In silico and in vitro comparative activity of novel experimental derivatives against Leishmania major and Leishmania infantum promastigotes

• Published in: Experimental parasitology 2013-10, Vol.135 (2), p.208-216
• Main Authors: Khademvatan, Shahram, Adibpour, Neda, Eskandari, Alborz, Rezaee, Saeed, Hashemitabar, Mahmoud, Rahim, Fakher
• Format: Article
• Language: English
• Subjects: Antileishmanial activity; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Biuret - analogs & derivatives; Biuret - chemistry; Biuret - pharmacology; Biurets; Colorimetry; In silico; In vitro; Leishmania infantum - cytology; Leishmania infantum - drug effects; Leishmania major - cytology; Leishmania major - drug effects; Meglumine - pharmacology; MTT; Organometallic Compounds - pharmacology; Phylogeny
• ISSN: 0014-4894; 1090-2449
• DOI: 10.1016/j.exppara.2013.07.004

•We homologically modeled the PTR1 of nine different leishmania and protozoans.•PTR1 of leishmania significantly differs from the other protozoan.•New experimental derivatives could be a potential antileishmanial agent.•Combinatorial in vitro with in silico may serve as a noble tools in drug designing. This in silico and in vitro comparative study was designed to evaluate the effectiveness of some biurets (K1 to K8) and glucantime against Leishmania major and Leishmania infantum promastigotes. Overall, eight experimental ligands and glucantime were docked using AutoDock 4.3 program into the active sites of Leishmania major and Leishmania infantum pteridine reductase 1, which were modeled using homology modeling programs. The colorimetric MTT assay was used to find L. major and L. infantum promastigotes viability at different concentrations of biuret derivatives in a concentration and time-dependent manner and the obtained results were expressed as 50% and 90% of inhibitory concentration (IC50 and IC90). In silico method showed that out of eight experimental ligands, four compounds were more active on pteridine reductase 1. K3 was the most active against L. major promastigotes with an IC50 of 6.8μM and an IC90 of 40.2μM, whereas for L. infantum promastigotes was K8 with IC50 of 7.8μM. The phenylethyl derivative (K7) showed less toxicity (IC50s>60μM) in both Leishmania strains. Glucantime displayed less growth inhibition in concentration of about 20μM. In silico and especially docking results in a recent study were in accordance with the in vitro activity of these compounds in presented study and compound K3, K2 and K8 showed reasonable levels of selectivity for the Leishmania pteridine reductase 1.