Synthesis and development of bioactive compounds: soluble epoxide hydrolase inhibitors and antiviral molecules

Abstract

The present Thesis is divided in three chapters: 1. Design and synthesis of new soluble epoxide hydrolase inhibitors (sEHI) The synthesis of new soluble epoxide hydrolase inhibitors based on ureas as

the main pharmacophore, a benzohomoadamantane unit and different arylpiperidine groups. The aim was to broaden the spectrum of inhibitors previously developed by the group, taking as starting point the Astellas pharmaceutical product AS2586114. Twelve new urea-based sEHIs were synthesized and evaluated. Two of them were selected for further in vitro studies. The synthesis of new sEHI derived from the substitution of the urea group by and amide group, in order to extend the Markush formula of a patent that the group filled in two years ago and, on the other hand, to improve the solubility of the urea-containing sEHI. Twelve novel amide-based sEHI were synthesized and evaluated. One of them was selected for further in vitro studies demonstrating potent anti-inflammatory properties.

2. Design and synthesis of new anti-influenza virus molecules.

The development of new antiviral molecules against the influenza A virus H1/N1 subtype targeting the hemagglutinin of the virus, continuing previous research by our group. This part of the Thesis greatly improved and completed previous SAR studies on this kind of hemagglutinin inhibitors.

3. Design and synthesis of new anti-coronavirus molecules.

The development of new antiviral molecules against coronavirus 229E, continuing group’s research in the field carrying out a more complete SAR study. Guanidine-bearing molecules were endowed with a great potency against 229E subtype. The most active compound was selected for further mechanistic studies in order to identify the targeted protein. Unfortunately, the compounds were not active against the SARS-2 coronavirus.