Design, synthesis, antibacterial evaluation, and computational studies of hybrid oxothiazolidin–1,2,4‐triazole scaffolds

Abstract

Bacterial infections are a serious threat to human health due to the development of resistance against the presently used antibiotics. The problem of growing and widespread antibiotic resistance is only getting worse with the shortage of new classes of antibiotics, creating a substantial unmet medical need in the treatment of serious bacterial infections. Therefore, in the present work, we report 18 novel hybrid thiazolidine–1,2,4‐triazole derivatives as DNA gyrase inhibitors. The derivatives were synthesized by multistep organic synthesis and characterized by spectroscopic methods (1H and 13C nuclear magnetic resonance and mass spectroscopy). The derivatives were tested for DNA gyrase inhibition, and the result emphasized that the synthesized derivatives have a tendency to inhibit the function of DNA gyrase. Furthermore, the compounds were also tested for antibacterial activity against three Gram‐positive (Bacillus subtilis [NCIM 2063], Bacillus cereus [NCIM 2156], Staphylococcus aureus [NCIM 2079]) and two Gram‐negative (Escherichia coli [NCIM 2065], Proteus vulgaris [NCIM 2027]) bacteria. The derivatives showed a significant‐to‐moderate antibacterial activity with noticeable antibiofilm efficacy. Quantitative structure–activity relationship (QSAR), ADME (absorption, distribution, metabolism, elimination) calculation, molecular docking, radial distribution function, and 2D fingerprinting were also performed to elucidate fundamental structural fragments essential for their bioactivity. These studies suggest that the derivatives 10b and 10n have lead antibacterial properties with significant DNA gyrase inhibitory efficacy, and they can serve as a starting scaffold for the further development of new broad‐spectrum antibacterial agents.

Organocatalytic Synthesis and DNA Interactive Studies of New 1,2,3‐triazolyl‐thiazolidines Hybrids

“…[37] Notably, Verma and colleagues reported the synthesis, antibacterial evaluation, and computational studies of hybrids containing both oxo-thiazolinine and 1,2,4-triazole units. [38] These derivatives were tested for DNA gyrase inhibition, with results indicating their potential to inhibit the function of DNA gyrase. In 2018, Lüdtke and co-workers described the preparation of L-proline-1,2,3-triazole hybrids as nontrivial fluorescent sensors in solution for enantioselective sensing of carbohydrates and their interaction with bovine serum albumin.…”

“…Examples include thiazole‐thiazolidinedione hybrids, [35] spiro‐thiazolidines, [36] and thiazolidinone Cu(II) and Fe(III) complexes designed to investigate interactions with DNA and serum albumins [37] . Notably, Verma and colleagues reported the synthesis, antibacterial evaluation, and computational studies of hybrids containing both oxo‐thiazolinine and 1,2,4‐triazole units [38] . These derivatives were tested for DNA gyrase inhibition, with results indicating their potential to inhibit the function of DNA gyrase.…”

Synthesis and biological evaluation of ruthenium complexes bearing the 1,2,4-triazole group as potential membrane-targeting antibacterial agents towards Staphylococcus aureus

“…[25][26][27] 1,2,4-Triazole is a promising scaffold with widespread use in the discovery of new drugs due to its remarkable physicochemical advantages in the design of physiologically active molecules capable of interacting with a wide range of biological components. [28][29][30][31] It has been reported that 1,2,4-triazoles are able to interfere with bacterial cell-wall synthesis, leading to the breakdown of infectious organisms, and have the capacity to overcome drug resistance, reduce toxicity and improve pharmacokinetic profiles. Complexes of gold and 1,2,4-triazole derivatives, as reported, have shown effective antimicrobial activity against Gram-positive bacteria.…”

Design, Synthesis, and Antifungal Activity of Novel 1,2,4-Triazolo[4,3-c]trifluoromethylpyrimidine Derivatives Bearing the Thioether Moiety

“…And there are also triazolopyrimidine fungicides ametoctradin. 1,2,4-Triazole derivatives have been extensively applied in antifungal ( Sun et al, 2021 ), antitumor ( Abdelrehim, 2021 ), antibacterial ( Pathak et al, 2021 ), antiviral ( Shao et al, 2021 ), herbicidal ( Yang et al, 2022 ), and insecticidal ( Fan et al, 2019 ) agents.…”