Crystal structure and molecular docking studies of benzo[8]annulenes as potential inhibitors against Mycobacterium tuberculosis

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

Abstract


Tuberculosis is a disease caused by Mycobacterium tuberculosis. The bacterial cell wall has a characteristic low permeability, which essentially makes antibiotics ineffective. The cell wall material must be regulated so that its deposition does not compromise its structure. In this study, two new inhibitors, 2-amino-4-(4-cholorophenyl)-5,6,7,8,9,10-hexahydrobenzo[8] annulene-1,3,3(4H)-tricarbonitrile(Ia) and 2-amino-4-(4-bromophenyl)-5,6,7,8,9,10-hexahydrobenzo[8]annulene-1,3,3(4H)-tricarbonitrile(Ib) were synthesized. The crystal structures of the above compounds were determined by single crystal X-ray diffraction. The compounds C21 H19 Cl N3 (Ia) and C21 H19 Br N3 (Ib) were crystallized in the monoclinic and triclinic system. In both compounds, the cyclohexane ring was found to adopt a boat conformation. The cyclooctane ring of both compounds adopted a twisted chair-chair conformation.  In silico analyses revealed that both compounds showed good anti-mycobacterial activities against the enoyl-acyl carrier enzyme and the N-acetyl-gamma protein, both of which are critical for bacterial survival. Synthesis, structure determination, conformation, intra, inter-molecular interactions and docking studies of both compounds are presented herein.


Keywords


conformation; ring motif; anti-mycobacterial; molecular docking; mycobacterium tuberculosis; benzo[8]annulenes; crystal structure

References


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

Bradford WZ & Daley CL 1998 Multiple drug-resistant tuberculosis. Infect Dis Clin North Am 12 157-172

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

Cybis J & Davis RH 1975 Organization and control in the arginine biosynthetic pathway of Neurospora. J Bacteriol 123 196-202

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

Fun HK, Yeap CS, Ragavan RV, Vijayakumar V & Sarveswari S 2010 4,5,6,7,8,9-Hexahydro-2H-cyclo-octa[c]pyrazol-1-ium-3-olate. Acta Crystallogr Sect E Struct Rep Online 66 o3019

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

Koci J, Klimesova V, Waisser K, Kaustova J,Dahse H-M & Mollmann U 2002 Heterocyclic benzazole derivatives with antimycobacterial in vitro activity. Bioorg Med Chem Lett 12 3275-3278

Nagalakshmi RA, Suresh J, Maharani S & Ranjith Kumar R 2014 Crystal structure and molecular docking studies of octahydrocycloocta[b]pyridine-3-carbonitriles as potential inhibitors against Mycobacterium tuberculosis. J Mol Biochem 3 77-84

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 Myco-bacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate. J Biol Chem 274 15582-15589

Sanna P, Carta A & Nikookar ME 2000 Synthesis and antitubercular activity of 3-aryl substituted-2-[1H(2H)benzotriazol-1(2)-yl]acrylonitriles. Eur J Med Chem 35 535-543

Schluger NW, 2005 The pathogenesis of tuberculosis: the first one hundred (and twenty-three) years. Am J Respir Cell Mol Biol 32 251-256

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

Smith I 2003 Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin Microbiol Rev 16 463-496

Spek AL 2009 Structure validation in chemicalcrystal-lography. 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

Tiruviluamala P & Reichman LB 2002 Tuberculosis. Annu Rev Public Health 23 403-426

Vishnupriya R, Kowsalyadevi AVKM, Suresh J, Maharani S & Kumar RR 2014 Crystal structure and docking studies of hexahydrocycloocta[b]pyridine-3- carbonitriles. J Mol Biochem 3 50-57


Full Text: PDF

Refbacks

  • There are currently no refbacks.


Copyright © 2017 Lorem Ipsum Press