title: Selective leishmanicidal effect of 1,3,4-thiadiazole derivatives and possible mechanism of action against Leishmania species.
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 (IC(50)> or =80 microM), but high selectivity against intracellular amastigotes (selectivity index>12). Leishmania topoisomerases revealed impressive sensitivity to the agents (%inhibition >50 at IC(50) 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.
authors.affiliation: Institute of Biochemistry and Biophysics, Department of Biochemistry, University of Tehran, P.O. Box 13145-1365, Tehran, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Poorrajab
authors.forename: Sussan K
authors.initials: SK
authors.lastname: Ardestani
authors.forename: Alireza
authors.initials: A
authors.lastname: Foroumadi
authors.forename: Saeed
authors.initials: S
authors.lastname: Emami
authors.forename: Amina
authors.initials: A
authors.lastname: Kariminia
authors.forename: Mina
authors.initials: M
authors.lastname: Behrouzi-Fardmoghadam
authors.forename: Abbas
authors.initials: A
authors.lastname: Shafiee
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology; D018320:Leishmania major / Q000187:drug effects / Q000201:enzymology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D000981:Antiprotozoal Agents; D013830:Thiadiazoles; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C058949:1,3,4-thiadiazole