The Development of Novel Compounds Against Malaria: Quinolines, Triazolpyridines, Pyrazolopyridines and Pyrazolopyrimidines

Abstract

Based on medicinal chemistry tools, new compounds for malaria treatment were designed. The scaffolds of the drugs used to treat malaria, such as chloroquine, primaquine, amodiaquine, mefloquine and sulfadoxine, were used as inspiration. We demonstrated the importance of quinoline and non-quinoline derivatives in vitro with activity against the W2 chloroquine-resistant (CQR) Plasmodium falciparum clone strain and in vivo against Plasmodium berghei-infected mouse model. Among the quinoline derivatives, new hybrids between chloroquine and sulfadoxine were designed, which gave rise to an important prototype that was more active than both chloroquine and sulfadoxine. Hybrids between chloroquine–atorvastatin and primaquine–atorvastatin were also synthesized and shown to be more potent than the parent drugs alone. Additionally, among the quinoline derivatives, new mefloquine derivatives were synthesized. Among the non-quinoline derivatives, we obtained excellent results with the triazolopyrimidine nucleus, which gave us prototype I that inspired the synthesis of new heterocycles. The pyrazolopyrimidine derivatives stood out as non-quinoline derivatives that are potent inhibitors of the P. falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. We also examined the pyrazolopyridine and pyrazolopyrimidine nuclei.

An insight on medicinal attributes of 1,2,4-triazoles

“…Antimalarial evaluation of twenty six [1,2,4]triazolo[1,5- a ]pyrimidine derivatives 214 ( Fig. 42 ) against chloroquine-resistant W2 strain of P. falciparum revealed that compounds 214a-d displayed most effective antimalarial activity with IC 50 in the range of 0.023–0.55 μM [ 194 ].…”

Antimalarial Agents as Therapeutic Tools Against Toxoplasmosis—A Short Bridge between Two Distant Illnesses

“…Pyrazolo [1,5-a]pyrimidines are a class of structurally challenging compounds with interesting properties [75], including promising antibacterial activity, as seen, for example, in preliminary studies against Mycobacterium tuberculosis [76,77], as well as antiparasitic activity against Plasmodium spp. [78,79] and other protozoans, such as Trypanosoma spp. and Leishmania spp.…”

Crystal structure analysis of ethyl 6-(4-methoxyphenyl)-1-methyl-4-methylsulfanyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

“…Pyrazolopyridines, in which a group of three nitrogen atoms is incorporated into a bicyclic heterocycle, are privileged medicinal scaffolds, often utilized in drug design and discovery regimes (Kumar et al, 2019). Owing to the possibilities of the easy synthesis of a literally unlimited number of a combinatorial library of small organic molecules with a pyrazolopyridine scaffold, there has been enormous interest in these molecules among medicinal chemists (Kumar et al 2019;Pinheiro et al 2019;Hardy, 1984). Indeed, molecules with pyrazolopyridine in the core structure exhibit multifaceted medicinal properties such as anti-microbial, anti-viral, antifungal, anti-hypertensive, analgesic, antiquorum-sensing, anticancer, anti-inflammatory, anti-Alzheimer's, anti-diabetic, anti-nociceptive, anti-tuberculosis and anti-leishmanial activities (Hardy, 1984;Hawas et al, 2019;de Mello et al, 2004;El-Gohary et al, 2019;El-Gohary & Shaaban, 2018).…”