Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide-Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors.

Inhibition of Pancreatic lipase (PL) is considered to be a promising target for the management of obesity, owing to its crucial role in the digestion of dietary triglycerides. A series of 31 indolyl ketohydrazide-hydrazone analogs (5 aa-cm) were designed, synthesized and evaluated for their PL inhibitory potential. The analogs were designed using molecular modelling studies. The designed analogs were then synthesized by condensation of indolyl oxoacetohydrazide with various substituted benzaldehydes. All the synthesized analogs showed PL inhibitory activity in the range of 4.13-48.35 µM, as compared with orlistat (0.86±0.09 µM). The most potent analog 5 bi (IC50 =4.13±0.95 µM) was found to show a competitive type of inhibition with Ki value of 0.725 µM. Additionally, the molecular docking study proved the binding of analog 5 bi at the active site of PL (PDB ID: 1LPB) with MolDock score of -141.279 kcal/mol. It also exhibited various interactions with the key amino acids namely Phe77, Phe215, Tyr114, Ser152, Arg256, His263, etc. Furthermore, the protein-ligand complex of analog 5 bi was found to be stable in molecular dynamics simulation for 100 ns with RMSD of less than 3.2 and 4 Šfor the protein and ligand, respectively. The current work hereby provides a basis for the potential role of indolyl ketohydrazide-hydrazone analogs in PL inhibition and further optimization could result in the generation of new leads as anti-obesity agents.

Chromone Containing Hybrid Analogs: Synthesis and Applications in Medicinal Chemistry.

The use of privileged scaffolds has proven beneficial for generating novel bioactive scaffolds in drug discovery program. Chromone is one such privileged scaffold that has been exploited for designing pharmacologically active analogs. The molecular hybridization technique combines the pharmacophoric features of two or more bioactive compounds to avail a better pharmacological activity in the resultant hybrid analogs. The current review summarizes the rationale and techniques involved in developing hybrid analogs of chromone, which show potential in fields of obesity, diabetes, cancer, Alzheimer's disease and microbial infections. Here the molecular hybrids of chromone with various pharmacologically active analogs or fragments (donepezil, tacrine, pyrimidines, azoles, furanchalcones, hydrazones, quinolines, etc.) are discussed with their structure-activity relationship against above-mentioned diseases. Detailed methodologies for the synthesis of corresponding hybrid analogs have also been described, with suitable synthetic schemes. The current review will shed light on various strategies utilized for the design of hybrid analogs in the field of drug discovery. The importance of hybrid analogs in various disease conditions is also illustrated.