Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.

A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively.

Benzoheterocyclic amodiaquine analogues with potent antiplasmodial activity: synthesis and pharmacological evaluation.

The synthesis and evaluation of antiplasmodial activity of benzothiazole, benzimidazole, benzoxazole and pyridine analogues of amodiaquine is hereby reported. Benzothiazole and benzoxazole analogues with a protonatable tertiary nitrogen atom possessed excellent activity against the W2 and K1 chloroquine resistant strains of Plasmodium falciparum, with IC(50)s ranging from 7 to 22 nM.

Artemisinin derivatives: a patent review (2006 - present).

INTRODUCTION: The isolation of artemisinin from an ancient Chinese remedy in the early 1970s heralded the beginning of a new era in antimalarial drug therapy culminating in artemisinin-based combination therapies currently being the mainstay of malaria treatment worldwide. Ongoing research on this compound and its derivatives has revealed its potential use in treating other infectious and noninfectious diseases. AREAS COVERED: This review provides a summary of patents published globally from January 2006 to June 2012 covering promising artemisinin derivatives and artemisinin-based drug combinations developed for use in various therapeutic areas. EXPERT OPINION: The diversity of semi-synthetic artemisinin derivatives has been limited to the same design strategy of modifying the artemisinin molecule at the same positions due to inherent synthetic challenges. To address this, future endeavors should include: the use of biotransformation strategies to modify other positions in the sesquiterpene ring while retaining the endoperoxide bridge; the design and synthesis of synthetic ozonides based on the pharmacophoric endoperoxide motif and drug repositioning approaches to artemisinin-based combination therapy. A better understanding of the mechanism of action of artemisinin derivatives and their biomolecular targets may provide an invaluable tool for the development of derivatives with a wider array of activity and greater clinical utility than currently appreciated.