4-Aminoquinolines

Abstract

Chloroquine (CQ) is generally considered to be one of the most fascinating, useful and versatile drugs developed during the modern era of synthetic organic chemistry (Knox and Owens 1966; Sams 1967). It was first prepared in 1934 by H. Andersag in the Elberfeld-Leverkusen laboratories of the I. G. Farbenindustrie, as part of a programme which included the synthesis of such important compounds as mepacrine, pentaquine, isopentaquine, pamaquine, primaquine, and sontoquine (Coatney 1963). The objective of this programme was to develop substitutes for quinine which, except for its prompt effect in alleviating the symptoms of an acute attack, is the poorest of antimalarial drugs (Walker 1949; 1950). The hope in preparing CQ was that it would prove to be less toxic than mepacrine. When this hope appeared not to be realised (Coatney 1963; see also Table 1), CQ was given only a very limited clinical trial, and it was then abandoned (in favour of sontoquine) as being “too toxic for human use.” The magnitude of this error of judgement became apparent when, in the course of the American wartime antimalarial survey (Wiselogle 1946), CQ proved to be the best of the many compounds which were tested for prophylactic-suppressive activity. Others of this group seemed worthy of further intensive study (see Table 1) including those assigned Survey Nos. (SN) 8137, 9584, 10751, and 13425. Trials in man (Berliner et al. 1948), involving initially the administration of 200 mg/week, and building up to 600 mg/week by the 5th week, revealed the incidence of side effects to be greatest for SN 9584 and least for SN 8137.