Medicinal Chemistry

In Vivo Evaluation of Leishmanicidal Activity of Benzophenone Derivatives by qPCR

Abstract

Fabio Antonio Colombo, Rayssa Azara Reis, Juliana Barbosa Nunes, Danielle Ferreira Dias, Marcelo Henrique dos Santos, Claudio Viegas Junior and Marcos José Marques

In many tropical areas, infections by Leishmania species are endemic and include visceral leishmaniasis (VL), which is often fatal if untreated. Outside India, VL treatment and control are based on long-term administration of highly toxic pentavalent antimonials. Previously, we described the synthesis and in vitro leishmanicidal activity of a series of nine benzophenone derivatives with low toxicity towards murine macrophages. Here in, we report the in vivo evaluation of the most promising active compounds of that series in an experimental model of established VL by L. (L). infantum chagasi in hamsters. Importantly, parasite DNA (amastigote form) quantification in infected tissues was performed by real time PCR, for improved detection accuracy and speed. Compounds 2-Hydroxy-4- O-(3,3-dimethyl)-allylbenzophenone (LFQM-117 (1)), 4-O-(3,3-Dimethyl)-allylbenzophenone (LFQM-120 (2)) and 4,4′-Di-methoxybenzophenone (LFQM-121 (3)) were administered as oral suspensions (50 mg/kg/day) for 10 days, after 50 days of parasite inoculation, and their efficacy was compared to pentavalent antimonial Glucantime (GLU). Compound 1 significantly reduced the number of parasites in the spleen (1.64 × 102 amastigotes/g, vs. 1.16 × 106 amastigotes/g in the untreated control), while compound 2 significantly reduced (p<0.05) the number of parasites in the liver (1.28 × 104 amastigotes/g, vs. 1.76 × 105 amastigotes/g in the untreated control) of infected animals. Glucantime was the most effective in the treatment of infected animals (1.15 × 101 and 3.20 × 102 amastigotes/g in the spleen and liver, respectively), but with higher toxicity then the most active compounds LFQM-117 (1) and LFQM-120 (2).