In vitro and in silico Approaches to the Identification of New Compounds with Antibacterial Profile

Carlos R. Rodrigues, Bruno Leal, Kely N. De Oliveira, Ariane S. S. R. Ferreira, Alice Bernardino, Ricardo J. Nunes, Vitor Ferreira, Maria C. De Souza, Anna C. Cunha, Helena C. Castro

The emergence of multidrug-resistant bacterial strains is a world problem that increases the need for new and more effective antimicrobials. On that purpose, derivatives of cyclic systems may serve as new leads for discovering new active molecules. In this work we evaluated the antibacterial profile of 243 molecules derived from the systems thienopyridine, pyrazolopiridine, quinolone, chalcone, hydrazone and lapachone against Gram-positive and Gram-negative susceptible and multiresistant strains also comparing them with antibiotics of clinical use. Our results showed that among the 243 molecules tested, only eight derivatives were active with promissing MIC values (2-64mg/mL). Our theoretical in silico analysis showed that all active compounds fulfilled Lipinski rule of five (molecular weight = 344.37–409.24, clogP = 3.15–4.11, nHBA = 6–7, and nHBD = 2), similarly to commercial drugs as well as presented better druglikeness values (from -3.68 to 0.12) than chloramphenicol (-4.61) and linezolid (-4.08). Most of the active derivatives presented a low in silico toxicity risk profile, similar to oxacillin, ampicillin, and penicillin G, and even lower than that observed for chloramphenicol and linezolid. Theoretically HOMO and the electrostatic protential distribution may be contributing for this safer profile. This study used computacional tools and may help to deal with an important world health problem.

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