New phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamides as dual inhibitors against α-glucosidase and PTP-1B for the treatment of type 2 diabetes.

This study describes the design, synthesis, and evaluation of a novel series of phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamide derivatives (7a-l) as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1-B (PTB-1B). The latter enzymes are two important targets in the treatment of type 2 diabetes. The in vitro obtained data demonstrated that all title compounds 7a-l were more potent than the standard inhibitor acarbose against α-glucosidase while only four derivatives (7a, 7g, 7h, and 7h) were more potent than the standard inhibitor suramin against PTP-1B. Furthermore, these data showed that the most potent α-glucosidase inhibitor was compound 7i, with sixfold higher inhibitory activity than acarbose, and the most potent PTP-1B inhibitor was compound 7a with 3.5-fold higher inhibitory activity than suramin. Kinetic studies of compounds 7i and 7a revealed that they inhibited their target enzymes in a competitive mode. The docking study demonstrated that compounds 7i and 7a well occupied the active site pockets of α-glucosidase and PTP-1B, respectively. In silico pharmacokinetic and toxicity assays of the most potent compounds were performed, and the obtained results were compared with those of the standard inhibitors.

A potential therapeutic agent for the treatment of hyperuricemia and gout: 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide.

Uric acid, the metabolic product of purines, relies on xanthine oxidase (XOD) for production. XOD is a target for the development of drugs for hyperuricemia (HUA) and gout. Currently, treatment options remain limited for gout patients. 3, 4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a derivative of the natural product protocatechualdehyde with good biological activity. In this work, we identify a DHNB thiosemicarbazide class of compounds that targets XOD. 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazone can effectively inhibit XOD activity (IC50 value: 0.0437 µM) and exhibits a mixed inhibitory effect. In a mouse model of acute hyperuricemia, a moderate dose (10 mg/kg.w) of 3,4-dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide effectively controlled the serum uric acid content and significantly inhibited serum XOD activity. In addition, 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide showed favorable safety profiles, and mice treated with the target compound did not show any symptoms of general toxicity following a single dose of 500 mg/kg. In the allopurinol group, 50 % of the mice died. These results provide a structural framework and mechanism of XOD inhibition that may facilitate the design of hyperuricemia and gout treatments.

Thiazolation of phenylthiosemicarbazone to access new thiazoles: anticancer activity and molecular docking.

Aim: Novel thiazole hybrids were synthesized via thiazolation of 4-phenylthiosemicarbazone (4). Materials & methods: The anticancer activity against the NCI 60 cancer cell line panel. Results: Methyl 2-(2-((1-(naphthalen-2-yl)ethylidene)hydrazineylidene)-4-oxo-3-phenylthiazolidin-5-ylidene)acetate (6a) showed significant anticancer activity at 10 µM with a mean growth inhibition (GI) of 51.18%. It showed the highest cytotoxic activity against the ovarian cancer OVCAR-4 with an IC50 of 1.569 ± 0.06 µM. Compound 6a inhibited PI3Kα with IC50 = 0.225 ± 0.01 µM. Moreover, compound 6a revealed a decrease of Akt and mTOR phosphorylation in OVCAR-4 cells. In addition, antibacterial activity showed that compounds 11 and 12 were the most active against Staphylococcus aureus. Conclusion: Compound 6a is a promising molecule that could be a lead candidate for further studies.

Novel naphthalene-azine-thiazole hybrids 5-12 were synthesized via late-stage thiazolation of the corresponding 4-phenylthiosemicarbazone 4. Compound 6a showed significant anticancer activity at single-dose screening and yielded excellent inhibitory activity with a mean GI of 51.18%. Compound 6a showed the highest cytotoxic activity against OVCAR-4 with an IC₅₀ of 1.569 ± 0.06 µM. Moreover, compound 6a exhibited an IC₅₀ of 31.89 ± 1.19 µM against normal ovarian cell line (OCE1) and a selectivity index of 19.1. Compound 6a inhibited PI3Kα with IC₅₀ = 0.225 ± 0.01 µM compared with alpelisib (IC₅₀ = 0.061 ± 0.003 µM). Moreover, compound 6a revealed a powerful decrease of Akt and mTOR phosphorylation in the OVCAR-4 cell line. The cell cycle analysis showed that compound 6a caused an arrest at the G2/M phase. The compound also increased the total apoptosis by 26.8-fold and raised the level of caspase-3 by 4.34 times in OVCAR-4. In addition, antibacterial activity was estimated against Gram-positive and Gram-negative bacterial strains. Compounds 11 and 12 were the most active derivatives, with MIC value of 256 µg/ml against Staphylococcus aureus. Molecular docking was done and showed that 6a interlocked and fitted well into the ATP binding site of PI3Kα kinase (Protein Data Bank ID: 4JPS) with a fitness value (-119.153 kcal/mol) and forms the key H-bonds with Val851 and Ser854 like the marketed PI3Kα inhibitor alpelisib. Consequently, 6a is the most promising molecule that could be a lead candidate for further studies.