Synthesis, biological evaluation and SAR of sulfonamide 4-methoxychalcone derivatives with potential antileishmanial activity.
Despite clinical importance of leishmaniasis, an infectious disease that affects 12 thousand million people in 88 countries, the treatment is still unsatisfactory due to its limited efficacy, cost expensive and undesirable side effects. Aiming to develop new antileishmanial lead compounds, we used a rational approach to synthesize a new set of sulfonamide 4-methoxychalcone derivatives (3a-3i) and evaluate the sulfonamide and methoxy moieties as promising adding-groups to chalcones. For that purpose we tested this new set against Leishmania braziliensis promastigotes and intracellular amastigotes and determined its cell toxicity profile. Interestingly all compounds presented a concentration-dependent antileishmanial profile and the benzylamino derivative (3i) showed a biological activity better than pentamidine. None of these compounds affected Trypanosoma cruzi epimastigotes, which suggests a specific antileishmanial profile. The structure-activity analysis of these sulfonamide 4-methoxychalcone derivatives pointed the molecular volume, the HOMO density concentrated in the chalcone moiety and the conformational structure of the compounds as important structural and stereoelectronic features for the antileishmanial activity. In addition, these compounds also fulfilled Lipinski rule of 5 and presented druglikeness similar to antileishmanial drugs. Altogether these results point the sulfonamide 4-methoxychalcone derivatives as potential lead compounds for designing new candidates for leishmaniasis treatment.
Departamento de Química, Universidade Federal de Santa Catarina, UFSC, Campus Universitário Trindade, CEP 88040900 Florianópolis, SC, Brazil.
Carla R
CR
Andrighetti-Fröhner
Kely N
KN
de Oliveira
Daniela
D
Gaspar-Silva
Letícia K
LK
Pacheco
Antônio C
AC
Joussef
Mário
M
Steindel
Cláudia M O
CM
Simões
Alessandra M T
AM
de Souza
Uiaran O
UO
Magalhaes
Ilídio F
IF
Afonso
Carlos R
CR
Rodrigues
Ricardo J
RJ
Nunes
Helena C
HC
Castro
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002599:Chalcone / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D007892:Leishmania braziliensis / Q000187:drug effects; D008958:Models, Molecular; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
D000981:Antiprotozoal Agents; D013449:Sulfonamides; D002599:Chalcone