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Antimicrobial resistance is a serious challenge to modern medicine. Besides imposing high financial burden, multidrug resistant infections are directly responsible for high morbidity and mortality. Even though a number of antibiotics are currently available to treat infections caused by ESKAPE organisms, more and more bacterial strains are becoming resistant to these drugs. Prevailing circumstances pose an urgent unmet need for the development of newer antimicrobials to treat the infections caused by MDR organisms. Rhodanine and structurally related 5‐membered heterocycles possess wide range of pharmacological activities. A number of these derivatives have shown good to potent inhibition against various microorganisms. They are reported to alter the function of DNA gyrase B, metallo‐β‐lactamases, penicillin binding protein (PBP), Mur ligases, RNA polymerase, Enoyl ACP reductases, 1‐deoxy‐d‐xylulose‐5‐phosphate reductoisomerase. etc which are vital in bacterial growth, survival and replication. In this study, we have generated a library of Rhodanine and related 5 membered heterocyclic derivatives and screened them against a panel of pathogens. Among all the compounds, 2a–i, 3a–b, 3g, 4, 6b–c, 6e, 6g, 12a–b and 14b–c have demonstrated good to moderate inhibition against S. aureus (MIC 0.125–8 μg/mL). Further, compound 17b demonstrated moderate activity against A. baumannii (MIC 8 μg/mL). In addition, compounds 2a, 2e, 4, 6c, 6g and 14b have shown good to mild inhibition against MDR S. aureus including VRSA (MIC 0.5–16 μg/mL) with good selectivity index 20–1600. In addition, compound 2e inhibited the growth gradually after 6 h in time kill kinetic studies and not antagonized with the tested FDA approved drugs.

A series of 1,2,3‐triazole derivatives based on the quinoline–benzimidazole hybrid scaffold was designed, synthesized, and screened against a panel of NCI‐60 humanoid cancer cell lines for in vitro cytotoxicity evaluation, which revealed that compound Q6 was the most potent cytotoxic agent with excellent GI50, TGI, and LC50 values on multiple cancer cell lines. Q6 was tested further on the BT‐474 breast cancer line to evaluate the mechanism of action. Preliminary screening studies based on the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay revealed that compound Q6 had an excellent antiproliferative effect against human breast cancer cells, BT‐474, with IC50 values of 0.59 ± 0.01 μM. The detailed study based on the acridine orange/ethidium bromide staining (AO/EB) and the 4′,6‐diamidino‐2‐phenylindole (DAPI) assay suggested that the antiproliferative activity shown was due to the induction of apoptosis on exposure to Q6. Further, DCFDA staining showed the generation of reactive oxygen species, altering the mitochondrial potential and leading to the initiation of apoptosis. This was further supported by JC‐1 staining, indicating that this scaffold can contribute to the development of more potent derivatives.

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In pursuit of potent anti‐TB agents active against drug resistant tuberculosis (DR‐TB), herein we report synthesis and bio‐evaluation of a new series of isoxazole‐carboxylic acid methyl ester based 2‐substituted quinoline derivatives. Preliminary evaluation indicated selectivity towards Mtb H37Rv, with no inhibition of non‐tubercular mycobacterial (NTM) & bacterial pathogen panel. Out of 36 synthesized compounds, majority exhibited substantial inhibition of Mtb H37Rv (MIC 0.5–8 μg/mL). Cell viability test against Vero cells revealed no significant cytotoxicity. Further, screening against drug resistant strains (DR‐Mtb) found hit compound displaying promising potency (MIC 1–4 μg/mL). Structure optimization of the hit led to the identification of lead compound demonstrating potent inhibition of both drug‐susceptible Mtb (MIC 0.12 μg/mL) and drug‐resistant Mtb (MIC 0.25–0.5 μg/mL) along with a high selectivity index (SI) >80. Taken together, with appreciable selectivity and potent activity, these chemotypes show prospect to be turned into a potential anti‐TB candidate.

In our continued efforts to find potential chemotherapeutics active against drug-resistant (DR) Mycobacterium tuberculosis (Mtb), causative agent of Tuberculosis (TB) and to curb the current burdensome treatment regimen, herein we describe the synthesis and biological evaluation of urea and thiourea variants of 5-phenyl-3-isoxazolecarboxylic acid methyl esters as promising anti-TB agent. Majority of the tested compounds displayed potent in vitro activity not only against drug-susceptible (DS) Mtb H37Rv but also against drug-resistant (DR) Mtb. Cell viability test against Vero cells deemed these compounds devoid of significant toxicity. 3,4-Dichlorophenyl derivative (MIC 0.25 µg/mL) and 4-chlorophenyl congener (MIC 1 µg/mL) among urea and thiourea libraries respectively exhibited optimum potency. Lead optimization resulted in the identification of 1,4-linked analogue of 3,4-dichlorophenyl urea derivative demonstrating improved selectivity. Further, in silico study complemented with previously proposed prodrug like attributes of isoxazole esters. Taken together, this molecular hybridization approach presents a new chemotype having potential to be translated into an alternate anti-Mtb agent. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10543-0.

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