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

Diego F Rodríguez,Pedro Olivares,Flavia C Zacconi,Yorley Duarte,Kamal Dua,Yanina Moglie,Francisca Durán-Osorio

doi:10.3390/pharmaceutics14010033

Abstract

Green chemistry implementation has led to promising results in waste reduction in the pharmaceutical industry. However, the early sustainable development of pharmaceutically active compounds and ingredients remains a considerable challenge. Herein, we wish to report a green synthesis of new pharmaceutically active peptide triazoles as potent factor Xa inhibitors, an important drug target associated with the treatment of diverse cardiovascular diseases. The new inhibitors were synthesized in three steps, featuring cycloaddition reactions (high atom economy), microwave-assisted organic synthesis (energy efficiency), and copper nanoparticle catalysis, thus featuring Earth-abundant metals. The molecules obtained showed FXa inhibition, with IC50-values as low as 17.2 μM and no associated cytotoxicity in HEK293 and HeLa cells. These results showcase the environmental potential and chemical implications of the applied methodologies for the development of new molecules with pharmacological potential.

Highlights

Introduction iationsThe factor Xa (FXa) is a serine protease playing a pivotal role in the activation of the blood clotting cascade
As direct FXa inhibitors, while considering the Principles of Green Chemistry (Figure 3, Here, we report the synthesis of a new series of molecules with promising activity as low catalyst loading, copper nanoparticles CuNPs, green solvents, microwave-assisted direct FXa inhibitors, while considering the Principles of Green Chemistry (Figure 3, low chemistry and one-pot procedures) [27]
HEK-293 cells did not show any cell mortality in the studied ranges of concentration with any of the compounds. These results indicate a potential applicability of the compounds as FXa inhibitors without a prejudicial degree of toxicity

Summary

Introduction

The factor Xa (FXa) is a serine protease playing a pivotal role in the activation of the blood clotting cascade. A new generation of direct FXa inhibitors for the treatment and prevention of thromboembolic disorders has emerged: DOACS, direct oral anticoagulants (apixaban, rivaroxaban, edoxaban and betrixaban), applied for the treatment of deep vein thrombosis, stroke, and pulmonary embolism [2]. Recent research has revealed the increased risk of thromboembolic manifestations associated with COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARSs-CoV-2) [3]. The underlying mechanisms by which COVID-19 induces an increase in the procoagulant state leading to thrombosis are still unknown [4].

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Results

Conclusion