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

Abstract

Background: 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 (EC 50 = 632 nM) and 4 (EC 50 = 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 π-π 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.

Molecular docking analysis and anti-hyperglycaemic activity of Synacinn™ in streptozotocin-induced rats

“…Hydrophobic contact residues were observed in the interactions of quinazoline-4-one derivatives with glucokinase activators. 38 These interactions t well in the binding pocket of 14VS. The docked conformation of rosmarinic acid (Fig.…”

Insights into the Origin and Therapeutic Implications of Benzopyran and Its Derivatives

“…The first ChemistrySelect clinically developed drugs were neuraminidase inhibitor drugs and laninamivir (41) structure is similar to zanamivir and its pro-drug is laninamivir octanoate. [111][112] Pyran-skeleton containing drugs are commercially available for clinical trials. The 4H-pyranonaphtoquinone's moiety structure is an analogous structure of some naturally occurring anticancer potential compounds.…”

“…Zanamivir ( 40 ) was approved for the treatment of influenza A and B. The first clinically developed drugs were neuraminidase inhibitor drugs and laninamivir ( 41 ) structure is similar to zanamivir and its pro‐drug is laninamivir octanoate [111–112] . Pyran‐ skeleton containing drugs are commercially available for clinical trials.…”

A multicentre, randomized, double‐blind, parallel, active‐ and placebo‐controlled Phase 3 clinical study of the glucokinase activator PB‐201 in treatment‐naive patients with type 2 diabetes mellitus: A study protocol

“…GK activators (GKAs) manage the balance between appearance and breakdown of glucose by favouring glucose breakdown, which results in lowering of glucose levels to values in the hypoglycaemic range. GKAs function by increasing glucose‐stimulated insulin secretion and hepatic glucose uptake in response to glycaemic levels and by reducing hepatic glucose output, thus maintaining glucose homeostasis 5,9,10 . Hepatoselective GKAs have been developed that act with or without disrupting the GK‐glucokinase regulatory protein interaction in hepatic cells, as opposed to systemic GKAs (such as piragliatin or dorzagliatin) 11,12 .…”

“…GKAs function by increasing glucose-stimulated insulin secretion and hepatic glucose uptake in response to glycaemic levels and by reducing hepatic glucose output, thus maintaining glucose homeostasis. 5,9,10 Hepatoselective GKAs have been developed that act with or without disrupting the GK-glucokinase regulatory protein interaction in hepatic cells, as opposed to systemic GKAs (such as piragliatin or dorzagliatin). 11,12 Additionally, full GKAs are distinguished from partial GKAs (such as agent PB-201).…”