Selective leishmanicidal effect of 1,3,4-thiadiazole derivatives and possible mechanism of action against Leishmania species |
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Authors: | Fatemeh Poorrajab Alireza Foroumadi Amina Kariminia Abbas Shafiee |
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Institution: | a Institute of Biochemistry and Biophysics, Department of Biochemistry, University of Tehran, P.O. Box 13145-1365, Tehran, Iran b Department of Medicinal Chemistry, Faculty of Pharmacy & Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14174, Iran c Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran d Department of Immunology, Pasteur Institute of Iran, Tehran, Iran |
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Abstract: | With the aim of determining selectivity and the possible target(s) of nitroheteroaryl-1,3,4-thiadiazoles considered as possible leads for the development of anti-leishmanial agents, we studied 5-nitroimidazole, 5-nitrofuran and 5-nitrothiophene analogs of N-substituted-piperazinyl-1,3,4-thiadiazoles. We investigated 21 representative compounds 1-3(a-g) for the following properties: selectivity and efficiency against different Leishmania wild type species and intracellular parasite, toxicity against host cells and inhibition of topoisomerases I and II. Our results indicate that the nitroimidazole analogs 1a and 1f, and nitrofuran derivatives 2a, 2b, 2c, 2f, and 2g exhibited low toxicity against the host cells (IC50 ? 80 μM), but high selectivity against intracellular amastigotes (selectivity index > 12). Leishmania topoisomerases revealed impressive sensitivity to the agents (%inhibition >50 at IC50 doses of compounds against Leishmania). Our findings showed that at least part of leishmaniacidal effect of the compounds could be attributed to disruption DNA-relaxed activities of topoisomerases I and II, and cleavable-complex formation. |
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Keywords: | Leishmania sp Toxicity assays Selectivity Index DNA topoisomerases I and II Inhibitory effects |
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