Aim: To synthesize a series of new thiazolidinone–pyrazole hybrids (5a–o) and assess their anticancer (in vitro and in vivo) and antimicrobial activities. Results: The compounds 5h (against Ehrlich ascites carcinoma cells), 5e and 5i (against the human breast cancer [MDA-MB231] cell line) exhibited potent anticancer activity. All the compounds except 5g and 5e found to be less toxic for the human dermal fibroblast cells. The effective interactions of the compounds in silico with MDM2 exemplified their inhibitory potency. The derivatives also showed moderate antimicrobial activity. Conclusion: The halogen atoms on various positions of the N-arylamino ring played an advantageous role in elevating the potency of the molecules. Thus, these conjugates could be used as a lead for further optimization to achieve promising therapeutics. Graphical abstract

Hepatocellular carcinoma (HCC) is the leading cause of cancer death worldwide that lacks proper medical prognosis and treatment. In the present study, the anti-tumoral potential of troxerutin (TX), an ethnomedicine, was examined in relation to its effects on the promoter 2-acetylaminofluorene (2-AAF) in N-nitrosodiethylamine (NDEA) initiated HCC, as compared to its effects on HCC induced by NDEA alone. Liver samples from each experimental group were collected and evaluated for histological, biochemical and cellular characterization. The protein expressions of apoptotic and cell proliferation markers were determined via immunohistochemistry and western blotting. Molecular docking was also performed to delineate the inhibitory mechanism of TX on HCC. The results show that only higher doses of TX showed a significant reduction in the incidence of hepatic nodule formation, and they also counteracted NDEA plus 2-AAF induced alterations in the enzymic status. The frequencies of glutathione-S-transferase and proliferating cell nuclear antigen, markers of S phase progression, were markedly reduced during TX treatment. TX also modulated the imbalance in the MDM2–p53 interaction. The molecular docking results confirmed the interaction of TX with the upstream kinases that regulate apoptosis. This study provides evidence that a copious dose of TX is required to counteract the differential mitoinhibitory effect of 2-AAF in NDEA initiated hepatomas, and TX exhibits an anti-tumoral effect via suppressing oxidative stress, regulating liver function enzymes, inhibiting inflammatory responses and modulating MDM2–p53 interactions, thus inducing apoptosis, and thereby suggesting that TX may provide promising therapeutic effects for the chemoprevention of HCC.

A novel series of thiazinone derivatives were obtained from unexpected cyclization of dimethyl acetylenedicarboxylate (DMAD) and diethyl acetylenedicarboxylate (DEAD) with corresponding 3-alkyl-2,6-diarylpiperidin-4-one thiosemicarbazones in dry methanol without catalyst under mild conditions. The structures of newly synthesized compounds were established on the basis of FT-IR, HR-Mass, ¹H-NMR, ¹³C-NMR, ¹H-¹H COSY, ¹H-¹³C COSY, DEPT-135, and HMBC spectral techniques. From ¹H NMR, all newly synthesized compounds 17–24 were found to adopt chair conformation. The theoretical studies were carried out using Schrödinger software suite for the structure prediction, biochemical properties investigation and docking studies of all novel compounds. To study the antitumor activity, all the novel compounds were screened in vitro for their cytotoxicity and apoptosis activity against Hep G2 human liver cancer cell line. The biological analysis revealed that the newly synthesized compounds have good/moderate inhibitory activity against the tested cell line.