Antimalarial Pyrido[1,2-a]benzimidazoles Exert Strong Parasiticidal Effects by Achieving High Cellular Uptake and Suppressing Heme Detoxification

Abstract

Pyrido­[1,2-a]­benzimidazoles (PBIs) are synthetic antiplasmodium agents with potent activity and are structurally differentiated from benchmark antimalarials. To study the cellular uptake of PBIs and understand the underlying phenotype of their antiplasmodium activity, their antiparasitic activities were examined in chloroquine (CQ)-susceptible and CQ-resistant Plasmodium falciparum in vitro. Moreover, drug uptake and heme detoxification suppression were examined in Plasmodium berghei-infected mice. The in vitro potency of PBIs is comparable to most 4-aminoquinolines. They have a speed of action in vitro that is superior to that of atovaquone and an ability to kill rings and trophozoites. The antiparasitic effects observed for the PBIs in cell culture and in infected mice are similar in terms of potency and efficacy and are comparable to CQ but with the added advantage of demonstrating equipotency against both CQ susceptible and resistant parasite strains. PBIs have a high rate of uptake by parasite cells and, conversely, a limited rate of uptake by host cells. The mechanism of cellular uptake of the PBIs differs from the ion-trap mechanism typically observed for 4-aminoquinolines, although they share key structural features. The high cellular uptake, attractive parasiticidal profile, and susceptibility of resistant strains to PBIs are desirable characteristics for new antimalarial agents.

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

“…Compounds (103-105) reported strong binding interactions with wild and mutant type PfDHFR-TS in docking analysis and in vitro study shown as the most potent antimalarial property with low toxicity and high selectivity. [118] Next, they also synthesized tetrahydrobenzo [4,5]thieno[2,3- In their experiments, Murwih et al used the Claisen-Schmidt condensation to synthesised the thiophene derivatives (108)(109)(110). Through a ring-closing process involving the previously synthesized chalcones, twelve pyrazolines and eight pyrimidines have been synthesized.…”

“…Sousa and co-workers reported pyrido[1,2-a]benzimidazole (95) acting on the trophozoites of P. falciparum with IC 50 of 60.8 nM (Pf3D7) and 58.8 nM (PfW2) along with its exhaustive in vitro and in vivo profile claiming it as the suitable drug candidate for malaria. [109] Patel and co-workers reported the imidazole derivative (96) against P. falciparum with IC 50 of 0.15 μg/mL with reference to quinine (IC 50 of 0.268 μg/mL). [110] Further, it has been also investigated for its potential against S. aureus, E. coli and M. tuberculosis along with the additional in silico molecular docking and ADMET studies.…”

State-of-the-art Review on the Antiparasitic Activity of Benzimidazolebased Derivatives: Facing Malaria, Leishmaniasis, and Trypanosomiasis

“…Sousa et al . [ 85 ] identified three potent pyrido [ 1 ,2- a ]benzimidazole inhibitors 6a-c endowed with comparable in vitro activities against 3D7 and CQ-resistant W2 strains (Table 6 ). In particular, 6a was found to be the most effective, and so it was selected for addressing further studies on the mechanism of action, using some conventional drugs for the purpose of comparison.…”