Coumarins derived from natural methoxystilbene as oxidative stress-related disease alleviators: Synthesis and in vitro-in silico study

Abstract

3,4,5-Trimethoxy-3′-hydroxy-4′-methoxystilbene (TMHMS) is an anticancer natural stilbene that targets tubulin polymerization. According to research, oxidative stress and inflammation are linked to cancer, and lowering both of these hazards may have a detrimental influence on tumor development. TMHMS was used as a building block in this investigation to generate 28 coumarins with increased medicinal value. TMHMS-COU-1, the first coumarin derivative, was activated by thionyl chloride and subsequently linked with different phenols, yielding 27 TMHMS-COU variants. This natural product was used as a reference for oxidative stress-alleviated activities such as anticancer activity against eight cancerous cellular lines, antioxidant activity on H2O2-treated human SH-SY5Y populations, and anti-inflammatory activity against three enzyme-based representatives of inflammation. TMHMS and its coumarins were tested for their impact on the normal development of three cell types as well as human erythrocyte hemolysis in biocompatibility tests. Finally, utilizing two web-based programs, the pharmacokinetic profiles of the building component and its variants were computed. The inclusion of an electron-donating group on the off-side aromatic ring directly boosted the oxidative stress-alleviated activities, according to the results. These activities were also boosted when this group occupied the para or meta position. When this aromatic ring was trisubstituted with this group type, the greatest activities were found, with the trimethoxy aromatic ring having preferential activities. In terms of biocompatibility, the synthesized coumarins showed a high level of compatibility with the tested normal cells as well as human erythrocytes. Furthermore, the in silico research confirmed the synthesized coumarins' ability to provide prospective therapeutic candidates. According to the author, the coumarin-structural change might open the way for the development of novel, powerful, and biosafe TMHMS derivatives. This work provided various insights into the structure-function connections that can direct subsequent studies on TMHMS-based derivatives.