Synthesis and antileishmanial activity of novel 2,4,6-trisubstituted pyrimidines and 1,3,5-triazines.

A series of 2,4,6-trisubstituted pyrimidines and 1,3,5-triazines have been synthesized and screened for their in vitro and in vivo antileishmanial activity against Leishmania donovani. Among all, 14 compounds have shown promising inhibition of 80-100% at 10 microg/ml against promastigotes and IC(50) in the range of 0.89-9.68 microg/ml against amastigotes. Three compounds 13, 32 and 33 with good selectivity index (S.I.) were screened for their in vivo activity in golden hamsters (Mesocricetus auratus) infected with MHOM/IN/80/Dd(8) strain of L. donovani and have shown moderate in vivo inhibition of 48-56% at a dose of 50 mg/kg x 5, i.p. route for 5 days.

Aryloxy cyclohexyl imidazoles: a novel class of antileishmanial agents.

Thirteen novel aryloxy cyclohexane-based mono and bis imidazoles were synthesized and evaluated in vitro as antileishmanials against Leishmania donovani and cytotoxicity assessed. These compounds were better than the existing drugs, sodium stibogluconate and pentamidine in respect to IC(50) and SI values. Promising compounds were tested further in vivo. Among all, the bis methylimidazole with 2-fluoro, 4-nitro aryloxy group (9) exhibited significant in vivo inhibition of 77.9%, thus providing new structural lead for antileishmanials.

Synthesis and biological evaluation of indolyl bisphosphonates as anti-bone resorptive and anti-leishmanial agents.

A series of indole conjugated bisphosphonate derivatives have been synthesized and evaluated for their in vitro anti-bone resorptive activity using bone marrow osteoclast culture. Two bisphosphonates 23 and 24 significantly inhibited osteoclastogenesis, 23 showed inhibition at 10 and 100 pM which was lower than the concentration of standard drug alendronate, and 24 inhibited osteoclastogenesis at 100 nM which was comparable to alendronate. Two other compounds 13 and 14 also showed inhibition comparable to alendronate, but were cytotoxic in the osteoblast cells. The two active bisphosphonates 23 and 24 induced significant osteoclast apoptosis at concentrations 100 nM for compound 24 and at 10 pM for compound 23 compared to alendronate. In vivo effect of active bisphosphonates 23 and 24 resulted in osteoclastogenesis of bone marrow cells (BMCs) to almost 40-50% (23 showing 8.4% decrease and 24 showing 9.0%) compared to 16.5% of the ovariectomized group. Further, screening of anti-leishmanial activity, four compounds 24-25 and 27-28 showed more than 80% inhibition against both the promastigote and amastigote stages of the Leishmania parasite.

Synthesis of marine alkaloid: 8,9-dihydrocoscinamide B and its analogues as Novel class of antileishmanial agents.

A series of marine alkaloid 8,9-dihydrocoscinamide B, its analogues and indolylglyoxylamide derivatives have been synthesized and screened for their in vitro antileishmanial activity profile in promastigote and amastigote models. Compounds 7 and 10 have shown 99-100% inhibition against promastigotes and 97-98% inhibition against amastigotes at a concentration of 10 microg/ml.