated docking of flexible ligands: Applications of au-todock J Mol Recog 9 1-5

Pieters J 2008 Mycobacterium tuberculosis and the macrophage: Maintaining a Balance. Cell Host Microbe 3 399-407

Punkvang A, Saparpakorn P, Hannongbua S, Wolschann P, Beyer A & Pungpo P 2010 Investigating the structural basis of arylamides to improve potency against M. tuberculosis strain through molecular dynamics simulations. Eur J Med Chem 45 5585-5593

Rajni & Meena LS 2011 Unique characteristic features of Mycobacterium tuberculosis in relation to immune system. Am. J Immunol 7 1-8

Rozwarski DA, Grant GA, Barton DH, Jacobs WR Jr & Sacchettini JC 1998 Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Science 279 98-102

Rozwarski DA, Vilchèze C, Sugantino M, Bittman R & Sacchettini JC 1999 Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate. J Biol Chem 274 15582-15589

Sheldrick GM 2008 A short history of SHELX. Acta Cryst A 64 112-122

Sriram D, Yogeeswari P & Madhu K 2006 Synthesis and in Vitro Antitubercular Activity of Some 1-[(4-sub) Phenyl]-3-(4-{1-[(Pyridine-4 Carbonyl) Hydrazono] Ethyl}Phenyl)Thiourea. Bioorg Med Chem Lett 16 876-878

Spek AL 2009 Structure validation in chemicalcrystallography. Acta Cryst D 65 148-155

Suresh,J, Vishnu Priya R, Sivakumar S & Ranjith Kumar R 2012 Spectral analysis and crystal structure of two substituted spiro acenaphthene structures J Mol Biochem 1 183-188

Takayama K, Wang L & David HL 1972 Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2 29-35

Temple C, Rener GA, Raud WR & Noker PE 1992 Antimitotic agents: structure-activity studies with some pyridine derivatives. J Med Chem 35 3686-3690

Tummino PJ & Copeland RA 2008 Residence time of receptor-ligand complexes and its effect on biological function. Biochemistry 47 5481-5492

Quémard A, Lacave C & Lanéelle G 1991 Isoniazid inhibition of mycolic acid synthesis by cell free extracts of sensitive and resistant strains of Mycobacterium aurum. Antimicrob Agents Chemother 35 1035-1039

Quemard A, Sacchettini JC, Dessen A, Vilcheze C, Bittman R, Jacobs WR Jr & Blanchard JS 1995 Enzymatic characterization of the target for isoniazid in Mycobaterium tuberculosis. Biochemistry 34 8235-8241

Vilcheze C, Morbidoni HR, Weisbrod TR, Iwamoto H, Kuo M, Sacchettini JC & Jacobs WR Jr 2000 Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoyl-acyl carrier protein reductase induces accumulation of the FASI end products and cell lysis of Mycobacterium smegmatis. J Bacteriol 182 4059-4067

Wang LQ, Falany CN & James MO 2004 Triclosan as a substrate and inhibitor of 3'-phosphoadenosine 5'-phosphosulfate-sulfotransferase and UDP-glucuronosyl transferase in human liver fractions. Drug Metab Dispos 32 1162-1169

Winder FG 1982 Mode of action of the antimycobacterial agents. In The Biology of the Mycobacteria, vol. 1, pp. 353-438. Edited by C. Ratledge & J. Stanford. London: Academic Press

Winder FG & Collins PB 1970 Inhibition by isoniazid of synthesis of mycolic acids in Mycobacterium tuberculosis. J Gen Microbiol 63 41-48

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