Computer-aided design, synthesis, and characterization of molecular hybrids of dihydropyrazoles, aminopyrimidines, and thiazolidin-4-ones as potential inhibitors of the penicillin-binding protein 3 (PBP-3) of Escherichia coli

Abstract

A computer-assisted approach was used to model and study privileged heterocyclic scaffolds containing dihydropyrazole, pyrimidin-2-amine, and thiazolidin-4-one moieties (hybrid pharmacophores) to obtain novel and promising antimicrobial prototype molecules. Main bioavailability descriptors were determined in order to assess the drug-likeness of the designed compounds and to pre-filter eleven compounds exhibiting the best profiles, thus passing to molecular docking study against a key penicillin-binding protein type-3 from enterotoxygenic E. coli. Seven structures were chosen by theirenergies of affinity and docking interactions with key residues in the active site of the receptor. Seven compounds with the highest docking scores belonging to the series of chalcones, dihydropyrazoles, aminopyrimidines, and thiazolidin-4-ones were prepared via condensation or cyclocondensation reactions. The structural elucidation of the final products was carried out by infrared spectra analysis and NMR experiments. Such molecular hybrids considered as potential hits in the search for new antibacterial compounds will be tested in vitro in further studies.

A Comparative Study of Microwave-Assisted and Conventional Heating Approaches for the Multicomponent Synthesis of 4,6-Diarylpyrimidines

“…Pyrimidine derivatives have played a key role in the development of heterocyclic chemistry and organic and medical chemistry, due to their unique properties and pervasive occurrence in biological structures, for instance in the nitrogenous bases constituting nucleosides and nucleotides in DNA and RNA molecules [1]. Moreover the well-studied role of this heterocyclic core as antiviral [1,2,3], anthelmintic [4], analgesic [5], and anti-depressor (e.g., barbituric acid) [6,7,8], among others [9,10,11] has led to its classification as a central scaffold in therapeutic research [12]. Additionally, pyrimidine derivatives possess broad optoelectronic properties, such as high electron conjugation (especially in aryl-substituted examples), low band gaps, and good electron transmission capacity, which can lead to future developments in the field of materials chemistry [13].…”