Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4'-fluoro and 4'-chloro analogues of amodiaquine. Identification of a suitable "back-up" compound for N-tert-butyl isoquine.
نویسندگان
چکیده
On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.
منابع مشابه
Synthesis and study of effects of new 4-chloro – amodiaquine analogues against two resistant and sensitive forms to chloroquine Plasmodium Falciparum, in vitro
Background: Resistance to chloroquine (CQ) in Plasmodium falciparum malaria has become a major health concern of the developing countries.This resistance has prompted a re-examination of the pharmacology of alternative antimalarials that may be effective against resistant strains. Amodiaquine (AQ) is a 4-aminoquinoline antimalarial which is effective against many chloroquine-resistant strains o...
متن کاملساخت آنالوگ‌های جدید 4- فلوروآمودیاکین و بررسی اثرات ضد مالاریایی دارو علیه سویه‌های حساس و مقاوم به کلروکین پلاسمودیوم فالسیپاروم
Background and Objective: Resistance to chloroquine (CQ) in Plasmodium falciparum malaria has become a major health concern in the developing countries. This problem has prompted investigators for finding alternative antimalarials that may be effective against resistant strains. Amodiaquine (AQ) is an antimalarial which is effective against many chloroquine-resistant strains of P. falciparum. H...
متن کاملIntroducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review
Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resist...
متن کاملSynthesis and Antimalarial Screening of Some New Isoquine Analogues
Amodiaquine is a 4-aminoquinoline antimalarial that can cause adverse side effects including hepatic and haematological toxicity. The drug toxicity involves the formation of a reactive metabolite, amodiaquine quinoneimine (AQQI), which binds to cellular macromolecules, leading to hepatotoxicity and agranulocytosis. Interchange of the 3 ́ hydroxyl and the 4 ́ Mannich side-chain function of amodiaq...
متن کاملDiastereoselective synthesis of potent antimalarial cis-β-lactam agents
Fifteen novel β-lactams bearing the N-ethyl tert-butyl carbamate group 5a-o and fifteen N-(2-aminoethyl) β-lactams 6a-o were synthesized by the ketene-imine [2+2] cycloaddition reaction (Staudinger ). The cycloaddition reaction was found to be totally diastereoselective leading exclusively to the formation of the cis-β-lactam derivatives. These newly synthesized β-lactams were evaluated for the...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Journal of medicinal chemistry
دوره 52 7 شماره
صفحات -
تاریخ انتشار 2009