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Background/Objectives: DPP4 is an enzyme with multiple natural substrates and probable involvement in various mechanisms. It constitutes a drug target for the treatment of diabetes II, although, also related to other disorders. While a number of drugs with competitive inhibitory action and covalent binding capacity are available, undesired side effects exist partly attributed to drug kinetics, and research for finding novel, potent, and safer compounds continues. Despite the research, a low number of uncompetitive and non-competitive inhibitors, which could be of worth for pharmaceutical and mechanism studies, was mentioned. Methods: In the present study sixteen 3-(benzo[d]thiazol-2-yl)-2-aryl thiazolidin-4-ones were selected for evaluation, based on structural characteristics and docking analysis and were tested in vitro for DPP4 inhibitory action using H-Gly-Pro-amidomethyl coumarin substrate. Their mode of inhibition was also in vitro explored. Results: Twelve compounds exhibited IC50 values at the nM range with the best showing IC50 = 12 ± 0.5 nM, better than sitagliptin. Most compounds exhibited a competitive mode of inhibition. Inhibition modes of uncompetitive, non-competitive, and mixed type were also identified. Docking analysis was in accordance with the in vitro results, with a linear correlation of logIC50 with a Probability of Binding Factor(PF) derived using docking analysis to a specific target box and to the whole enzyme. According to the docking results, two probable sites of binding for uncompetitive inhibitors were highlighted in the wider area of the active site and in the propeller loop. Conclusions: Potent inhibitors with IC50 at the nM range and competitive, non-competitive, uncompetitive, and mixed modes of action, one better than sitagliptin, were found. Docking analysis was used to estimate probable sites and ways of binding. However, crystallographic or NMR studies are needed to elucidate the exact way of binding especially for uncompetitive and non-competitive inhibitors.

Unlike most attempts to find compounds with activity against SARS-CoV-2 aimed at reusing approved drugs, our goal was to find compounds with antiviral activity among the 1,2-dithioloquinoline derivatives we synthesized. These compounds exhibit pleiotropic effects, having a novel structure compared to known pharmaceuticals. In this work, we diversified the structure of 1,2-dithioloquinoline by introducing various substituents (chlorine atom, ether, amide, sulfonamide groups, pharmacophore heterocycles) into different positions of this tricyclic framework. Using docking with further quantum chemical post-processing of calculations of the created virtual library of 404 structures, more than ten compounds of the aryl(4,4-dimethyl-4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-ylidene)amine series were discovered, synthesized and experimentally studied. The bioactive screening of newly synthesized compounds revealed that six of them demonstrate suppression of SARS-CoV-2 replication in Vero E6 cell culture in the micromolar range of EC50 values (from 0.27 to 98.48 μM). The best compound, in the structure of which fragments of tricyclic dithioloquinoline and streptocide are combined, demonstrated a highest ability to protect Vero E6 cells from SARS-CoV-2 with EC50 = 0.27 μM, as well as low cytotoxicity with a selectivity index SI > 370, exceeding all reference values compounds used in the study (remdesivir, GC376, ML188). [ABSTRACT FROM AUTHOR]

Background/Objectives: DPP4 is an enzyme with multiple natural substrates and probable involvement in various mechanisms. It constitutes a drug target for the treatment of diabetes II, although, also related to other disorders. While a number of drugs with competitive inhibitory action and covalent binding capacity are available, undesired side effects exist partly attributed to drug kinetics, and research for finding novel, potent, and safer compounds continues. Despite the research, a low number of uncompetitive and non-competitive inhibitors, which could be of worth for pharmaceutical and mechanism studies, was mentioned. Methods: In the present study sixteen 3-(benzo[d]thiazol-2-yl)-2-aryl thiazolidin-4-ones were selected for evaluation, based on structural characteristics and docking analysis and were tested in vitro for DPP4 inhibitory action using H-Gly-Pro-amidomethyl coumarin substrate. Their mode of inhibition was also in vitro explored. Results: Twelve compounds exhibited IC50 values at the nM range with the best showing IC50 = 12 ± 0.5 nM, better than sitagliptin. Most compounds exhibited a competitive mode of inhibition. Inhibition modes of uncompetitive, non-competitive, and mixed type were also identified. Docking analysis was in accordance with the in vitro results, with a linear correlation of logIC50 with a Probability of Binding Factor(PF) derived using docking analysis to a specific target box and to the whole enzyme. According to the docking results, two probable sites of binding for uncompetitive inhibitors were highlighted in the wider area of the active site and in the propeller loop. Conclusions: Potent inhibitors with IC50 at the nM range and competitive, non-competitive, uncompetitive, and mixed modes of action, one better than sitagliptin, were found. Docking analysis was used to estimate probable sites and ways of binding. However, crystallographic or NMR studies are needed to elucidate the exact way of binding especially for uncompetitive and non-competitive inhibitors. [ABSTRACT FROM AUTHOR]

The synthesis of pyrimido[2,1-f][1,2,4]triazines was performed in four steps. Compounds obtained by acylation of the starting amino esters of thieno[2,3-b]pyridines were reacted with various amines. The resulting amino derivatives underwent cyclization in the presence of hydrazine hydrate leading to new aminomethyl derivatives of thieno[3,2-d]pyrimidines. Further cyclization of the latter resulted to the synthesis of new unique heterocyclic systems: pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-f][1,2,4]triazines. The uniqueness of these systems lies in the fact that even the combination of the last two cycles represents a new heterocyclic system., (© 2025 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)