Multicomponent synthesis, DFT calculations and molecular docking studies of novel thiazolyl-pyridazinones as potential antimicrobial agents against antibiotic-resistant bacteria

Abstract

Novel series of aryl(hetaryl)thiazolylpyridazinedione derivatives were synthesized via one-pot three-component synthesis of maleic anhydride, thiosemicarbazide and the appropriate α-bromoketones using cellulose sulfuric acid (CSA) as an eco-friendly catalyst under microwave irradiation (MWI) in high, efficient yields and short reaction time and the achieved results showed the tremendous synergistic effect between CSA and MWI. All the prepared compounds were fully characterized by spectral methods (IR, Mass, 1H NMR and 13C NMR) and an alternate method. Moreover, in-vitro biological activities of the obtained candidate molecules as antibacterial and/or antifungal agents were investigated against S. aureus, MRSA and C. albicans, and the results were compared with those of standard compounds. The results showed that compound 19 has an excellent antibacterial (S. aureus, MIC: 0.12 μg/mL) and antifungal (C. albicans, MIC: 3.90 μg/mL) activities. In addition, compound 5c demonstrated the highest antibacterial activity against P. aeruginosa (MIC: 0.12 μg/mL). The molecular structures, reactivity and electronic properties of candidate compounds demonstrating the best promising antimicrobial activities were studied at the B3LYP/6–311 G level of theory and their quantum mechanical parameters were computed. The energy gaps of all of the selected compounds were found to range between 3.1 and 3.6 eV. Furthermore, molecular docking with the most common protein receptors of the microorganisms of interest (SAP2 and FabI) was performed.