Dipeptidyl peptidase IV (DPP-IV) is a serine protease whose inhibition has been an object of considerable interest in the context of developing novel treatments for type 2 diabetes mellitus. The development of novel DPP-IV inhibitors from natural or synthetic origin has seen a growing scientific interest in recent years, especially during the SARS-CoV-2 pandemic, when DPP-IV inhibitors were found to be of beneficial therapeutic value for COVID-19 patients. The present manuscript aims to summarize the most recent information on the synthesis of different DPP-IV inhibitors, emphasizing the various heterocyclic scaffolds that can be found in them. Special attention is devoted to DPP-IV inhibitors that are currently in clinical trials. Different synthetic approaches for the construction of DPP-IV inhibitors are discussed, as well as the most recent developments in the field.

Recent studies have discovered that aryl-substituted pyrido[2,1-a]isoquinolines have the potential to be highly active DPP IV inhibitors. In previous studies, we reported a novel synthetic approach for the construction of their sulfur-containing bioisosteric [1,4]thiazino[3,4-a]isoquinolines analogues, incorporating an additional aryl substituent. The present study aims to investigate the DPP IV inhibitory activity and cytotoxicity of the synthesized molecules by in vitro assay. The geometry optimization and molecular docking of the synthesized compounds were used to determine their binding modes to the active site of DPP IV. The docking analysis revealed that the energy-minimized poses of the studied compounds are close to the most important selectivity cliffs for DPP IV inhibition, forming hydrogen bonds and hydrophobic interactions with them. These results can be considered as a preliminary step towards further structural activity modifications.

The synthesis of the compound 9,10-dimethoxy-4-oxo-1-phenyl-1,3,4,6,7,11b-hexahydro-[1,4]thiazino[3,4-a]isoquinoline-1-carboxylic acid (4) was described for the first time using a reaction between 6,7-dimethoxy-3,4-dihydroisoquinoline and phenyl-substituted thiodiacetic anhydride 3. The reaction proceeded in excellent yield and furnished the compound 4 as a single diastereomer. The structure and relative configuration of 4 was elucidated using a combination of spectroscopic techniques–¹H, ¹³C, COSY, HSQC, HMBC, and NOESY NMR spectra, as well as elemental analysis.