Discovery, synthesis and in combo studies of Schiff's bases as promising dipeptidyl peptidase-IV inhibitors.

Diabetes mellitus is a main global health apprehension. Macrovascular illnesses, neuropathy, retinopathy, and nephropathy are considered some of its severe hitches. Gliptins are a group of hypoglycemic agents that inhibit dipeptidyl peptidase-IV (DPP-IV) enzyme and support blood glucose-lowering effect of incretins. In the current research, synthesis, characterization, docking, and biological evaluation of fourteen Schiff's bases 5a-f and 9a-h were carried out. Compound 9f revealed the best in vitro anti-DPP-IV activity of 35.7% inhibition at a concentration of 100 µM. Compounds 9c and 9f with the highest in vitro DPP-IV inhibition were subjected to the in vivo glucose-lowering test using vildagliptin as a positive inhibitor. Vildagliptin, 9c, and 9f showed significant reduction in the blood glucose levels of the treated mice after 30 min of glucose administration. Moreover, induced fit docking showed that these derivatives accommodated the enzyme binding site with comparable docking scores. Schiff's bases can serve as promising lead for the development of new DPP-IV inhibitors.

Alterations in the gene expression of drug and arachidonic acid-metabolizing Cyp450 in the livers of controlled and uncontrolled insulin-dependent diabetic mice.

BACKGROUND: Diabetic patients have lower capacity to metabolize drugs in comparison to normal people. Therefore, the present study aimed to investigate the alterations in gene expression of drug and arachidonic acid metabolizing cytochrome p450s (cyp450s) in the livers of controlled (CDM) and uncontrolled (UDM) insulin-dependent diabetic mice. METHODS: Balb/c mice were treated with single dose of streptozocin (240 mg/kg) to induce diabetes and compared with control group, which was treated with citric buffer (pH =4.5). After 3 days, the blood glucose level was measured to confirm the induction of diabetes. Normalization of blood glucose level in diabetic mice was achieved after 0.1 mL/kg Mixtard® insulin therapy for more 5 days. Then, the mice livers were isolated to extract RNA and convert it to cDNA. The gene expression of 14 genes, which play a major role in drug and arachidonic acid metabolism, were measured using quantitative real-time polymerase chain reaction technique. RESULTS: It was found that the gene expression was downregulated (ANOVA test, P-value <0.05) in the livers of UDM mice. The most downregulated genes were cyp4a12, cyp1a2, and slc22a1 with more than 10-fold reduction. The livers of CDM mice showed significantly (P-value <0.05) higher levels of mRNA than UDM mice, but still lower than the non-diabetic mice. CONCLUSION: This study concluded that hepatic gene expression of drug metabolizing and arachidonic acid- cyp450 enzymes is reduced in insulin-dependent diabetic mice, which can explain, at least in part, the variation in drug and fatty acid metabolism between normal and diabetic patients.

N-(3-Benzoylphenyl)-1H-Indole-2-Carboxamide decreases triglyceride levels by downregulation of Apoc3 gene expression in acute hyperlipidemic rat model.

Hyperlipidemia is a known cause of coronary vascular diseases, which is a major cause of death in many parts of the world. Targeting several pathways that lead to increase in lipid profiles is of great potential to control diseases. 1H-indole-2-carboxamide derivatives were tested for their hypolipidemic activity at the molecular level in comparison with bezafibrate. The gene expression profiles of lipoprotein signaling and cholesterol metabolism and fatty acid metabolism PCR arrays were determined in rats with acute hyperlipidemia induced by Triton WR1339. Lipid profiles of serum from treated rats showed significant hypolipidemic effect by the compounds. Several genes of potential interest were reported to be overexpressed by Triton WR1339 including Apoc3, Apob, Hmgcs2, Apoa1, Apoe, Apof, acsl1, and Decr1. Most of the overexpressed genes were downregulated by N-(3-Benzoylphenyl)-1H-Indole-2-Carboxamide with significant decreases in Apoc3, Apob, Acaa2, Acsl1, and Slc247a5 gene expression levels. N-(4-Benzoylphenyl)-1H-Indole-2-Carboxamide and bezafibrate did not significantly affect the gene expression levels which were increased with acute hyperlipidemia induced by Triton WR1339. In conclusion, gene expression profiling identified the possible mechanism in which Triton WR1339 induces its acute hyperlipidemic effect which was reversed by the use of N-(3-Benzoylphenyl)-1H-Indole-2-Carboxamide.