Design, Synthesis, in Vitro, and in Silico Evaluations of 1,3,4‐Oxadiazole Derivatives Linked to the Pyrrolo[2,3‐d]pyrimidine Moieties as Potent Antimicrobial Targets

Abstract

Abstract1,3,4‐Oxadiazole and its derivatives are well known assorted motif in drug design and development. The development of bacterial infection drug resistance serves as justification for the discovery of novel antimicrobial drugs. Thus, a novel series of 1,3,4‐oxadiazole derivatives linked to pyrrolo[2,3‐d]pyrimidine 6 a–f and 7 a–e was designed, synthesized and fully characterized by 1H‐NMR, 13C‐NMR, FT‐IR and mass spectroscopic analysis. All of the compounds′ in‐vitro antibacterial and antifungal activities were reported, and final oxadiazoles 6 d, 6 e, 6 f, and 7 e showed excellent antimicrobial inhibitory activity as compared to standard drugs. The compounds 6 f and 7 a exhibited potent antifungal activity as a potent inhibitor against C. albicans with MICs 4.0±0.03, 7.5±0.02 μg/mL respectively. In order to determine the different binding interactions that the most active oxadiazoles had with the Staphylococcus aureus DHFR enzyme, a docking study was conducted. The results indicated that the residues of amino acid Thr96(X), Leu62(X), Arg44(X), Asn18(X), Glu17(X), Lys45(X), Thr121(X), Gln95(X), Asp120(X), Ser64(X), Gly94(X), and Phe16(X) had promising energy value, within the range of −6.84 to −9.63 kcal/mol (PDB: 3FRA). The most effective inhibitors, 6 and 7, also underwent in silico ADMET tests to predict their pharmacokinetic and physicochemical characteristics.