title: Synthesis and antileishmanial activity of novel 5-(5-nitrofuran-2-y1)-1,3,4-thiadiazoles with piperazinyl-linked benzamidine substituents.
abstract: In order to optimize the antileishmanial activity of piperazinyl-linked 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazoles, we synthesized a series of 5-(5-nitrofuran-2-y1)-1,3,4-thiadiazoles with piperazinyl-linked benzamidine substituent as scaffold found in pentamidine related antiprotozoals. The structure of target compounds was confirmed by IR, 1H NMR, 13C NMR and Mass spectral data. All compounds were tested for in vitro activity against the promastigote and amastigote forms of Leishmania major. From the results, we found that the substitution on amidine nitrogen has profound role in the biological activity of these compounds. The 5-nitrofuran-2-yl-1,3,4-thiadiazoles having n-propyl, n-butyl and benzyl side chain on benzamidine (as in compounds 2d, 2e and 2g, respectively) showed very good activity in both forms of promastigote and amastigote. The most active compound was N-propyl-4-(4-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl)piperazin-1-yl) benzamidine hydrochloride (2d) with IC50 value of 0.08 μM in promastigote model. This compound showed a very low level of toxicity against macrophages (CC50=785 μM), with the highest selectivity index (SI=78.5) among the tested compounds.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy and Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Azar
authors.initials: A
authors.lastname: Tahghighi
authors.forename: Farzane Rezazade
authors.initials: FR
authors.lastname: Marznaki
authors.forename: Farzad
authors.initials: F
authors.lastname: Kobarfard
authors.forename: Siavoush
authors.initials: S
authors.lastname: Dastmalchi
authors.forename: Javid Shahbazi
authors.initials: JS
authors.lastname: Mojarrad
authors.forename: Sepideh
authors.initials: S
authors.lastname: Razmi
authors.forename: Sussan Kabudanian
authors.initials: SK
authors.lastname: Ardestani
authors.forename: Saeed
authors.initials: S
authors.lastname: Emami
authors.forename: Abbas
authors.initials: A
authors.lastname: Shafiee
authors.forename: Alireza
authors.initials: A
authors.lastname: Foroumadi
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001550:Benzamidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D021261:Parasitic Sensitivity Tests; D010879:Piperazines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D001550:Benzamidines; C560937:N-propyl-4-(4-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl)piperazin-1-yl)benzamidine; D010879:Piperazines; D013830:Thiadiazoles; C032157:benzamidine