Antimalarials. 16. Synthesis of 2-substituted analogs of 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline as candidate antimalarials

Abstract

A series of 2-substituted analogues of the exceptional drug 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3- (trifluoromethyl)phenoxy]quinoline (I) were prepared and evaluated for both suppressive and prophylactic antimalarial activity. The preparation of analogues of compound I was of interest due to the high level of both blood and tissue schizonticidal activity demonstrated by this compound. One analogue, 8a, was found to be both more active and less toxic than the parent compound I. In addition, three analogues of example 8a were prepared. Although two of the three analogues showed significant antimalarial activity, both were inferior to compound 8a.

Primaquine revisited six decades after its discovery

“…This produced almost 200 PQ derivatives (Tables 2-4) bearing diverse groups in one or more given positions of the ring [6,46,[161][162][163][164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179]. Globally, the most favourable substituent insertions towards anti-malarial activity where those of methyl groups at positions 4 and 2, tert-butyl at position 2, simultaneous insertion of ethyl substituents at positions 2 and 4 and pentyloxy at position 5, as well as insertion at position 5 of alkoxy, fluoro, and 3-or 4-substituted phenoxy groups [51,163].…”

New synthesis of 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones

“…(4)). Results are given in Table 1 (entries [1][2][3][4][5][6]. The reaction of 2a with diethyl malonate and sodium hydride proceeded smoothly in dry toluene at room temperature, producing 2-substituted malonic acid diethyl ester 4a in high yield (Scheme 1, Eq.…”

“…In contrast, treatment of 5 and 6a-6d with an excess of polyphophoric acid at 130 8C for a short period gave 2-trifluoromethyl-2,3-dihydroquinolin-4-ones 8 and 9a-9d in fair to good yields (Scheme 4, Eqs. (2) and (3), and Table 4, entries [1][2][3][4][5]. Under the same conditions, treatment of the 4,4,4-trifluoro-3-otolylaminobutyric acid (6e) gave only a small amount of the 2,3-dihydroquinolin-4-one 9e (entry 6).…”

“…Of the hetereocyclic compounds, 4-quinolinones and 4-chloroquinolines are very useful intermediates in the synthesis of the highly active 4-aminoquinoline groups of antimalarial drugs [2]. Trifluoromethylated quinolines and 2-or 4-quinolinones have been synthesized to clarify the effects of fluorine substitution [3].…”

Synthesis and evaluation of naphthyridine compounds as antimalarial agents

“…It has been reported that introducing an alkyl or alkoxy group at position 2 of the aromatic ring reduces the toxicity of a compound (induction of methemoglobin). 20,21 Scheme 1 describes the synthesis of compound 1. Compounds 2-6 were synthesized in similar routes.…”