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Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis (Mtb). In the present study, we aimed to chemically tailor INH to overcome this resistance. We obtained thirteen novel compounds by linking INH to in-house synthesized sulfonate esters via a hydrazone bridge (SIH1–SIH13). Following structural characterization by FTIR, 1H NMR, 13C NMR, and HRMS, all compounds were screened for their antitubercular activity against Mtb H37Rv strain and INH-resistant clinical isolates carrying katG and inhA mutations. Additionally, the cytotoxic effects of SIH1–SIH13 were assessed on three different healthy host cell lines; HEK293, IMR-90, and BEAS-2B. Based on the obtained data, the synthesized compounds appeared as attractive antimycobacterial drug candidates with low cytotoxicity. Moreover, the stability of the hydrazone moiety in the chemical structure of the final compounds was confirmed by using UV/Vis spectroscopy in both aqueous medium and DMSO. Subsequently, the compounds were tested for their inhibitory activities against enoyl acyl carrier protein reductase (InhA), the primary target enzyme of INH. Although most of the synthesized compounds are hosted by the InhA binding pocket, SIH1–SIH13 do not primarily show their antitubercular activities by direct InhA inhibition. Finally, in silico determination of important physicochemical parameters of the molecules showed that SIH1–SIH13 adhered to Lipinski's rule of five. Overall, our study revealed a new strategy for modifying INH to cope with the emerging drug-resistant strains of Mtb. [ABSTRACT FROM AUTHOR]

The recent emergence of drug‐resistant strains of Mycobacterium tuberculosis (Mtb) has complicated and significantly slowed efforts to eradicate and/or reduce the worldwide incidence of life‐threatening acute and chronic cases of tuberculosis. To overcome this setback, researchers have increased the intensity of their work to identify new small‐molecule compounds that are expected to remain efficacious antimicrobials against Mtb. Here, we describe our effort to apply the principles of molecular hybridization to synthesize 16 compounds carrying thiophene and thiazole rings beside the core urea functionality (TTU1–TTU16). Following extensive structural characterization, the obtained compounds were initially evaluated for their antimycobacterial activity against Mtb H37Rv. Subsequently, three derivatives standing out with their anti‐Mtb activity profiles and low cytotoxicity (TTU5, TTU6, and TTU12) were tested on isoniazid‐resistant clinical isolates carrying katG and inhA mutations. Additionally, due to their pharmacophore similarities to the well‐known InhA inhibitors, the molecules were screened for their enoyl acyl carrier protein reductase (InhA) inhibitory potentials. Molecular docking studies were performed to support the experimental enzyme inhibition data. Finally, drug‐likeness of the selected compounds was established by theoretical calculations of physicochemical descriptors. [ABSTRACT FROM AUTHOR]

Sulfonamides represent the oldest synthetic antibacterial agents; however, their central position in controlling bacterial diseases has been seriously damaged by the development of widespread resistance. Herein, we revisited sulfathiazole, a commercial member of antibacterial sulfa drugs, intending to overcome sulfonamide resistance and identify new drug candidates through molecular modifications. We synthesized twelve sulfonamides (SA1–SA12) by replacing the amino group on the phenyl ring with various substituents and introducing a thiophene ring on the core scaffold of sulfathiazole. The obtained compounds and additionally two commercial sulfonamides, sulfathiazole and sulfadiazine, were extensively screened for their antimicrobial activities. The results indicated that new sulfonamides, unlike traditional ones, were selectively effective against various Staphylococcus aureus strains. Introducing a bulky lipophilic substituent at the para position of the phenyl ring significantly increased the antibacterial activities of the compounds against Staphylococcus aureus. The compounds demonstrating favourable selectivity indices were further evaluated for their membrane potential perturbation and DNA interaction properties. The obtained data showed that these are not supporting mechanisms for the antibacterial activities of the modified sulfathiazole derivatives. In order to rationalize the activity of the three most active compounds, SA7, SA11 and SA12, against S. aureus ATCC 25923, their binding hypotheses within the catalytic site of Staphylococcus aureus dihydropteroate synthase, the validated target enzyme of sulfonamides, were generated via molecular docking and further dissected using molecular dynamics simulations and dynamic 3D pharmacophores (dynophores). [ABSTRACT FROM AUTHOR]