Synthesis and molecular docking of isonicotinohydrazide derivatives as anti-tuberculosis candidates


  • Ruswanto Ruswanto Departement of Pharmacy, Bakti Tunas Husada of Health Science College
  • Richa Mardianingrum
  • Tresna Lestari
  • Tita Nofianti
  • Nur Rahayuningsih



N'-benzoylisonicotinohydrazide, Inhibin Alpha Subunit (InhA) inhibition, Anti-tuberculosis, Synthesis, Docking


Tuberculosis (TB) is a chronic disease as a result of Mycobacterium tuberculosis. It can affect all age groups, and hence, is a global health problem that causes the death of millions of people every year. One of the drugs used in tuberculosis treatment is isonicotinohydrazide (Isoniazid). In this study, N'-benzoylisonicotinohydrazide derivative compounds (a-l) were prepared using acylation reactions between isonicotinohydrazide and benzoyl chloride derivatives, employing the reflux method. Molecular docking studies suggested that all of the compounds had better interaction with Mycobactarium tuberculosis enoyl-acyl carrier protein reductase (InhA) than isonicotinohydrazide. It can be concluded that N'-benzoylisonicotinohydrazide derivatives (a-l) can be used as anti-tuberculosis candidates. The docking results obtained revealed that all of the compounds were interacted well with InhA, with compound g exhibiting the best interaction.


Alea, G. V., Lagua, F. M. G., Caparas, M. N. S. 2014. Synthesis and characterization of methyl-2-hydroxy-5-{(1)-1-[2- (pyridin-4-ylcar-bonyl) hydrazinylidene]butyl} benzoate, a new isonicotinoylhydrazone derivative of methyl salicylate. Presented at the DLSU Research Congress 2014. De La Salle University, Manila, Philippines. March, 6-8, 2014, pp. 1-5.

Asundaria, S. T., Patel, N. S. and Patel, K. C. 2011. Synthesis, characterization, and antimicrobial studies of novel 1,3,4-thiadiazolium-5-thiolates. Medicinal Chemistry Research, 21(7), 1199–1206. doi: 10.1007/s00044-011-9632-2.

Cassano, R., Trombino, S., Ferrarelli, T., Cavalcanti, P., Giraldi, C., Lai, F., Loy, G., Picci, N. 2012. Synthesis, characterization and in-vitro antitubercular activity of isoniazid-gelatin conjugate. Journal of Pharmacy and Pharmacology, 64(5), 712–718. doi: 10.1111/j.2042-7158.2012.01461.x.

Chollet, A., Mori, G., Menendez, C., Rodriguez, F., Fabing, I., Pasca, M.R., Madacki, J., Korduláková, J., Constant, P., Quémard, A., Bernardes-Génisson, V., Lherbet, C., Baltas, M. 2015. Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth, European Journal of Medicinal Chemistry, 101, 218–235. doi: 10.1016/j.ejmech.2015.06.035.

Coelho, T. S., Cantos, J. B., Bispo, M. L. F., Gonçalves, R. S. B., Lima, C. H. S., da Silva, P. E. A., Souza, M. V. N. 2012. In vitro anti-mycobacterial activity of (E)-N’-(monosubstituted-benzylidene) isonicotinohydrazide derivatives against isoniazidresistant strains. Infectious Disease Reports, 4(1), 49–51. doi: 10.4081/idr.2012.e13.

Ferreira, M. de L., Gonçalves, R. S. B., Cardoso, L. N. de F., Kaiser, C. R., Candéa, A. L. P., Henriques, M. das G. M. de O., Lourenço, M. C. S., Bezerra, F. A. F. M., de Souza, M. V. N. 2010. Synthesis and antitubercular activity of heteroaromatic isonicotinoyl and 7-chloro-4-quinolinyl hydrazone derivatives. The Scientific World Journal, 10, 1347–1355. doi: 10.1100/tsw.2010.124.

Ghorab, M. M., El-Gaby, M. S. A., Soliman, A. M., Alsaid, M. S., Abdel-Aziz, M. M., Elaasser, M. M. 2017. Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety. Chemistry Central Journal. Springer International Publishing, 11(1), p. 42. doi: 10.1186/s13065-017-0271-7.

Hearn, M. and Cynamon, M. 2003. In vitro and in vivo activities of acylated derivatives of isoniazid against mycobacterium tuberculosis. Drug Design and Discovery, 18(4), 103–108. doi: 10.1080/ 10559610390450705.

Kartasasmita, R. E., Herowati, R., Harmastuti, N., Gusdinar, T. 2009. Quercetin derivatives docking based on study of flavonoids interaction to cyclooxygenase-2, Indonesian Journal of Chemistry, 9(2), 297–302.

Khokra, S. L., Jyoti, C. K. P., Alam, M. M., Zaman, M. S., Ahmad, A., Khan, S. A., Husain, A. 2016. Quinoline based furanones and their nitrogen analogues: Docking, synthesis and biological evaluation. Saudi Pharmaceutical Journal, 24(6), 705–717. doi: 10.1016/j.jsps. 2015.05.002.

Kochi, A. and Vareldzis, B. I. 1992. Multidrug-resistant tuberculosis and its control, Research in Microbiology, 144(2), 104-110.

Laskowski, R. A., Swindells, M. B. 2011. LigPlot+: Multiple ligand a protein interaction diagrams for drug discovery. Journal of Chemical Information and Modeling, 51(10), 2778–2786.

Lougheed, K. E. A., Taylor, D. L., Osborne, S. A., Bryans, J. S., Buxton, R. S. 2009. New anti-tuberculosis agents amongst known drugs. Tuberculosis, 89(5), 364–370. doi: 10.1016/

Luckner, S. R., Liu, N., Am Ende, C. W., Tonge, P. J., Kisker, C. 2010. A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis. Journal of Biological Chemistry, 285(19), 14330–14337. doi: 10.1074/jbc.M109.090373.

Luscombe, N. M., Laskowski, R. A. and Thornton, J. M. 1997. NUCPLOT: A program to generate schematic diagrams of protein-nucleic acid interactions. Nucleic Acids Research, 25(24), 4940–4945. doi: 10.1093/nar/25.24.4940.

Malhotra, M., Arora, M., Samad, A., Sahu, K., Phogat, P., Deep, A. 2012 Synthesis and evaluation of some novel derivatives of 2- propoxybenzylideneisonicotinohydrazide for their potential antimicrobial activity. Journal of the Serbian Chemical Society, 77(5), 589–597. doi: 10.2298/JSC110310170M.

Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., Olson, A.J. 2009. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16), 2785–2791. doi: 10.1002/jcc.21256.AutoDock4.

Pahlavani, E., Kargar, H. and Sepehri Rad, N. 2015. A study on antitubercular and antimicrobial activity of isoniazid derivative. Zahedan Journal of Research in Medical Sciences, 17(7), 3–6. doi: 10.17795/zjrms1010.

Ragno, R., Marshall, G. R., Di Santo, R., Costi, R., Massa, S., Rompei, R., Artico, M. 2000. Antimycobacterial pyrroles: Synthesis, anti-Mycobacterium tuberculosis activity and QSAR studies. Bioorganic and Medicinal Chemistry, 8(6), 1423–1432. doi: 10.1016/S0968-0896(00)00061-4.

Rodrigues, M. O., Cantos, J. B., D’Oca, C. R. M., Soares, K. L., Coelho, T. S., Piovesan, L. A., Russowsky, D., Da Silva, P. A., D’Oca, M. G. M. 2013. Synthesis and antimycobacterial activity of isoniazid derivatives from renewable fatty acids. Bioorganic and Medicinal Chemistry. 21(22), 6910–6914. doi: 10.1016/j.bmc.2013.09.034.

Ruswanto, Mardhiah, Mardianingruma, R., Novitriani, K. 2015. Sintesis dan studi in silico senyawa 3-nitro-N'-[(Pyridin-4-Yl)carbonyl] benzohydrazide sebagai kandidat antituberkulosis. Chimica et Natura Acta, 3(2), 54-61. doi: 10.24198/cna.v3.n2.9183.

Ruswanto, Miftah, A. M., Tjahjono, D. H., Siswandono. 2015. Synthesis and in vitro cytotoxicity of 1-benzoyl-3-methyl thiourea derivatives. Procedia Chemistry, 17, 157–161. doi: 10.1016/j.proche.2015.12.105.

Rychtarcíková, Z., Krátký, M., Gazvoda, M., Komlóová, M., Polanc, S., Kocevar, M., Stolaríková, J., Vinšová, J. 2014. N-substituted 2-isonicotinoylhydrazinecarboxamides-new antimycobacterial active molecules. Molecules, 19(4), 3851–3868. doi: 10.3390/molecules 19043851.

Seifert, M., Catanzaro, D., Catanzaro, A., Rodwell, T.C. 2015. Genetic mutations associated with isoniazid resistance in Mycobacterium tuberculosis: A systematic review. PLoS ONE, 10(3), 1–13. doi: 10.1371/journal.pone.0119628.

Sharma, R., Nagda, D. P. and Talesara, G. L. 2006. Synthesis of various isoniazidothiazolidinones and their imidoxy derivatives of potential biological interest. Arkivoc, 2006(i), 1–12.

Thomas, B., and Harindran, J. 2016. Design, synthesis and evaluation of antitubercular activity of amino azetidinones from isoniazid. International Journal of Pharmaceutical Sciences and Research, 7(7), 2795–2804. doi: 10.13040/IJPSR.0975-8232.7(7).2795-04.

Vidhya, K. R., and Shafi, S. S.. 2014. Synthesis, characterization and antimicrobial studies of novel 2-Pyrazoline derivatives. International Journal of ChemTech Research, 6(4), 2558-2563.

Vilchèze, C., and Jacobs, W. R. Jr. 2007. The mechanism of isoniazid killing: Clarity through the scope of genetics. Annual Review of Microbiology, 61(1), 35–50. doi: 10.1146/annurev.micro.61.111606.122346.

WHO. 2016. Global tuberculosis report 2016. World Health Organization. 214 pp.