Development of a Novel Series of Anticancer and Antidiabetic: Spirothiazolidines Analogs

Abstract

4-(4-Aminophenyl)-1-thia-4-azaspiro[4.5]decan-3-one 1 was prepared and allowed to react with nitrogen nucleophiles to give the corresponding hydrazones 2–4. Further, compound 1 underwent diazotization and afforded the parallel hydrazono derivative 5; moreover, compound 1 refluxed with active methylene derivatives yielded the corresponding aminospirothiazolo pyridine–carbonitrile derivative 6 and spirothiazolopyridinone–carbonitrile derivative 7. Condensation of spirothiazolidine 1 with 4-chlorobenzaldehyde gave the corresponding spiro arylidiene derivative 8, which was utilized as a component of Micheal addition to react with excess of nitrogen nucleophiles to yield novel ring frameworks 4-(3′-(4-chlorophenyl)–spiro [cyclohexane-1,5′-pyrazolo[3,4-d]thiazol]-6′(1′H)-yl)aniline (9) and 4-(3′-(4-chlorophenyl)-6′H- spiro[cyclohexane-1,5′-thiazolo[5,4-d]isoxazol]-6′-yl)aniline (10). Finally, when spirothiazolo pyridinone–carbonitrile derivative 7 sodium salt generated in situ was reacted with different alkyl halides, it produced the corresponding N-derivatives 12–16. Three compounds, 6, 14, and 16, showed high significantly anticancer activities compared with Doxorubicin® (positive control) against human breast carcinoma (MCF-7) and human liver carcinoma (HepG-2) cell lines. On the other hand, compounds 6 and 9 showed higher therapeutic indices for both of alpha-amylase inhibitor and alpha-glucosidase inhibitor than the other tested compounds compared with the antidiabetic Acarbose (positive control).

Contemporary progress in the green synthesis of spiro-thiazolidines and their medicinal significance: a review

“…M. El-Shahat and co-researchers 89 synthesized new spiro thiazolidene compounds and their fused analogues and tested them for anticancer and antidiabetic efficacy. Three compounds 5′-amino-3′-(4-aminophenyl)-7′-argio-3′ H -spiro[cyclohexane-1,2′-thiazolo[4,5- b ]pyridine]-6′-carbonitrile ( 92 ), 2-(3′-(4-aminophenyl)-7′-argio-6′-cyano-5′-oxo-3′,5′-dihydro-4′ H -spiro[cyclohexane-1,2′-thiazolo[4,5- b ]pyridin]-4′-yl)acetic acid ( 93 ), and ethyl 2-(3'-(4-aminophenyl)-7′-argio-6′-cyano-5′-oxo-3′,5′-dihydro-4′ H -spiro[cyclohexane-1,2′-thiazolo[4,5- b ]pyridin]-4′-yl)acetate ( 94 ), demonstrated considerable anticancer activity against human breast carcinoma (MCF-7) and human liver carcinoma (HepG-2) cell lines when compared to doxorubicin as positive control.…”

Novel fluorinated pyrazole-based heterocycles scaffold: cytotoxicity, in silico studies and molecular modelling targeting double mutant EGFR L858R/T790M as antiproliferative and apoptotic agents

“…It simplifies the absorption of fluorinated molecules into cell membranes, improving selectivity, effectiveness, and bioavailability [49]. The inclusion of the azo group has also been shown to improve the biological activity of heterocyclic compounds [50][51][52]. Developing novel analogs based on established inhibitors is a significant way of detecting new anticancer medications with great efficiency, as is using a pharmacophore hybridization approach for synthesizing new bioactive chemicals in modern medicinal chemistry.…”

Synthesis, In‐Vitro Evaluation and Molecular Docking Study of N‐Substituted Thiazolidinediones as α‐Glucosidase Inhibitors

“…These drugs do not act as insulin secretagogues and do not cause hypoglycemia. Furthermore, α‐glucosidase inhibitors are employed as anti‐hepatitis, [7] anti‐HIV, [8] and anti‐cancer drugs [9] . But because of their small influence on HbA1c, and the risk of serious gastrointestinal side effects, this class of antidiabetic medication isn′t extensively used [10] .…”