Multistep Synthesis of Fluorine‐Substituted Pyrazolopyrimidine Derivatives With Higher Antibacterial Efficacy Based on <i>In Vitro</i> Molecular Docking and Density Functional Theory

Some new fluorine‐substituted pyrazolopyrimidine derivatives ( 1.3 – 1.5 ) have been synthesized by the multistep reactions, starting from reaction of 4‐fluorophenyl malanonitrile ( 1 ) with guanidine, followed by ring closure reaction with hydrazine to give 2,4‐diamino‐6‐aryl‐pyrimidine‐5‐carbonitrile ( 1.2 ). Structure of the compounds was conformed by the spectral and elemental analyses. The antibacterial activity of these compounds was tested in vitro by the disk diffusion assay against two Gram‐positive and two Gram‐negative bacteria, and then the minimum inhibitory concentration was determined with reference to the standard drug chloramphenicol. The results showed that compound 1.5 is better at inhibiting growth as compared with chloramphenicol of both types of bacteria (gram‐positive and gram‐negative). Molecular orbital calculations were carried out by using the density functional theory. The B3LYP/6‐311 + G** level of theory was employed to explore LUMO–HOMO gap energy and charge distribution of compounds 1.1 to 1.5 . Docking studies were performed on bacterial glucosamine‐6‐phosphate synthetase enzyme. Density functional theory calculations and docking studies support the in vitro findings.