Design and synthesis of novel 4-hydrazone functionalized/1,2,4-triazole fused pyrido[2,3- d ]pyrimidine derivatives, their evaluation for antifungal activity and docking studies

AbstractA series of novel 2-substituted 4-hydrazone functionalized pyrido[2,3-d]pyrimidine (8a–f and9a–e) and 1,2,4-triazole fused pyrido[2,3-d]pyrimidine derivatives (10a–f and11a–e) were prepared starting from ethyl 2-amino-6-(trifluoromethyl)nicotinate3 via acylation, cyclization, chlorination, hydrazine reaction, hydrazone formation followed by intramolecular cyclization. All the final products were screened against variousCandida strains for determining the antifungal activity, minimum fungicidal concentration and inhibition of ergosterol biosynthesis. Among the screened, compounds8c,8f,9c,10f,11d and11e were identified as promising antifungal agents. From a mechanistic perspective, the concomitant treatment of10f, 11d and11e on differentCandida strains showed inhibition of ergosterol biosynthesis, which also revealed the possible antifungal action of these compounds on the ergosterol biosynthetic pathway. The binding mode of active compounds by docking studies showed that they fit well into the active site cavity of target protein. Further, the SAR and molecular docking studies data presumed that the presence of fluoro, trifluoromethyl, bromo and nitro groups on phenyl and furyl rings in pyrido[2,3-d]pyrimidine were found to be crucial to promote antifungal activity. All the strains for Miconazole a control drug showed MIC values equal to 3.9  μg/mL. Lipinski’s parameters of all compounds are within the acceptable range defined for human use thereby indicat...

Source: Medicinal Chemistry Research - July 12, 2019 Category: Chemistry Source Type: research