Targeting the Erythrocytic and Liver Stages of Malaria Parasites with s‐Triazine‐Based Hybrids

Abstract

A diversity-oriented library of s-triazine-based hybrids was screened for activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The most striking result was sub-micromolar activity against cultured erythrocytic-stage parasites of hybrid molecules containing one or two 8-aminoquinoline moieties. These compounds were not clearly toxic to human cells. The most effective blood-schizontocidal s-triazine derivatives were then screened for activity against the liver stage of malaria parasites. The s-triazine hybrid containing two 8-aminoquinoline moieties and one chlorine atom emerged as the most potent against P. berghei liver-stage infection, active in the low nanomolar region, combined with good metabolic stability in rat liver microsomes. These results indicate that s-triazine-8-aminoquinoline-based hybrids are excellent starting points for lead optimization as dual-stage antimalarials.

Hybrid molecules based on 1,3,5‐triazine as potential therapeutics: A focused review

“…These test hybrids 10–14; Figure 3, reportedly possess better antimalarial activities compared to the standard drug primaquine. Furthermore, they also displayed high tolerability in Huh7 cell proliferation assay (Rodrigues et al, 2015). The critical findings from these investigations suggested that 4‐aminoquinoline‐triazine hybrids present a privileged profile for designing the pf DHFR inhibitors, whereas the hybrids bearing anilinoquinoline‐triazine system effectively target the parasitic enzyme falcipain‐2, owing to their appropriate basicity and lipophilicity.…”

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

“…The para ‐diaminophenyl tethered quinoline‐1,3,5‐triazine hybrids 146 (IC 50 : 3.01‐313 nM) were generally more potent than meta ‐diaminophenyl tethered analogs 147 (IC 50 : 26.30‐291.73 nM) against CQS 3D7 strain, and the majority of them (IC 50 : <10 nM) were far more active than CQ (IC 50 : 802 nM) against CQR K1 strain . Interestingly, the chloro‐containing quinoline‐1,3,5‐triazine hybrids 148 (IC 50 : 118‐807 nM) were also highly active against CQR W2 strain .…”

“…In particular, all mice were found to be survived in 146a and 146b (50 mg/kg by IP route, or 100 mg/kg by PO route) treated groups on day 28. Thus, both of them represented promising leads for the development of a novel class of potent antimalarials …”

Novel Synthesis of Imidazo‐based and Benzimidazo‐based privileged Templates on s‐Triazine Nucleus through a Phenoxyl Spacer

“…Considering the immensely rich diverse biological properties of s ‐triazine , imidazoles , and benzimidazoles , it was found of paramount interest to incorporate all these biologically active privileged pharmacophores into a single molecular framework by utilizing the reactivity of an active synthon imidate ester (Fig. ).…”