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, (1)H NMR, (13)C 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 IC(50) value of 0.08 mu M in promastigote model. This compound showed a very low level of toxicity against macrophages (CC(50) = 785 mu M), with the highest selectivity index (SI = 78.5) among the tested compounds. (C) 2011 Elsevier Masson SAS. All rights reserved.