Trimethoxy-chalcone derivatives inhibit growth of Leishmania braziliensis: Synthesis, biological evaluation, molecular modeling and structure-activity relationship (SAR)

In this work we described the synthesis, the antileishmanial activity and the molecular modeling and structure-activity relationship (SAR) evaluations of a series of chalcone derivatives. Among these compounds, the methoxychalcones 2h, 2i, 2j, 2k and 2l showed significant antileishmanial activity (IC50 <10 mu M). Interestingly 2i (IC50 = 2.7 mu M), 2j (IC50 = 3.9 mu M) and 2k (IC50 = 4.6 mu M) derivatives presented better antileishmanial activity than the control drug pentamidine (IC50 = 6.0 mu M). Our SAR study showed the importance of methoxy di-ortho substitution at phenyl ring A and the relationship between the frontier orbital HOMO coefficients distribution of these molecules and their activity. The most active compounds 2h, 2i, 2j, 2k, and 2l fulfilled the Lipinski rule-of-five which theoretically is important for good drug absorption and permeation through biological membranes. The potential profile of 2j (IC50 = 3.9 mu M and CC50 = 216 mu M) pointed this chalcone derivative as a hit compound to be further explored in antileishmanial drug design. (C) 2011 Elsevier Ltd. All rights reserved.