title: Leishmania amazonensis growth inhibitors: biological and theoretical features of sulfonamide 4-methoxychalcone derivatives.
abstract: Current drugs for treating leishmaniasis are still associated with significant toxicity and failure rates. Thus, new effective and less toxic antileishmanial agents are still in need. Herein, we tested a series of sulfonamide 4-methoxychalcone derivatives against L. amazonensis promastigote and amastigote forms to identify its antileishmanial profile against this species compared to L. braziliensis. In addition, we used molecular modeling tools to determine stereoelectronic features that may lead to the antileishmanial profile. Interestingly, all tested compounds were able to affect L. amazonensis promastigote form in a concentration-dependent manner and with low cytotoxicity, except for derivative 3g. However, our results showed that compound 3f (para-Cl) presents the best profile against both L. amazonensis forms (promastigote and amastigote), differently from that observed for L. braziliensis, when compound 3i was the most active. Structure-activity relationship (SAR) analysis of these derivatives pointed molecular volume, HOMO density, and conformational aspects as important characteristics for parasitic profile. Overall, sulfonamide 4-methoxychalcone derivatives may be pointed out not only as lead compounds for treating leishmaniasis (i.e., 3f) but also as experimental tools presenting parasite-selectivity (i.e., 3i).
authors.affiliation: ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Alessandra M T
authors.initials: AM
authors.lastname: Souza
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.forename: Monique A
authors.initials: MA
authors.lastname: Brito
authors.forename: Carla R
authors.initials: CR
authors.lastname: Andrighetti-Fröhner
authors.forename: Uiaran
authors.initials: U
authors.lastname: Magalhães
authors.forename: Kely N
authors.initials: KN
authors.lastname: Oliveira
authors.forename: Daniela
authors.initials: D
authors.lastname: Gaspar-Silva
authors.forename: Letícia K
authors.initials: LK
authors.lastname: Pacheco
authors.forename: Antônio C
authors.initials: AC
authors.lastname: Joussef
authors.forename: Mário
authors.initials: M
authors.lastname: Steindel
authors.forename: Cláudia M O
authors.initials: CM
authors.lastname: Simões
authors.forename: Dilvani O
authors.initials: DO
authors.lastname: Santos
authors.forename: Magaly G
authors.initials: MG
authors.lastname: Albuquerque
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Nunes
mesh_terms: D000818:Animals; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007892:Leishmania braziliensis / Q000187:drug effects / Q000254:growth & development; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D047188:Chalcones; D006131:Growth Inhibitors; D013449:Sulfonamides; C097470:4'-methoxychalcone