Quinazolin-4-one derivatives lacking toxicity-producing attributes as glucokinase activators: design, synthesis, molecular docking, and <i>in-silico</i> ADMET prediction

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dc.contributor.authorKhadse, Saurabh C.
dc.contributor.authorAmnerkar, Nikhil D.
dc.contributor.authorDave, Manasi U.
dc.contributor.authorLokwani, Deepak K.
dc.contributor.authorPatil, Ravindra R.
dc.contributor.authorUgale, Vinod G.
dc.contributor.authorCharbe, Nitin B.
dc.contributor.authorChatpalliwar, Vivekanand A.
dc.date.accessioned2025-01-23T19:58:08Z
dc.date.available2025-01-23T19:58:08Z
dc.date.issued2019
dc.description.abstractBackground A small library of quinazolin-4-one clubbed thiazole acetates/acetamides lacking toxicity-producing functionalities was designed, synthesized, and evaluated for antidiabetic potential as glucokinase activators (GKA). Molecular docking studies were done in the allosteric site of the human glucokinase (PDB ID: 1V4S) enzyme to assess the binding mode and interactions of synthesized hits for best-fit conformations. All the compounds were evaluated by in vitro enzymatic assay for GK activation. Results Data showed that compounds 3 (EC50 = 632 nM) and 4 (EC50 = 516 nM) showed maximum GK activation compared to the standards RO-281675 and piragliatin. Based on the results of the in vitro enzyme assay, docking studies, and substitution pattern, selected compounds were tested for their glucose-lowering effect in vivo by oral glucose tolerance test (OGTT) in normal rats. Compounds 3 (133 mg/dL) and 4 (135 mg/dL) exhibited prominent activity by lowering the glucose level to almost normal, eliciting the results in parallel to enzyme assay and docking studies. Binding free energy, hydrogen bonding, and pi-pi interactions of most active quinazolin-4-one derivatives 3 and 4 with key amino acid residues of the 1V4S enzyme were studied precisely. Preliminary in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was carried out using SwissADME and PreADMET online software which revealed that all the compounds have the potential to become orally active antidiabetic agents as they obeyed Lipinski's rule of five. Conclusion The results revealed that the designed lead could be significant for the strategic design of safe, effective, and orally bioavailable quinazolinone derivatives as glucokinase activators.
dc.fuente.origenWOS
dc.identifier.doi10.1186/s43094-019-0012-y
dc.identifier.eissn2314-7253
dc.identifier.issn2314-7245
dc.identifier.urihttps://doi.org/10.1186/s43094-019-0012-y
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/100755
dc.identifier.wosidWOS:000514648500001
dc.issue.numero1
dc.language.isoen
dc.revistaFuture journal of pharmaceutical sciences
dc.rightsacceso restringido
dc.subjectGlucokinase activator
dc.subjectGlucokinase
dc.subjectQuinazolinones
dc.subjectDocking
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleQuinazolin-4-one derivatives lacking toxicity-producing attributes as glucokinase activators: design, synthesis, molecular docking, and <i>in-silico</i> ADMET prediction
dc.typeartículo
dc.volumen5
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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