Novel 1,3,4-(thiadiazol-2-ylamino) methyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-thiones: synthesis, docking and antimycobacterial testing
Author(s)
Trupti S. Chitre,
Santosh Panda,
Shital M Patil,
Aparna S. Chothe,
G Vignesh,
M. K. Kathiravan*
Affiliation(s)
. Dept.of Pharmaceutical Chemistry, (PGwing), AISSMS College of Pharmacy, Kennedy Road, Near RTO, Pune-411001, Maharashtra, India..
. Dept.of Pharmaceutical Chemistry, (PGwing), AISSMS College of Pharmacy, Kennedy Road, Near RTO, Pune-411001, Maharashtra, India..
ABSTRACT
In the present study, a novel series of Mannich bases of 3-substituted 5-(pyridin-4-yl)-1,3, 4-oxadiazol-2-thione derivatives were synthesized. Docking study was performed to rationalize the possible interactions between the synthesized com-pounds and active site of 14DM. The test compounds were screened for antimycobacterial activity using Middlebrook 7H9 medium against M. tuberculosis H37Rv (ATCC 27294) as well as Isoniazid (INH) resistant clinical strain. Among the series 5c and 5a are found to be most potent (susceptible) while the compound 5f did not show activity against M. tuberculosis H37Rv (resistant). The SAR study reveals the importance of substitutions at para position for good activity.
In the present study, a novel series of Mannich bases of 3-substituted 5-(pyridin-4-yl)-1,3, 4-oxadiazol-2-thione derivatives were synthesized. Docking study was performed to rationalize the possible interactions between the synthesized com-pounds and active site of 14DM. The test compounds were screened for antimycobacterial activity using Middlebrook 7H9 medium against M. tuberculosis H37Rv (ATCC 27294) as well as Isoniazid (INH) resistant clinical strain. Among the series 5c and 5a are found to be most potent (susceptible) while the compound 5f did not show activity against M. tuberculosis H37Rv (resistant). The SAR study reveals the importance of substitutions at para position for good activity.
Cite this paper
nullChitre, T. , Panda, S. , Patil, S. , Chothe, A. , Vignesh, G. and Kathiravan, M. (2011) Novel 1,3,4-(thiadiazol-2-ylamino) methyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-thiones: synthesis, docking and antimycobacterial testing. Advances in Biological Chemistry, 1, 7-14. doi: 10.4236/abc.2011.12002.
nullChitre, T. , Panda, S. , Patil, S. , Chothe, A. , Vignesh, G. and Kathiravan, M. (2011) Novel 1,3,4-(thiadiazol-2-ylamino) methyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-thiones: synthesis, docking and antimycobacterial testing. Advances in Biological Chemistry, 1, 7-14. doi: 10.4236/abc.2011.12002.
References
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European Journal of Medicinal Chemistry, 44, 3954-3960. doi:10.1016/j.ejmech.2009.04.023 [20] Sriram, D., Yogeeswari, P. and Reddy, S. (2008) Anti-mycobacterial activities of novel 2-(sub)-3-fluoro/nitro- 5,12-dihydro-5-oxobenzothizolo[3,2-a]quinoline-6-carboxylic acid. Bioorganic & Medicinal Chemistry, 16, 3408- 3418. doi:10.1016/j.bmc.2007.11.016 [21] Joshi, S. and Khosla, N. (2004) In vitro study of some medicinally important Mannich bases derived from anti-tubercular agent. Bioorganic & Medicinal Chemistry, 12, 571-576. doi:10.1016/j.bmc.2003.11.001 [22] Singh, I.P., Saxena, A.K., Shankar, K. (1986) Synthesis and anti-inflammatory activity of oxadiazoline thione hydrochlorides. European Journal of Medicinal Che- mi-stry: Chimica Therapeutica, 21, 267-269. [23] Jorgensen, W., Maxwell, D., Tirado-Rives, J. (1996) Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids. Journal of American Chemical Society, 118, 11225-11236. doi:10.1021/ja9621760 [24] Podust, L., Poulos, T., Waterman, M. (2001) Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proceedings of the National Aca- demy of Sciences of U.S.A, 98, 3068-3073. doi:10.1073/pnas.061562898 [25] Hayes, M. J., Stein, M. and Weiser, J. (2004) Accurate Calculations of Ligand Binding Free Energies: Chiral Separation with Enantioselective Receptors. The Journal of Physical Chemistry, 108, 3572-3580. [26] Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.; Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T. (2006) Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein?Ligand Complexes. Journal of Medicinal Chemistry, 49, 6177. doi:10.1021/jm051256o [27] Elmer, W.K., Stephen, D.A., William, M.J., Paul, C.S. and Washing, C.W. (2002) Text book of Diagnostic Mi-crobiology 5 Lippincot-Pub, J. B. Lippincott Co., Phila-delphia, p. 125. [28] Goto, S., Jo, K., Kawakita, T., Kosakai, N., Mitsuhashi, S., Nishino, T., Ohsawa, N., Tanami, H. (1981) Determi- nation method of minimum inhibitory concentrations. Chemotherapy, 29, 76-79.
[1] WHO. Tuberculosis. November 2010. http://www.who.int/mediacentre/factsheets/fs104/en/ [2] Dye, C., Williams, B., Espinal, M. and Raviglion, M. (2002) Erasing the world’s slow stain: Strategies to beat multidrug-resistant tuberculosis. Science, 295, 2042- 2046. doi:10.1126/science.1063814 [3] Morris, S., Bai, G., Suffys, P., Portilo, L., Fairchok, M. and Rouse, D. (1995) Molecular Mechanisms of Multiple Drug Resistance in Clinical Isolates of Mycobacterium tuberculosis. Infectious Diseases, 171, 954-960. doi:10.1093/infdis/171.4.954 [4] Telzak, E., Sepkowitz, K., Alpert, P., Mannheimer, S., Mederd, F., El-Sadr, W., Blum, S., Gagliardi, A., Alomon, N. and Turett, G. (1995) Multidrug-Resistant Tuberculosis in Patients without HIV Infection. The New England Journal of Medicineogy, 333, 907-912. doi:10.1056/NEJM199510053331404 [5] Basso, L. and Blanchard, J. S. (1998) Resistance to anti-tubercular drugs. Advances in Experimental Medicine and Biology, 456, 115-144. doi:10.1007/978-1-4615-4897-3_7 [6] Navarrete-Vázquez, G., Molina-Salinas, G., Duarte- Fa-jardo Zetel, Z., Villarrea, J., Estrada-Soto, S., González- Salazar, F., Hernández-Nú?ez, E., Fernendez, S. S. (2007) Synthesis and antimycobacterial activity of 4-(5-substituted-1,3,4-oxadiazol-2-yl)pyridines. Bioorganic & Me- dicinal Chemistry, 5, 5502-5508. doi:10.1016/j.bmc.2007.05.053 [7] Shaban, M.A.E., Nasr, A.Z. and El-Badry, J. (1991) Syn-thesis and biological activities of some 1, 3, 4-oxadiazoles and bis (1, 3, 4-oxadiazoles). Journal of Islamic Academy of Sciences, 143, 184-186. [8] Karakus, S. and Rollas, S. (2002) Synthesis and antitu-berculosis activity of new N-phenyl-N′-[4-(5-alkyl/ arylamino-1,3,4-thiadiazole-2-yl)phenyl]thioureas. Far-maco, 57, 577-581. doi:10.1016/S0014-827X(02)01252-1 [9] Oruc, E., Rollas, S., Kandemirli, F., Shvets, N., Dimoglo, A. (2004) 1,3,4-Thiadiazole Derivatives. Synthesis, Structure Elucidation, and Structure?Antituberculosis Activity Relationship Investigation. Journal of Medicinal Chemistry, 47, 6760-6767. [10] Nilufer, S., Sevim, R. (2006) Synthesis and antitubercu-losis activity of 2-(aryl/alkylamino)-5-(4-aminophenyl)- 1,3,4-thiadiazoles and their Schiff bases. Arkivoc, 12, 173-181. [11] Macaev, F., Ghenadie, R., Serghei, P., Alexandru, G., Eugenia, S., Ludmila, V., Nathaly, S., Fatma, K., Anatholy, D. and Robert, R. (2005) Synthesis of novel 5-aryl-2-thio-1,3,4-oxadiazoles and the study of their structure—anti-mycobacterial activities. Bioorganic & Medicinal Chemistry, 13, 4842-4850. doi:10.1016/j.bmc.2005.05.011 [12] Wilder-Smith, A.E. (1966) Some recently synthesised tuberculostatic 4-substituted oxadiazolones and oxadiazol- thiones. Arzneimittelforschung, 16, 1034-1038. [13] Mamolo, M., Zampieri, D., Vio, L., Fermeglia, M., Fer-rone, M., Pricl, S., Scialino, G. and Banfi, E. (2005) An-timycobacterial activity of new 3-substituted 5-(pyridin-4-yl)-3H-1,3,4-oxadiazol-2-one and 2-thione derivatives. Preliminary molecular modeling investigations. Bioorganic & Medicinal Chemistry, 13, 3797-3809. doi:10.1016/j.bmc.2005.03.013 [14] Ali, M.S. and Shaharya, M. (2007) Oxadiazole mannich bases: Synthesis and antimycobacterial activity. Bio- organic & Medicinal Chemistry Letters, 17, 3314- 3316. doi:10.1016/j.bmcl.2007.04.004 [15] a) Foroumadi, A., Kiani, Z., Soltani, F. (2003) Antitu-berculosis agents VIII: Synthesis and in vitro antimyco-bacterial activity of alkylα-[5-(5-nitro-2-thienyl)-1,3,4- thiadiazole-2-ylthio]acetates. Farmaco, 58, 1073-1076. doi:10.1016/S0014-827X(03)00158-7 b)Foroumadi, A., Sakhteman, A., Sharifzadeh, Z., Mohammad, H., Hem-mateenejad, B., Moshafi, M., Vosooghi, M., Amini, M.K. and Shafiee, A. (2007) Synthesis, [16] antituberculosis activity and QSAR study of some novel 2-(nitroaryl)- 5-(nitrobenzylsulfinyl and sulfonyl)-1,3,4-thiadiazole de-rivatives. DARU Journal of Pharmaceutical Sciences, 15, 218-226. [17] Foroumadi, A., Zahra, K. (2006) Synthesis and antimy-cobacterial activity of some alkyl [5-(nitroaryl)-1,3,4- thiadiazol-2-ylthio]propionates. Bioorganic & Medicinal Chemistry Letters, 16, 1164-1167. doi:10.1016/j.bmcl.2005.11.087 [18] Karthikeyan, M., Prasad, D.J., Boja, P., Bhat, S., Bantwal, S. and Nalilu, S. (2006) Synthesis and biological activity of Schiff and Mannich bases bearing 2,4-dichloro- 5-fluorophenyl moiety. Bioorganic & Medicinal Che- mistry, 14, 7482-7489. doi:10.1016/j.bmc.2006.07.015 [19] Raparti, V., Chitre, T., Bothara, K.G., Kumar, V., Dangre, S., Khachane, C., Gore, S., Deshmane, B. (2009) Novel 4-(morpholin-4-yl)-N′-(arylidene)benzohydrazides: Syn-thesis, antimycobacterial activity and QSAR invest- tiga-tions. European Journal of Medicinal Chemistry, 44, 3954-3960. doi:10.1016/j.ejmech.2009.04.023 [20] Sriram, D., Yogeeswari, P. and Reddy, S. (2008) Anti-mycobacterial activities of novel 2-(sub)-3-fluoro/nitro- 5,12-dihydro-5-oxobenzothizolo[3,2-a]quinoline-6-carboxylic acid. Bioorganic & Medicinal Chemistry, 16, 3408- 3418. doi:10.1016/j.bmc.2007.11.016 [21] Joshi, S. and Khosla, N. (2004) In vitro study of some medicinally important Mannich bases derived from anti-tubercular agent. Bioorganic & Medicinal Chemistry, 12, 571-576. doi:10.1016/j.bmc.2003.11.001 [22] Singh, I.P., Saxena, A.K., Shankar, K. (1986) Synthesis and anti-inflammatory activity of oxadiazoline thione hydrochlorides. European Journal of Medicinal Che- mi-stry: Chimica Therapeutica, 21, 267-269. [23] Jorgensen, W., Maxwell, D., Tirado-Rives, J. (1996) Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids. Journal of American Chemical Society, 118, 11225-11236. doi:10.1021/ja9621760 [24] Podust, L., Poulos, T., Waterman, M. (2001) Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proceedings of the National Aca- demy of Sciences of U.S.A, 98, 3068-3073. doi:10.1073/pnas.061562898 [25] Hayes, M. J., Stein, M. and Weiser, J. (2004) Accurate Calculations of Ligand Binding Free Energies: Chiral Separation with Enantioselective Receptors. The Journal of Physical Chemistry, 108, 3572-3580. [26] Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.; Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T. (2006) Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein?Ligand Complexes. Journal of Medicinal Chemistry, 49, 6177. doi:10.1021/jm051256o [27] Elmer, W.K., Stephen, D.A., William, M.J., Paul, C.S. and Washing, C.W. (2002) Text book of Diagnostic Mi-crobiology 5 Lippincot-Pub, J. B. Lippincott Co., Phila-delphia, p. 125. [28] Goto, S., Jo, K., Kawakita, T., Kosakai, N., Mitsuhashi, S., Nishino, T., Ohsawa, N., Tanami, H. (1981) Determi- nation method of minimum inhibitory concentrations. Chemotherapy, 29, 76-79.