Explorations of multicomponent pyridine-thiophene clubbed pyrimidine hybrid: Synthesis, characterization, molecular Docking, toxicity and ADMET analysis as potent pharmacological agents

Abstract

Worldwide, with the overuse of antibiotics and the lack of an effective forum for their development, bacteria have slowly developed resistance to the majority of the currently used antibiotics. Therefore, the advancement of innovative and effective anti-infective medications needs to control multidrug resistance pathogens. In such view, hybrid series of multicomponent pyridine-thiophene clubbed 2-amino pyrimidine derivatives (8a-j) were synthesized as attractive scaffolds to be investigated in vitro antimicrobial and antituercular activities. Several spectroscopic methods, including mass spectrometry, elemental analysis, ¹H NMR and FT-IR were used to confirm the molecular structure of 2-amino pyrimidine derivatives. Some of the synthesized target compounds 8a, 8d, 8e, 8f, 8g, 8h and 8j demonstrated excellent pharmacological profiles when compared to the reference medicines. Molecular modeling investigations revealed possible binding interactions between the most potent hybrid compound, 8i, and Mycobacterium tuberculosis catalase-peroxidase.  In-silico ADME, drug-likeness, and toxicology prediction of the compounds revealed good pharmacokinetic features, including high gastrointestinal absorption, orally bioavailability and low toxicity. The results of this investigation confirm the design compounds as promising lead candidates for the treatment of multidrug-resistant tuberculosis.