In this study, two different classes of push–pull chromophores were synthesized in modest to excellent yields by formal [2+2] cycloaddition-retroelectrocyclization (CA-RE) reactions. N-Methyl indole was introduced as a new donor group to activate alkynes in the CA-RE transformations. Depending on the side groups’ size and donor/acceptor characteristics, N-methyl indole-containing compounds exhibited λ_max values ranging between 378 and 658 nm. The optoelectronic properties of the reported D–A-type structures were studied by UV/vis spectroscopy and computational studies. The complete regioselectivity observed in the products was elaborated by one-dimensional (1D) and two-dimensional (2D) NMR studies, and the electron donor strength order of N-alkyl indole and triazene donor groups was also established. The intramolecular charge-transfer characteristics of the target push–pull chromophores were investigated by frontier orbital depictions, electrostatic potential maps, and time-dependent density functional theory calculations. Overall, the computational and experimental results match each other. Integrating a new donor group, N-alkyl indole, into the substrates used in formal [2+2] cycloaddition-retroelectrocyclizations has significant potential to overcome the limited donor-substituted substrate scope problem of CA-RE reactions.

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.