Synthesis and Biological Evaluation of Thio-Derivatives of 2-Hydroxy-1,4-Naphthoquinone (Lawsone) as Novel Antiplatelet Agents.

Matías Monroy-Cárdenas,Andrés Trostchansky,Ramiro Araya-Maturana,Eduardo Fuentes,Maximiliano Martínez-Cifuentes,Diego Méndez

doi:10.3389/fchem.2020.00533

Abstract

We designed and synthesized in water, using conventional heating and microwave irradiation, new thio-derivatives of 2-hydroxy-1,4-naphthoquinone, a naturally occurring pigment known as lawsone or hennotannic acid, thus improving their antiplatelet activity with relevance to their potential future use in thrombus formation treatment. The structure-activity relationship showed that the thiophenyl moiety enhances the antiplatelet activity. Moreover, the position and nature of the substituent at the phenyl ring have a key effect on the observed biological activity. Compound 4 (2-((4-bromophenyl)thio)-3-hydroxynaphthalene-1,4-dione) was the most active derivative, presenting IC50 values for platelet aggregation inhibition of 15.03 ± 1.52 μM for TRAP-6, and 5.58 ± 1.01 μM for collagen. Importantly, no cytotoxicity was observed. Finally, we discussed the structure-activity relationships of these new lawsone thio-derivatives on inhibition of TRAP-6- and collagen-induced platelet aggregation.

Highlights

Cardiovascular diseases (CVD), one of the leading causes of deaths from non-communicable disease in the world, all have thrombus formation as a common process, with platelet activation at the dysfunctional vessel wall being one of the main steps during thrombosis (ISTH Steering Committee for World Thrombosis Day, 2014; Diamond, 2016).Platelets are fragments of megakaryocytes circulating within the bloodstream aiding in maintaining hemostasis with both blood components and endothelial cells (Paes et al, 2019)
It has been observed that some quinone and hydroquinone compounds protect mitochondrial damage and platelet activation generated by reactive oxygen species (ROS) (Kim et al, 2001; Cocheme et al, 2007); in this way, some structure-activity relationship studies with quinone derivatives have been reported (Chang et al, 1997; Cho et al, 1997; Kim et al, 2001)
We showed that lawsone and compounds 3 and 5 had a cytotoxic activity with an increase of Lactate Dehydrogenase (LDH) released by damaged platelets

Summary

INTRODUCTION

Cardiovascular diseases (CVD), one of the leading causes of deaths from non-communicable disease in the world, all have thrombus formation as a common process, with platelet activation at the dysfunctional vessel wall being one of the main steps during thrombosis (ISTH Steering Committee for World Thrombosis Day, 2014; Diamond, 2016). Recent work has shown conflicting results (Fuentes et al, 2018). In this way, 3’-methoxyflavone quinone inhibited arachidonic acid-induced platelet aggregation at low micromolar concentration with an IC50 of ∼ 10 μM (Chang et al, 2000). Lawsone (1) and its synthetic derivatives have shown promising biological results with antibacterial, antifungal, antitumor, and antiparasitic effects (Rahmoun et al, 2012; Barani et al, 2018; Al Nasr et al, 2019), their use, or study as antiplatelet agents have not been described, the antiplatelet activity of other quinones has been reported (Fuentes et al, 2018). The current work aims to evaluate the antiplatelet effects of a series of lawsone thio-derivatives, which were obtained using on-water methodology, which was optimized by microwave irradiation for those cases that yielded poor results with conventional heating

MATERIALS AND METHODS

RESULTS AND DISCUSSION

Limitation and Perspectives

ETHICS STATEMENT