Topliss method in the optimization of salicylic Acid derivatives as potential antimycobacterial agents.
The Topliss method was used to guide a synthetic path in support of drug discovery efforts toward the identification of potent antimycobacterial agents. Salicylic acid and its derivatives, p-chloro, p-methoxy, and m-chlorosalicylic acid, exemplify a series of synthetic compounds whose minimum inhibitory concentrations for a strain of Mycobacterium were determined and compared to those of the reference drug, p-aminosalicylic acid. Several physicochemical descriptors (including Hammett's sigma constant, ionization constant, dipole moment, Hansch constant, calculated partition coefficient, Sterimol-L and -B4 and molecular volume) were considered to elucidate structure-activity relationships. Molecular electrostatic potential and molecular dipole moment maps were also calculated using the AM1 semi-empirical method. Among the new derivatives, m-chlorosalicylic acid showed the lowest minimum inhibitory concentration. The overall results suggest that both physicochemical properties and electronic features may influence the biological activity of this series of antimycobacterial agents and thus should be considered in designing new p-aminosalicylic acid analogs.
da Silva
Márcia
M
Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, PB 502, ZIP 14801-902, Araraquara, SP, Brazil. silvam@fcfar.unesp.br
Menezes
Carla Maria Souza
CM
Ferreira
Elizabeth Igne
EI
Leite
Clarice Queico Fujimura
CQ
Sato
Daisy Nakamura
DN
Correia
Cristiane Cardoso
CC
Pimenta
Carolina Pereira
CP
Botelho
Kátia Cirlene Alves
KC
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D015195:Drug Design; D008722:Methods; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects*; D020156:Salicylic Acid / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D020156:Salicylic Acid