Synthesis and Development of N-2,5-Dimethylphenylthioureido Acid Derivatives as Scaffolds for New Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive Pathogens

Abstract

The growing antimicrobial resistance to last-line antimicrobials among Gram-positive pathogens remains a major healthcare emergency worldwide. Therefore, the search for new small molecules targeting multidrug-resistant pathogens remains of great importance. In this paper, we report the synthesis and in vitro antimicrobial activity characterisation of novel thiazole derivatives using representative Gram-negative and Gram-positive strains, including tedizolid/linezolid-resistant S. aureus, as well as emerging fungal pathogens. The 4-substituted thiazoles 3h, and 3j with naphthoquinone-fused thiazole derivative 7 with excellent activity against methicillin and tedizolid/linezolid-resistant S. aureus. Moreover, compounds 3h, 3j and 7 showed favourable activity against vancomycin-resistant E. faecium. Compounds 9f and 14f showed broad-spectrum antifungal activity against drug-resistant Candida strains, while ester 8f showed good activity against Candida auris which was greater than fluconazole. Collectively, these data demonstrate that N-2,5-dimethylphenylthioureido acid derivatives could be further explored as novel scaffolds for the development of antimicrobial candidates targeting Gram-positive bacteria and drug-resistant pathogenic fungi.

Synthesis, Characterization and Antibacterial Assays of Novel N,N1‐Disubstituted 2,2′‐Dithiodianiline Derivatives

“…The 1 H NMR spectra of hydrazones 8 – 21 exhibited NH group singlets in the region of 11.25–11.88 ppm, and in addition CH=N singlets in the range of 7.76–8.41 ppm, which along with the increased intensity of the proton signals in the aromatic field of the spectrum approved the formed new structures (Figures S9–S22 in Supplementary Material). The presence of amide NH−CO bond caused the restricted rotation around it and at the same time determined the splitting of the proton resonances indicating that in DMSO‐d 6 solutions hydrazones exist as a mixture of Z/E conformers where usually the Z ‐form predominates [53–56] . The 1 H NMR spectra of the prepared hydrazones 8 – 21 displayed double sets of resonances of the CH=N and CO−NH groups protons with signal intensity ratio of 60 : 40.…”

“…The presence of amide NHÀ CO bond caused the restricted rotation around it and at the same time determined the splitting of the proton resonances indicating that in DMSO-d 6 solutions hydrazones exist as a mixture of Z/E conformers where usually the Z-form predominates. [53][54][55][56] The 1 H NMR spectra of the prepared hydrazones 8-21 displayed double sets of resonances of the CH=N and COÀ NH groups protons with signal intensity ratio of 60 : 40.…”

Synthesis and Biological Studies of New 2-Benzoxazolinone Derivatives as Antibacterial Agents

“…As for rotamers, they are formed by the restricted rotation of the amide CO-NH group. The Z conformer is a predominating one [42,50]. From the NMR spectra, hydrazones 8-23 exist as mixtures of E/Z rotamers in DMSO-d6 solutions.…”

“…Considering the above-documented therapeutic efficacy including the broad antimicrobial properties of benzoxazole derivatives and our previous successful studies in the synthesis and discovery of effective antimicrobial agents among azole-and hydrazonecontaining compounds [42][43][44][45] led us to the selection of this scaffold and its combinations with hydrazone and azole moieties in the molecules for our further studies. To achieve set goals, a new series of compounds with an integrated benzoxazolin-2-one scaffold were developed to discover the antibacterial potential against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Salmonella Enteritidis pathogens.…”