RATIONAL DESIGN, SYNTHESIS AND CHARACTERIZATION OF HYBRID MOLECULES WITH PYRAZOLINE, PYRIMIDINE AND THIAZOLIDINE NUCLEI AS POTENTIAL ANTIBACTERIAL AGENTS

Abstract

In this paper, a set of computational tools were used to design and evaluate molecular structures resulting from the combination of the biologically interesting pyrazoline, aminopyrimidine and thiazolidine nuclei (molecular modification) to obtain new bioactive compounds. Key physicochemical properties were calculated (absorption, distribution, metabolism, excretion and toxicity), to determine the bioavailability of the designed compounds and to perform a preselection of 12 derivatives which were then optimized and studied by molecular docking with the receptor PBP3 (4bjp) from Escherichia coli. By these studies, 8 compounds were selected by their binding energies (from -5,36KJ/mol to – 7,05KJ/mol) and significant interactions with the amino acids of the receptor in its active site. In general, the synthesis of the selected compounds was carried out from the α,β-unsaturated carbonyl compounds as precursors. The dihydropyrazole derivatives were obtained from the reaction of chalcones with one equivalent of hydrazine derivatives by one-step cyclocondensations. The pyrimidine series were synthesized starting by the reaction of chalcones and guanidine, giving rise to the corresponding amonopyrimidines, which were then reacted with aromatic and heteroaromatic aldehydes to obtain the acyclic azomethine compounds. The thiazolidine-4-ones were obtained from the aminopyrimidines synthesized above, using three-component cyclocondensation reactions with 2-mercaptoacetic acid and benzaldehyde, in anhydrous toluene or benzene as solvents and using conditions of reflux with Dean- Stark. Finally, assays were carried out aiming to the formation of β-lactam rings, using the Staudinger-type cycloaddition reaction of 2-chloroacetyl chloride with cyclic imines. All the obtained compounds were fully characterized by IR spectroscopy, as well as mono- and bidimensional NMR techniques. The most promising compounds will be evaluated by in vitro assays as potential antibacterial agents.