Abstract
A computation model has been developed for the rational design of bioactive pharmacophore sites as anti-Mycobacterium tuberculosis and anti-Trypanosoma cruzi (TC) candidates. The 40 compounds 1–40 analyzed have been previously screened for their antitubercular and antitrypanosomal activity. The highest anti-TC activity is obtained for compounds 8 and 18 which exhibited low IC50 values (9.2 and 10.8 μM), almost equal to clinical drug, nifurtimox (7.7 μM; 100 % Inhib.). This could be attributed to the existence of two synergic (Oδ−–Nδ−) and (Oδ−–Oδ−) antitrypanosomal pharmacophore sites. In contrast to compounds 8 and 18 which contain electro-attractor groups (R1, R2 = F), analog compounds 1 and 13 with electro-donor or only hydrogen (R1, R2 = CH3, H) show best antibacterial activity (MIC = 0.977 and 1.190 μg/mL) very close to antitubercular activity of Rifampicin (MIC = 0.125 μg/mL). This could be attributed to the existence of (Oδ−–NHδ+) antibacterial pharmacophore site.
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Acknowledgments
Prof. T. Ben Hadda and Dr. J. Sheikh would like to thank the ACTELION; the Biopharmaceutical Company of Swiss, for molecular properties calculations. The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project Number RGP-VPP-007.
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Hadda, T.B., Bendaha, H., Sheikh, J. et al. Computational POM evaluation of experimental in vitro Trypanosoma cruzi and Mycobacterium tuberculosis inhibition of heterocyclic-2-carboxylic acid (3-cyano-1,4-di-noxidequinoxalin-2-yl)amide derivatives. Med Chem Res 23, 1956–1965 (2014). https://doi.org/10.1007/s00044-013-0781-3
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DOI: https://doi.org/10.1007/s00044-013-0781-3