International Journal of New Chemistry
ISC, DOAJ, CAS, Google Scholar......

Design, Synthesis and Biological Evaluation of Chromone Fused 1,3,4-Thiadiazoles as Highly Potent Nontoxic Inhibitors of Enoyl-Acyl Carrier Proteins in M. tuberculosis

Document Type : Research Paper

Authors

Babasaheb V Kendre 1
Pawan S Hardas 2
Rajashri c Pat 2
Rushikesh B Kendre 3
Mahadev G Landge 4
Sudhakar R Bhusare 5

1 Ambajogai road, parli-Vaijnath Dist. Beed

2 Vaidyanath College, Parli-Vaijnath

3 MIMSR Ambajogai road, Latur Dist. Beed

4 Vaidyanath College, Ambajogai road, parli-Vaijnath Dist. Beed

5 DSM, College, Parbhani

https://doi.org/10.22034/ijnc.2024.2020026.1369
Abstract
A series of 12 novel chromone fused 1,3,4-thiadiazoles were designed and synthesized via an efficient and convenient synthetic route starting from a 3-formyl chromone. In vitro evaluation of all the derivatives was carried out to demonstrate their inhibitory potential against Mtb. Anti-tubercular evaluation via the MABA assay revealed that compounds 5b, 5d, 5f, 5 g and 5 h significantly inhibited the Mycobacterium tuberculosis H37Rv strain, with MICs in the range of 3.0-8.0 µg ml-1. Moreover, the experimental results demonstrated the excellent anti-tubercular potential of compounds 5d and 5f against Mtb with MICs of 3.0 and 4.0µg ml-1. In addition, molecular docking was performed to determine more favorable molecular interactions with the four target enzymes. Molecular docking and binding energy studies revealed the potential of four selected compounds to bind to the enoyl-acyl carrier protein reductase of Mtb which is involved in the biosynthesis of mycolic acid. Interestingly, the binding energies (-8.50 to -10.08 kcal/mol) of all the selected compounds were found to be greater than that of standard drugs. The chemoinformatics study revealed excellent ADME profiles for all the selected compounds, confirming their importance in the treatment of Mtb.

Keywords

Minimum inhibitory concentration (MIC)
Molecular docking
Topological polar surface area (TPSA)
Structure-activity relationships (SARs)
Subjects
[1] S. V. Gordon and T. Parish, Microbiology., 164(4), 437–439 (2018).
[2] K. Dheda, M. Tomasicchio, A. Reuter, M. Davids, G. Calligaro, J. Furin, P. van Helden,
and R. Warren, Encyclopedia of Respiratory Medicine (Second Edition)., 75–98 (2022).
[3] M. G. Moule and J. D. Cirillo, Frontiers in Cellular and Infection Microbiology., 10, 65
(2020).
[4] V. Makarov, E. Salina, R. C. Reynolds, P. P. K. Zin, and S. Ekins, Journal of Medicinal
Chemistry., 63(17), 8917–8955 (2020).
[5] C. Vilcheze and W. R. Jacobs, Microbiology Spectrum., 2, MGM2-0014-2013 (2014).
[6] J. Reis, A. Gaspar, N. Milhazes, and F. Borges, Journal of Medicinal Chemistry., 60(19),
7941–7957 (2017).
[7] A. B. Svendsen and J. J. C. Scheffer, Pharmaceutisch Weekblad Scientific Edition., 4, 93–
103 (1982).
[8] B. A. Berman and R. N. Ross, Clinical Reviews in Allergy., 1, 105–121 (1983).
[9] M. Ceylan-Ünlüsoy, E. J. Verspohl, and R. Ertan, Journal of Enzyme Inhibition and
Medicinal Chemistry., 25(6), 784–789 (2010).
[10] H. M. Hiruy, D. Bisrat, A. Mazumder, and K. Asres, Natural Product Research., 35(6),
1052–1056 (2021).
[11] C. F. Silva, D. C. Pinto, and A. M. Silva, ChemMedChem., 11(20), 2252–2260 (2016).
[12] J. Reis, A. Gaspar, N. Milhazes, and F. Borges, Journal of Medicinal Chemistry., 60(19),
7941–7957 (2017).
[13] K. C. Rajanna, F. Solomon, M. M. Ali, and P. K. Saiprakash, Tetrahedron., 52(10), 3669–
3682 (1996).
[14] D. Ameen and T. J. Snape, Synthesis., 47(2), 141–158 (2015).
[15] D. A. Williams, C. Smith, and Y. Zhang, Tetrahedron Letters., 54(32), 4292–4295 (2013).
[16] I. T. Hwang, S. A. Lee, J. S. Hwang, and K. I. Lee, Molecules., 16(8), 6313–6321 (2011).
[17] E. Petschek and H. Simonis, Berichte der Deutschen Chemischen Gesellschaft., 46, 2014
(1913).
[18] J. W. Zhang, W. W. Yang, L. L. Chen, P. Chen, Y. B. Wang, and D. Y. Chen, Organic
and Biomolecular Chemistry., 17, 7461–7467 (2019).
[19] S. Maddila, S. Gorle, C. Sampath, and P. Lavanya, Journal of Saudi Chemical Society.,
20(1), S306–S312 (2016).
[20] S. Turner, M. Myers, B. Gadie, A. J. Nelson, R. Pape, J. F. Saville, J. C. Doxey, and T.
L. Berridge, Journal of Medicinal Chemistry., 31(5), 902–906 (1988).
[21] A. A. Othman, M. Kihel, and S. Amara, Arabian Journal of Chemistry., 12(7), 1660–1675
(2019).
[22] E. E. Oruç, S. Rollas, F. Kandemirli, N. Shvets, and A. S. Dimoglo, Journal of Medicinal
Chemistry., 47(27), 6760–6767 (2004).
[23] M. R. Stillings, A. P. Welbourn, and D. S. Walter, Journal of Medicinal Chemistry.,
29(11), 2280–2284 (1986).
[24] M. N. Noolvi, H. M. Patel, S. Kamboj, and S. S. Cameotra, Arabian Journal of Chemistry.,
9(2), S1283–S1289 (2016).
[25] J. Matysiak, Mini Reviews in Medicinal Chemistry., 15(9), 762–775 (2015).
[26] R. F. Rodrigues, K. S. Charret, E. F. da Silva, A. Echevarria, V. F. Amaral, L. L. Leon,
and M. M. Canto-Cavalheiro, Antimicrobial Agents and Chemotherapy., 53(2), 839–842
(2009).
[27] a) V. A. Obakachi, B. Kushwaha, N. D. Kushwaha, S. Mokoena, A. M. Ganai, T. K.
Pathan, W. E. van Zyl, and R. Karpoormath, Journal of Sulfur Chemistry., 42(6), 670–691
(2021); b) D. Chandra Sekhar, D. V. Venkata Rao, and A. Tejeswara Rao, Russian Journal of
General Chemistry., 89, 770–779 (2019).
[28] K. Brodowska and E. Lodyga-Chruscinska, Chemik., 68(2), 129–134 (2014).
[29] L. Kaviarasan, B. Gowramma, R. Kalirajan, M. Mevithra, and S. Chandralekha, Journal
of the Iranian Chemical Society., 17(8), 2083–2094 (2020).
[30] a) L. B. Leonard, J. Coronel, M. Siedner, L. Grandjean, L. Caviedes, P. Navarro, R. H.
Gilman, and D. A. J. Moore, Journal of Clinical Microbiology., 46(10), 3526–3529 (2008); b)
C. Ryan, B. T. Nguyen, and S. J. Sullivan, Journal of Clinical Microbiology., 33(7), 1720–
1726 (1995).
[31] I. Li de la Sierra, H. Munier-Lehmann, A. M. Gilles, O. Bârzu, and M. Delarue, Journal
of Molecular Biology., 311(1), 87–100 (2001).
[32] E. Morgunova, W. Meining, B. Illarionov, I. Haase, G. Jin, A. Bacher, M. Cushman, M.
Fischer, and R. Ladenstein, Biochemistry., 44(8), 2746–2758 (2005).
[33] C. Vilchèze, H. R. Morbidoni, T. R. Weisbrod, H. Iwamoto, M. Kuo, J. C. Sacchettini,
and W. R. Jacobs Jr., Journal of Bacteriology., 182, 4059–4067 (2000).
[34] E. Dhamija, S. Yabaji, A. Chatterjee, A. Mishra, R. K. Dubey, A. Narain, and K. K.
Srivastava, European Respiratory Journal., 54(Suppl. 63), PA4592 (2019).
[35] T. A. Halgren, R. B. Murphy, R. A. Friesner, H. S. Beard, L. L. Frye, W. T. Pollard, and
J. L. Banks, Journal of Medicinal Chemistry., 47, 1750–1759 (2004).
[36] K. Mdluli and M. Spigelman, Current Opinion in Pharmacology., 6, 459–467 (2006).
[37] A. Daina, O. Michielin, and V. Zoete, Scientific Reports., 7, 42717 (2017). [38] C. A.
Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney, Advanced Drug Delivery Reviews.,
46(1–3), 3–26 (2001).
[39] a) K. T. Savjani, et al., ISRN Pharmaceutics., (2012); b) J. A. Arnot and S. L. Planey,
Expert Opinion on Drug Discovery., (2012).
[40] D. E. Clark, Journal of Pharmaceutical Sciences., 88, 815–821 (1999).
[41] P. R. Twentyman and M. Luscombe, British Journal of Cancer., 56, 279–285 (1987).
International Journal of New Chemistry
Volume 12, Issue 4
Winter 2025
Pages 581-606

Home

Reviewers