Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

Abstract

The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73–93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (µ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29–31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.

Green by Design: Convergent Synthesis, Computational Analyses, and Activity Evaluation of New FXa Inhibitors Bearing Peptide Triazole Linking Units

“…The specific alignment of rivaroxaban in the active site allows for the chlorine on the thiophene moiety to interact with the Tyr228 residue in the S1 pocket, mainly through noncovalent halogen-π interactions. This interaction has been described as key for the ligand binding and recognition to the enzyme representing a similar relevance to halogen bond interactions [44,45]. A common halogen-π bond describes the aromatic rings as donors and the C-X bonds (with X = F, Cl, Br, I) as acceptors [46].…”

The Riveting Chemistry of Poly‐aza‐heterocycles Employing Microwave Technique: A Decade Review

“…Moreover, ZnO‐supported copper nanoparticles have been effectively used for the synthesis of triazoles 8 (Scheme 3). [9b] …”

Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

“…1,2,3,4-Tetrahydroquinolines (5,6) with phenyl and methyl substituents [18,21] as well as 1,2-dihydroquinolines containing N-acetylaminomethyl groups at C 4 (8) [22] (see Figure 4) are also proven to form a structural basis for compounds with anticoagulant activity. Inhibitory activity against factor FXa was also detected for other 1,2,3,4-tetrahydroquinolines [23]. On the other hand, the introduction of piperazine fragments into the structure of biologically active compounds is considered as one of the most promising directions in medicinal chemistry for the construction of hybrid molecules [24][25][26].…”

“…Molecules 2020, 25, x FOR PEER REVIEW 5 of 17 against factor FXa was also detected for other 1,2,3,4-tetrahydroquinolines [23]. On the other hand, the introduction of piperazine fragments into the structure of biologically active compounds is considered as one of the most promising directions in medicinal chemistry for the construction of hybrid molecules [24][25][26].…”