title: Trimethoxy-chalcone derivatives inhibit growth of Leishmania braziliensis: synthesis, biological evaluation, molecular modeling and structure-activity relationship (SAR).
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.
authors.affiliation: Laboratório de Modelagem Molecular e QSAR (ModMolQSAR-3D), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Murilo Lamim
authors.initials: ML
authors.lastname: Bello
authors.forename: Louise Domeneghini
authors.initials: LD
authors.lastname: Chiaradia
authors.forename: Luiza Rosaria Sousa
authors.initials: LR
authors.lastname: Dias
authors.forename: Letícia Kramer
authors.initials: LK
authors.lastname: Pacheco
authors.forename: Taisa Regina
authors.initials: TR
authors.lastname: Stumpf
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mascarello
authors.forename: Mário
authors.initials: M
authors.lastname: Steindel
authors.forename: Rosendo Augusto
authors.initials: RA
authors.lastname: Yunes
authors.forename: Helena Carla
authors.initials: HC
authors.lastname: Castro
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D002599:Chalcone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D007892:Leishmania braziliensis / Q000187:drug effects / Q000254:growth & development*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D002599:Chalcone