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AbstractObesity is a multifactorial metabolic disorder, growing in an alarming rate across the world. Amongst the numerous targets explored for obesity management, inhibition of pancreatic lipase (PL) is considered as one of the promising approaches. Orlistat is the only PL inhibitory drug approved for long term treatment of obesity. However, it is reported to possess hepatotoxicity and nephrotoxicity. Thus, novel drug candidates that act through PL inhibition are considered the hour’s need. Based on this aim, a series of quinazolinone hybrid analogues have been synthesized, characterized and evaluated for their PL inhibitory potential. The physicochemical properties and toxicity parameters suggested that these parameters are in an acceptable range for the screened analogues. Amongst the synthesised analogues, QH-25 exerted potential PL inhibition (IC50= 16.99 ± 0.54 µM). Further, enzyme inhibition studies suggested a reversible competitive inhibition. Molecular docking of these analogues was in line with in vitroresults, wherein the obtained MolDock scores exhibited a significant correlation with their inhibitory activity (Pearson’s r = 0.6629). To further confirm the stability of the QH-25-PL complex in a dynamic environment, a molecular dynamics study (100 ns) was carried out and the results suggested that this complex is stable at dynamic conditions. Overall, these results shed light on the quinazolinone hybrids as potential PL inhibitors. Further structural modification may result in the development of potent anti-obesity agents which acts through PL inhibition.Communicated by Ramaswamy H. Sarma

AbstractPancreatic lipase is a digestive enzyme involved in the hydrolysis of dietary fats. Orlistat, a potent pancreatic lipase inhibitor, is widely prescribed for long-term obesity treatment. Nevertheless, orlistat is reported for severe adverse effects including hepatotoxicity and pancreatitis. In the present study, a novel series of 11 benzyloxy substituted indole glyoxylamides were designed, synthesized and evaluated for in vitropancreatic lipase inhibitory activity. Three analogues, 10b, 11band 11c, exhibited potent activity (IC50≤ 2.5 µM), with 11bexhibiting a potent IC50of 1.68 µM comparable to orlistat (IC50= 0.99 µM). Further, 11bexhibited reversible competitive inhibition with an inhibitory constant value of 0.98 μM. Molecular docking of these analogues was in agreement with in vitroresults, wherein the MolDock scores exhibited significant correlation with their inhibitory activity (Pearson’s r = 0.7122). A 50 ns molecular dynamics simulation of 11b-pancreatic lipase complex confirmed the role of extended alkyl interactions along with π-π stacking and π-cation interactions, in stabilizing the ligand (Maximum RMSD ≈ 3 Å) in the active site. Gastro-intestinal absorption and toxicity prediction of the three potent analogues highlighted the suitability of 11bfor in vivoexperiments. 11bat a dose of 20 mg/kg exhibited anti-obesity efficacy comparable to orlistat (10 mg/kg), wherein the serum triglycerides were found to be 94.95 and 83.85 mg/dL, respectively. Further, faecal triglyceride quantification indicated 11bto act through pancreatic lipase inhibition similar to orlistat. The present study identified a novel pancreatic lipase inhibitory benzyloxy substituted bis(indolyl) glyoxylamide 11b,with promising anti-obesity activity.Communicated by Ramaswamy H. Sarma

Imported fire ants are significant agricultural pests. Repellents can be used to prevent foraging fire ants from entering sensitive areas, including electrical equipment, nursing homes, and hospitals. Bioassay-guided fractionation of the essential oil extracted from gurjun balsam (Dipterocarpus turbinatus) resulted in the identification of (−)-α-copaene (1) as the repellent constituent with a minimum repellent effective dose (MRED) of 15.6 μg/g against both red imported fire ants (Solenopsis invicta) and hybrid imported fire ants (Solenopsis invicta× Solenopsis richteri). Stereoselective oxidation of 1via autoxidation and chemical methods produced (−)-5R-hydroperoxy-α-copaene (2), (+)-3S-hydroperoxycopa-4-ene (3), (−)-α-copaene oxide (4), (+)-β-copaen-4α-ol (5), copaenediol (6), and copaene ketol (7). Reduction of 2and 3with triphenylphosphine afforded (−)-5R-hydroxy-α-copaene (2a) and (+)-3S-hydroxycopa-4-ene (3a), respectively, which led to the structural revision of copa-3-en-2α-ol and copa-2-en-4-ol as 2aand 3, respectively. The configurational assignment of compound 4in the literature was also clarified by the detailed analysis of 2D NMR spectroscopic data. Compounds 2–7showed repellency with MREDs ranging from 3.9 to 15.6 μg/g against hybrid and red imported fire ants, indicating that chemical modification can enhance the repellent effect of (−)-α-copaene.