In silico design, synthesis and evaluation of a less toxic octinoxate alternative with suitable photoprotection properties

Autores organización

• Diana Milena Millan Cortes

  Autor

• 

  James Oswaldo Guevara Pulido

  Autor

Autores

• Zambrano D

Grupos de investigación

• Grupo de Investigación Básica y Traslacional (GIBAT)

  Investigador

  Rafael Antonio Guerrero Rojas

• Investigación en Química Aplicada INQA

  

  Investigador

  James Oswaldo Guevara Pulido

Resumen

Excessive UV exposure leads to several skin pathologies such as sunburns, photoaging and carcinogenesis. Currently, sunscreen use is the most important factor in protecting skin from photoinduced damage. Octinoxate is a commonly used UV filter, but its use has become controversial because it acts as an endocrine disruptor in both humans, and marine animals. Research has relied on biotechnology, structure activity relationship (SAR) studies and combinatorial chemistry to find new and less toxic UV filters. However, there are no current examples that describe the possible applications of in silico techniques for obtaining these compounds. Thus, this project sought to design an octinoxate analog that could be used as a less toxic, but equally effective, photoprotective alternative through ligand based virtual screening (LBVS). We designed 213 novel molecules based on the (E)-cinnamoyl moiety of octinoxate, but only 23 were found to be less toxic than the parent compound. Then, an artificial neural network (ANN) based model was built to predict the molar absorptivity of those 23 molecules, and the molecule that presented a similar molar absorptivity to that of octinoxate was chosen for synthesis (analog 4, 3-phenylpropyl (E)-3-(4-methoxyphenyl)acrylate). Synthesis for analog 4 resulted in a 90% yield, and its photoprotective properties, lipophilicity and cytotoxicity were then evaluated. Analog 4 absorbed UV radiation in the range of 250–340 nm, and it presented a molar absorptivity of 36,155 M - 1cm-1. Its lipophilicity was evaluated with RP-HPLC resulting in a logkw of 2.49 and its LC50 was greater than octinoxate's (67.41 nM vs. 45.67 nM). Therefore, results showed that ligand based virtual screening is an effective strategy for the development of new organic UV filters, because it guided the design of less toxic analogs and pinpointed the most likely analog to exhibit UV properties similar to those of octinoxate. In this case, analog 4 is a promising alternative to its parent compound since it proved to be more effective and less toxic. © 2022

Copyright © 2022. Published by Elsevier B.V.

Keywords

• Animals; Cinnamates; Humans; Ligands; Sunscreening Agents; Ultraviolet Rays; 3 phenylpropyl 3 (4 methoxyphenyl)acrylate; 4 methoxycinnamic acid 2 ethylhexyl ester; skin protective agent; unclassified drug; cinnamic acid; ligand; octylmethoxycinnamate; sunscreen; Article; artificial neural network; cell survival; cell viability; computer model; controlled study; cytotoxicity; drug absorption; drug carcinogenicity; drug design; drug efficacy; drug safety; drug screening; drug structure; drug synthesis; LC50; lipophilicity; physical chemistry; reversed phase high performance liquid chromatography; skin protection; ultraviolet radiation; adverse event; animal; human; ultraviolet radiation