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

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 16; pp. 5046 - 5052
• Main 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
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-08-2011; Elsevier
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antileishmanial activity; Antiparasitic agents; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Biological and medical sciences; chalcone; Chalcone - analogs & derivatives; Chalcone - chemistry; Chalcone - pharmacology; Chalcones; Drug development; Drugs; inhibitory concentration 50; Leishmania braziliensis; Leishmania braziliensis - drug effects; Leishmania braziliensis - growth & development; Medical sciences; Models, Molecular; Molecular modeling; Molecular modelling; Pentamidine; pharmacokinetics; Pharmacology. Drug treatments; SAR; Structure-Activity Relationship; Structure-activity relationships; Leishmania braziliensis; Chalcones; SAR; Molecular modeling; Antileishmanial activity; Kinetoplastida; Protozoa; Ether; Benzene derivatives; In vitro; Modeling; Antiprotozoal agent; Structure activity relation; Molecular model; Parasiticide; Chemical synthesis; Enone; Electrostatic model
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.06.023

In this work we described new trimethoxy-chalcones and among them 2i (IC50=2.7μM), 2j (IC50=3.9μM) and 2k (IC50=4.6μM) derivatives presented better antileishmanial activity than the control drug pentamidine (IC50=6.0μM). 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.
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<10μM). Interestingly 2i (IC50=2.7μM), 2j (IC50=3.9μM) and 2k (IC50=4.6μM) derivatives presented better antileishmanial activity than the control drug pentamidine (IC50=6.0μM). 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=3.9μM and CC50=216μM) pointed this chalcone derivative as a hit compound to be further explored in antileishmanial drug design.