Recent updates in the discovery and development of novel antimalarial drug candidates

Abstract

Though morbidity and mortality due to malaria have declined in the last 15 years, emerging resistance to first-line artemisinin-based antimalarials, absence of efficacious vaccines and limited chemotherapeutic alternatives imperil the consolidation of these gains. As a blueprint to steer future designs of new medicines, malaria drug discovery recently adopted a descriptive proposal for the ideal candidate molecules and drugs likely to successfully progress into the final stages of clinical development. As an audit of recent developments in the chemotherapy of malaria in the last five years, this review captures a landscape of diverse molecules at various stages of drug development and discusses their progress. In brief, we also discuss how omics data on has been extensively leveraged to identify potential vaccine candidates and putative targets of molecules in development and clinical use as well as map loci implicit in their modes of resistance. Future perspective on malaria drug development should involve a reconciliation of some of the challenges of the target candidate profiles (TCPs), specifically TCP3, with the promise of effective anti-hypnozoite medicines. Similarly, with the recent development of a humanized mouse model that can evaluate the prophylactic potential of candidate drugs, we argue for increased effort at identifying more liver-stage molecules, which are often only secondarily prioritized in conventional screening programs.

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…The first of these to be exploited, MMV010576 ( 460 ), was identified through a phenotypic screen as a potent and selective inhibitor of P. falciparum in vitro. An exhaustive integrated optimisation programme resulted in the identification of 461 , which was identified as an orally efficacious single‐dose cure of murine P. berghei , and has since entered clinical trials for the treatment of malaria …”

Chalcone hybrids and their antimalarial activity

“…[ 3 ] However, clinical applications of ACTs are impaired by (a) the poor solubility of artemisinin and its derivatives; (b) the high recrudescence rate; (c) short‐plasma half‐life, and (d) the emergence of drug resistance. [ 86–90 ] Artemisinin in combination with chalcone derivatives showed synergistic effect against P. falciparum , and decreased hemozoin formation in parasitized erythrocytes.…”

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

“…Many hybrid molecules are under clinical evaluations for the treatment of various diseases including those caused by drug‐resistant organisms, so hybridization represents a promising strategy to develop new drugs . Hybridization of quinoline moiety with other antimalarial pharmacophores is prone to provide novel antimalarial candidates with high in vitro and in vivo potency against drug‐resistant P falciparum . There are four major types of quinoline hybrids reported during the last 10 years: Type I quinoline‐artemisinin (or its derivatives), Type II quinoline‐synthetic peroxide, Type III quinoline‐resistance reverse agents, and Type IV quinoline‐novel antimalarial pharmacophores (Figure ) …”