Trimethoxy-chalcone derivatives inhibit growth of Leishmania braziliensis: synthesis, biological evaluation, molecular modeling and structure-activity relationship (SAR) |
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Authors: | Bello Murilo Lamim Chiaradia Louise Domeneghini Dias Luiza Rosaria Sousa Pacheco Letícia Kramer Stumpf Taisa Regina Mascarello Alessandra Steindel Mário Yunes Rosendo Augusto Castro Helena Carla Nunes Ricardo José Rodrigues Carlos Rangel |
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Institution: | Laboratório de Modelagem Molecular e QSAR (ModMolQSAR-3D), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. |
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Abstract: | 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 (IC(50)<10 μM). Interestingly 2i (IC(50)=2.7 μM), 2j (IC(50)=3.9 μM) and 2k (IC(50)=4.6 μM) derivatives presented better antileishmanial activity than the control drug pentamidine (IC(50)=6.0 μM). 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 (IC(50)=3.9 μM and CC(50)=216 μM) pointed this chalcone derivative as a hit compound to be further explored in antileishmanial drug design. |
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