A four step microwave-mediated synthesis, enzymatic assay of new triazoles scaffold derivatives as Factor Xa Inhibitors vs Antibacterial Activity Assays

YANINA MOGLIE; IGNACIO POBLETE-CASTRO; FABIAN SANTANA ROMO; FLAVIA ZACCONI

Estambul

Simposio; 12th AIMECS 2019 AFMC INTERNATIONAL MEDICINAL CHEMISTRY SYMPOSIUM; 2019

Asian Federation for Medicinal Chemistry

The Haemostasis process involves the bodies response to blood vessel injury and bleeding. It includes a coordinated effort between blood vessels, platelets, many blood clotting proteins, inhibitors, and the fibrinolytic system. Haemostasis requires the interaction of platelets as a coagulation factor in tandem activation reactions. A deficiency or over supply of any one of these components may lead to either bleeding or thrombosis. Under normal conditions, these components are involved in a dynamic equilibrium from activation, propagation, and termination on the haemostatic pathways [1]. Nowadays, scientists focus all their research efforts on the factor Xa (FXa), due to its essential characteristic of being the central point of the coagulation cascade. The primary purpose is to allow more fluid blood flow and avoid the formation of an embolus from the clotting detachment. Embolus formation can trigger pathologies such as venous thromboembolism (VTE), deep vein thrombosis (DVT) or pulmonary embolism (PE) [2].In this research, we proposed a synthesis of potential triazole derivatives made from an initial lactam ring scaffold present in commercial drugs such as Rivaroxaban and Apixaban [3]. The Protein Data Bank (PDB) data shows meaningful enzyme-ligand interactions for lactam-moiety. S4 pocket on the active site reports strong π-π aromatic interactions with Trp215 and Phe174. An Enzymatic FXa assay of 16 final derivatives shows an inhibition percentage from 19.8 to 56.7. At the same time, there is clear data that shows the coagulation cascade inhibition. Moreover, smaller molecules obtained with green methodologies [4], exhibited a four step reaction and a 84-96% yield thereby justifying the design and synthesis of these compounds (Figure 1).Furthermore, all the compounds were tested for their antibacterial activity against Gram-positive bacteria. Due to the triazole scaffold moiety, pharmacological actions such as, antiviral, anticonvulsant, anti-inflammatory, antibacterial, antifungal and anti-tuberculosis have been reported. It can act as an indispensable tool for medicinal chemists to develop innovative compounds possessing a triazole moiety that could be a better agent in terms of efficacy and safety [5]. Consequently, physical properties can be achieved as well. For instance, bio-degradable, anti-fouling, self-heating, hybrid nanocomposite, antimicrobial, and finally corrosion coatings. Consider that, we perform an Antibacterial activity assay, and it was measured at around 50-80%.