Theoretical Investigation of Some Anti-Staphylococcus aureus Halogenated Hydrazide Derivatives.

Abstract

Growing incidences of widespread resistance to existing antibiotics are threatening to revert humanity to the pre-antibiotic era where fatality and mortality rates due to bacterial infections were outrageously high. A way out of this public health concern is a deliberate search for novel drug candidates in the drug development pipeline. In this study, a data set of bioactive halogenated hydrazide derivatives was subjected to QSAR modeling using the Genetic Function Approximation technique. Before model building, the compounds were subjected to geometry optimization using the DFT method of Spartan 14 software at the B3LYP level of theory and 6-31G** basis set to obtain their minimum energy geometries. The validated penta-parametric QSAR model (R² = 0.76, R²_Adj = 0.70, Q²_LOO = 0.63, R²_Pred = 0.59) hinted the predominance of L3m, RDF135s, RDF60m, minHBint7, and ATSC5i descriptors on the observed MIC of the molecules. The validated model predicted the MIC of three newly designed hydrazide analogs; C1, C2, and C3 as 0.0003, 0.0003, and 0.0007 µg/mL, respectively. The predicted MIC values of the novel ligands revealed that they possess better potencies than the most potent molecules in the data set. Molecular docking simulations of designed ligands against the active sites of DNA gyrase of the bacterium recorded binding energy values of -8.8, -8.7, and -8.8 kcal/mol, respectively. Furthermore, ADMET profiles of the designed ligands revealed their excellent pharmacokinetic and toxicological profiles. It is envisaged that the wealth of information derived from this work could help in the discovery and development of novel antibiotics against S. aureus