Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights

This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications

2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

In this study, different assortments of 2-arylquinolines and 2,6-diarylquinolines have been developed. Recently, we have developed a new series of 6,7-dimethoxy-4-alkoxy-2-arylquinolines as Topoisomerase I (TOP1) inhibitors with potent anticancer activity. Utilising the SAR outputs from this study, we tried to enhance anticancer and TOP1 inhibitory activities. Though target quinolines demonstrated potent antiproliferative effect, specifically against colorectal cancer DLD-1 and HCT-116, they showed weak TOP1 inhibition which may be attributable to their non-coplanarity. Thereafter, screening against kinase panel revealed their dual inhibitory activity against EGFR and FAK. Quinolines 6f, 6h, 6i, and 20f were the most potent EGFR inhibitors (IC50s = 25.39, 20.15, 22.36, and 24.81 nM, respectively). Meanwhile, quinolines 6f, 6h, 6i, 16d, and 20f exerted the best FAK inhibition (IC50s = 22.68, 14.25, 18.36, 17.36, and 15.36 nM, respectively). Finally, molecular modelling was employed to justify the promising EGFR/FAK inhibition. The study outcomes afforded the first reported quinolines with potent EGFR/FAK dual inhibition

Exploratory Assessment to Evaluate Seed Sprouting under Elevated CO2 Revealed Improved Biomass, Physiology, and Nutritional Value of Trachyspermum ammi

Elevated atmospheric CO2 (eCO2) can significantly enhance plant metabolism and improve their nutritional quality. Although several studies addressed the effect of eCO2 on plants, to our knowledge, there are no studies that have applied eCO2 to improve growth, chemical composition, and biological properties of ajwain (Trachyspermum ammi) during sprouting. Herein, eCO2 (620 µmol mol−1) was employed to enhance photosynthetic reactions. Improved photosynthesis induced primary and bioactive secondary metabolism, which led to improved biological activities of T. ammi sprouts in comparison with control sprouts and seeds. eCO2-treated sprouts showed significantly (p < 0.05) higher levels of most measured nutritional primary and secondary metabolites like soluble sugars, essential amino acids, organic acids, essential oils, phenolics, and flavonoids than control sprouts, which had significantly higher values than control seeds. eCO2 significantly improved the antimicrobial properties of T. ammi sprouts against 11 out of 13 microbial species than control sprouts, which had more potent antimicrobial activities than seeds. The significant increase in the antioxidant potential of treated sprouts was indicated by improved levels of ferric reducing antioxidant power (FRAP), DPPH, and oxygen radical absorbance capacity (ORAC). In addition, the anticancer activity against four different human tumor cell lines was significantly (p < 0.05) boosted by both sprouting and eCO2 exposure. Thus, the present study confirms the synergistic effect of sprouting with eCO2 exposure as promising approaches to produce ajwain sprouts with rich nutraceuticals, effective phytochemicals, and enhanced biological activities

Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII

In this work, different series of benzothiazole-based sulphonamides 8a-c, 10, 12, 16a-b and carboxylic acids 14a-c were developed as novel SLC-0111 analogues with the goal of generating potent carbonic anhydrase (CA) inhibitors. The adopted strategy involved replacing the 4-fluorophenyl tail in SLC-0111 with a benzothiazole motif that attached to the ureido linker to produce compounds 8c and its regioisomers 8a-b. In addition, the ureido spacer was elongated by methylene or ethylene groups to afford the counterparts 10 and 12. In turn, the primary sulfamoyl zinc binding group (ZBG) was either substituted or replaced by carboxylic acid functionality in order to provide the secondary sulphonamide-based SLC-0111 analogues 16a-b, and the carboxylic acid derivatives 14a-c, respectively. All compounds (8a-c, 10, 12, 14a-c and 16a-b) were tested for their ability to inhibit CA isoforms CA I, II, IX and XII. Additionally, the in vitro anticancer properties of the developed CAIs were evaluated.</p

Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and <i>in silico</i> insights

From Crossref journal articles via Jisc Publications RouterHistory: received 2023-05-24, revised 2023-06-23, accepted 2023-06-25, epub 2023-07-20, issued 2023-07-20, published 2023-07-20, ppub 2023-12-31Article version: VoRPublication status: PublishedFunder: King Saud University, Riyadh, Saudi Arabia; Grant(s): RSPD2023R74

Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and <i>in silico</i> insights

This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications.</p