Heterocyclic Compounds as Dipeptidyl Peptidase-IV Inhibitors with Special Emphasis on Oxadiazoles as Potent Anti-Diabetic Agents (original) (raw)
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Overview of Oxadiazole-Containing Compounds as Potential Antidiabetic Agents
International journal of health sciences
1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives are amongst the family of heterocycles which showed many promising pharmaceutical applications.Extensive literature survey of 1,3,4-oxadiazole scaffold revealed the activities such as antimicrobial, anti-inflammatory, anti-tubercular, anti-oxidant, anti-cancer, anti-convulsant, anti-diabetic and analgesic properties. 1,2,4-oxadiazole, have shown activity against a variety of diseases like Alzheimer's, parasitic worms (helminths) and other internal parasites, edema, infectious diseases, diabetes, pain and cramp, cardiovascular disease, HIV, tuberculosis, antioxidant, cancer, seizure disorders, and arthritis.As oxadiazoles exhibited many different types of pharmacological activities, we reviewed its pharmacological activities reported by different researchers in the field.In present article we reviewed different articles which has been published in English literature. The search engine used to search for the articles were Scopus, G...
Asian Journal of Pharmaceutical and Clinical Research, 2021
Objective: The study contemplates in silico modeling, synthesis and in-vitro anti-diabetic evaluation of benzothiazole substituted oxadiazole derivatives. [{5-[(1, 3-benzothiazol-2-ylsulfanyl) methyl]-1, 3, 4-oxadiazol-2-yl} sulfanyl) methyl] derivatives were synthesized by a conventional method. Methods: All the newly synthesized derivatives were characterized by determining their melting point, retention factor from thin-layer chromatography, and spectral methods (Infrared, 1 H NMR spectroscopy, 13 C NMR spectroscopy, Mass spectroscopy) and evaluated for their anti-diabetic activity. Results: [{5-[(1, 3-benzothiazol-2-ylsulfanyl) methyl]-1, 3, 4-oxadiazol-2-yl} sulfanyl) methyl] derivatives have been made and characterized using physical and spectral methods. The in-vitro anti-diabetic screening study revealed that BZT1 and BZT4 exhibited high inhibition against glucose uptake assay and alpha-amylase enzyme. But only the derivative BZT4 showed inhibition against alpha-glucosidase enzyme. Conclusion: Various benzothiazole substituted oxadiazole derivatives were synthesized, characterized by spectral studies. The anti-diabetic studies revealed that the synthesized derivatives have significant anti-diabetic properties and further structure-activity relationship studies may develop more potent and less toxic molecules.
Bioorganic chemistry, 2018
A series of new benzothiazole-1,3,4-oxadiazole-4-thiazolidinone hybrid analogs (Tz1-Tz28) were synthesized in search of potential anti-diabetic agents. Molecular docking study was conducted with binding pocket of peroxisome proliferator activated receptor-gamma to elucidate the binding interactions of newly synthesized targets. Seven selected compounds with best docking scores were further screened for in vivo anti-hyperglycemic efficacy by oral glucose tolerance test in non-diabetic rats and on streptozotocin induced diabetic rat models. All the tested compounds demonstrated excellent to moderate reduction in blood glucose levels. Three of the compounds (Tz21, Tz7 and Tz10) showed excellent anti-diabetic effect by reducing concentration of glucose to 157.15 ± 1.79 mg/dL, 154.39 ± 1.71 mg/dL, 167.36 ± 2.45 mg/dL, respectively better than the standard drug, pioglitazone, 178.32 ± 1.88 mg/dL. Moreover, three derivatives Tz21, Tz4 and Tz24 with IC50 values of 0.21 ± 0.01 µM, 9.03 ± 0.1...
Bioorganic chemistry, 2018
A small library of new benzothiazole clubbed oxadiazole-Mannich bases (M-1 to M-22) were synthesized and characterized by IR, NMR, Mass and Elemental analysis results. Molecular docking studies were done to assess the binding mode and interactions of synthesized hits at binding site of receptor Peroxisome proliferator-activated receptor, PPAR-γ or PPARG (PDB 1FM9). Among the synthesized compounds, nine compounds were selected on the basis of docking score and evaluated for their in vivo anti-diabetic activity using Oral Glucose Tolerance Test (OGTT) in normal rats followed by Streptozotocin (STZ) - induced diabetes. Results indicated that compound M-14 (161.39 ± 4.38) showed the highest reduction of blood glucose level comparable to that of the standard drug glibenclamide (140.29 ± 1.24) in STZ model. Other compounds exhibited moderate to good anti hyperglycaemic activity. ADME studies was done using Molinspiration online software, revealed that all compounds (except M-11) are likel...
PLOS ONE, 2016
Dipeptidyl peptidase IV (DPP-4) enzyme is responsible for the degradation of incretins that stimulates insulin secretion and hence inhibition of DPP-4 becomes an established approach for the treatment of type 2 diabetics. We studied the interaction between DPP-4 and its inhibitor drugs (sitagliptin 1, linagliptin 2, alogliptin 3, and teneligliptin 4) quantitatively by using fragment molecular orbital calculations at the RI-MP2/cc-pVDZ level to analyze the inhibitory activities of the drugs. Apart from having common interactions with key residues, inhibitors encompassing the DPP-4 active site extensively interact widely with the hydrophobic pocket by their hydrophobic inhibitor moieties. The cumulative hydrophobic interaction becomes stronger for these inhibitors and hence linagliptin and teneligliptin have larger interaction energies, and consequently higher inhibitory activities, than their alogliptin and sitagliptin counterparts. Though effective interaction for both 2 and 3 is at S 0 2 subsite, 2 has a stronger binding to this subsite interacting with Trp629 and Tyr547 than 3 does. The presence of triazolopiperazine and piperazine moiety in 1 and 4, respectively, provides the interaction to the S 2 extensive subsite; however, the latter's superior inhibitory activity is not only due to a relatively tighter binding to the S 2 extensive subsite, but also due to the interactions to the S 1 subsite. The calculated hydrophobic interfragment interaction energies correlate well with the experimental binding affinities (K D) and inhibitory activities (IC 50) of the DPP-4 inhibitors.
Navigating the chemical space of dipeptidyl peptidase-4 inhibitors
Drug Design, Development and Therapy, 2015
Drug Design, Development and Therapy Dovepress submit your manuscript | www.dovepress.com Dovepress 4515 O r i g i n a l r e s e a r c h open access to scientific and medical research Open access Full Text article http://dx.
Objective: Druggability of a target protein depends on the interacting micro-environment between the target protein and drugs. Therefore, a precise knowledge of the interacting micro-environment between the target protein and drugs is requisite for drug discovery process. To understand such micro-environment, we performed in silico interaction analysis between a human target protein, Dipeptidyl Peptidase-IV (DPP-4), and three anti-diabetic drugs (saxagliptin, linagliptin and vildagliptin). Materials and Methods: During the theoretical and bioinformatics analysis of micro-environmental properties, we performed drug-likeness study, protein active site predictions, docking analysis and residual interactions with the protein-drug interface. Micro-environmental landscape properties were evaluated through various parameters such as binding energy, intermolecular energy, electrostatic energy, van der Waals'+H-bond+desolvo energy (E VHD) and ligand efficiency (LE) using different in silico methods. For this study, we have used several servers and software, such as Molsoft prediction server, CASTp server, AutoDock software and LIGPLOT server. Results: Through micro-environmental study, highest log P value was observed for lina-gliptin (1.07). Lowest binding energy was also observed for linagliptin with DPP-4 in the binding plot. We also identified the number of H-bonds and residues involved in the hydro-phobic interactions between the DPP-4 and the anti-diabetic drugs. During interaction, two H-bonds and nine residues, two H-bonds and eleven residues as well as four H-bonds and nine residues were found between the saxagliptin, linagliptin as well as vildagliptin cases and DPP-4, respectively. Conclusion: Our in silico data obtained for drug-target interactions and micro-environmental signature demonstrates linagliptin as the most stable interacting drug among the tested anti-diabetic medicines.