title: Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold.
abstract: Malaria disease continues to be a major health problem worldwide due to the emergence of multidrug-resistant strains ofPlasmodium falciparum. In recent days, artemisinin (ART)-based drugs and combination therapies remain the drugs of choice for resistantP. falciparummalaria. However, resistance to ART-based drugs has begun to appear in some parts of the world. Endoperoxide compounds (natural/semisynthetic/synthetic) representing a huge number of antimalarial agents possess a wide structural diversity with a desired antimalarial effectiveness against resistantP. falciparummalaria. The 1,2,4-trioxane ring system lacking the lactone ring that constitutes the most important endoperoxide structural scaffold is believed to be the key pharmacophoric moiety and is primarily responsible for the pharmacodynamic potential of endoperoxide-based antimalarials. Due to this reason, research into endoperoxide, particularly 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based scaffolds, has gained significant interest in recent years for developing antimalarial drugs against resistant malaria. In this paper, a comprehensive effort has been made to review the development of endoperoxide antimalarials from traditional antimalarial leads (natural/semisynthetic) and structural diversity of endoperoxide molecules derived from 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based structural scaffolds, including their chimeric (hybrid) molecules, which are newer and potent antimalarial agents.
authors.affiliation: Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, India.
authors.forename: Mithun
authors.initials: M
authors.lastname: Rudrapal
authors.affiliation: Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, India.
authors.forename: Dipak
authors.initials: D
authors.lastname: Chetia
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004351:Drug Resistance; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D015394:Molecular Structure; D010545:Peroxides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D013329:Structure-Activity Relationship
chemical_list: C503429:1,2,4-trioxane; D000962:Antimalarials; D037621:Artemisinins; D006571:Heterocyclic Compounds; D010545:Peroxides
keywords: 1,2,4-trioxane; antimalarial; endoperoxide; pharmacodynamic; pharmacophore; structural diversity