Last Updated: 02/05/2025
New triazolopyrimidines as selective inhibitors of the plasmodium falciparum di-idroorotate dehydrogenase enzyme
Objectives
To develop and evaluate a new series of [1,2,4]triazolo[1,5-a]pyrimidine-based compounds as selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), integrating medicinal chemistry, biological assays, and molecular modeling to identify potential antimalarial drug candidates capable of overcoming current resistance challenges.
According to the World Health Organization (WHO) malaria is one of the world’s most serious problems of public health reaching mainly African countries however the increase in the number of cases in first world countries have drawn the attention of the authorities.
Plasmodium’s ability to develop resistance associated with the limited number of drugs has been the greatest challenge for the treatment of this disease, necessitating the development of more selective and effective drugs.
The implementation of a project in the area of medicinal chemistry, which integrates interdisciplinary areas such as organic chemistry and biological activity research and molecular modeling is essential for the discovery of new drugs for the treatment of malaria. Combined drug therapy is indicated by the WHO in order to prevent the onset of resistance.
A research group has published a series of papers reporting the anti-P. falciparum in vitro and in vivo activity of various compounds. The [1,2,4] triazolo [1,5-a] pyrimidine derivative containing the CF3 and β-naphthylamine groups showed better activity in the IC50 series of 0.023 μM, ten times more active than chloroquine and showed no toxicity, and is a selective inhibitor of Plasmodium falciparum Di-idroorotato dehydrogenase (PfDHODH). The results of the trials pointed out that this molecule can be used as a prototype in the planning of new drug candidates.
Continuing this line of reasoning and with inspiration in this molecule, 24 novel compounds 4 – ((5-methyl- [1,2,4] triazolo [1,5-a] pyrimidin-7 have been devised and synthesized) -yl) amino) -N-phenylbenzenesulfonamides.
These compounds will be evaluated in vitro for anti-P. falciparum activity and inhibition tests of the enzyme PfDHODH and Homo sapiens (HsDHODH) will be performed, followed by molecular modeling studies.
Nov 2017 — May 2021
