ABSTRACT
Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour as the active component against Plasmodium falciparum, but exhibits toxic side effects. In this study novel febrifugine analogues were designed and efficiently synthesized. New compounds underwent efficacy and toxicity evaluation. Some compounds are much less toxic than the natural product febrifugine and existing antimalarial drugs and are expected to possess wide therapeutic windows. In Aotus monkeys infected with the chloroquine resistant FVO strain of P. falciparum, one interesting compound possesses a 50% curative dose of 2mg/kg/day and a 100% curative dose of 8 mg/kg/day. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Plasmodium falciparum/drug effects , Quinazolines/chemistry , Quinazolines/pharmacology , Animals , Antimalarials/therapeutic use , Antimalarials/toxicity , Aotus trivirgatus , Drug Evaluation, Preclinical , Malaria/drug therapy , Piperidines/therapeutic use , Piperidines/toxicity , Quinazolines/therapeutic use , Quinazolines/toxicityABSTRACT
Febrifugine is an alkaloid isolated from Dichroa febrifuga as the active component against Plasmodium falciparum. Adverse side effects have precluded febrifugine as a potential clinical drug. As part of an ongoing malaria chemotherapy project, novel febrifugine analogues were designed and synthesized. Lower toxicity of these newly designed compounds was achieved by reducing or eliminating the tendency to form chemically reactive and toxic intermediates. New compounds possess excellent in vivo antimalarial activity and most of them become less toxic than the natural product febrifugine. Some of the compounds possess a therapeutic index over ten times superior to that of febrifugine and the commonly used antimalarial drug chloroquine. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Quinazolinones/chemical synthesis , Quinazolinones/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/toxicity , Cell Line , Drug Evaluation, Preclinical , Mice , Mice, Inbred ICR , Plasmodium falciparum/drug effects , Quinazolinones/chemistry , Quinazolinones/toxicityABSTRACT
Residue based control of specific helical folding is explored in hybrid peptide oligomers consisting of alternating L-Ala and cis-beta-furanoid sugar amino acid (FSAA) residues as building blocks; two series of these hybrid oligomers are designed, synthesized and extensively characterized by using NMR, CD, FT-IR and MD simulation studies; results show the co-existence of left-handed 11- and 14/15-helical conformations in these short oligomers of Boc-(alpha/beta) and Boc-(beta/alpha) series.
Subject(s)
Alanine/chemistry , Carbohydrates/chemistry , Computer Simulation , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Peptides , Spectroscopy, Fourier Transform InfraredABSTRACT
A highly chemoselective conjugate reduction of electron-deficient Michael acceptors, including alpha,beta-unsaturated ketones, carboxylic esters, nitriles and nitro compounds with PMHS in the presence of catalytic B(C6F5)3 is described.