Modifications of primaquine as antimalarials. 1. 5-Phenoxy derivatives of primaquine

Abstract

Various 5-phenoxy derivatives of primaquine have been prepared which are more active and less toxic than the parent compound in murine and monkey antimalarial screens. An improved method for the phthalimido alkylation of amines is described.

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].…”

Synthesis of some 4-substituted 8-amino-6-methoxyquinolines as potential antimalarials

“…6-Methoxy-8-nitro-4-vinylquinoIine (7). 6-Methoxy-8nitro-4-[d-(trimethylamino)ethyl]quinoline iodide (6; 44.3 g, 0.106 mol) was suspended in a mixture of 750 mL of 1 N NaOH and 750 mL of chloroform and stirred vigorously at 25 °C for 6 h. (All of the solid had dissolved.)…”

“…8-Amino-6-methoxy-4-vinylquinoline (3a). To a suspension of 1.21 g of granular tin, 38.7 g of SnCl2, 80 mL of concentrated hydrochloric acid, and 40 mL of ethanol cooled to 0 °C was added 10.0 g (43.5 mmol) of 6-methoxy-8-nitro-4-vinylquinoline (7) portionwise such that the temperature never exceeded 10 °C. After the addition, the temperature was brought to 10 °C for 1 h and then 25 °C for 2 h, whereupon the reduction was complete.…”

“…Neutralization of 5 followed by treatment with methyl iodide gave 6-methoxy-8-nitro-4-[/3-(trimethylamino)ethyl]quinoline iodide (6). Treatment of 6 with aqueous sodium hydroxide gave 6-methoxy-8-nitro-4-vinylquinoline (7). Condensation of 6 with p-fluorothiophenol and p-methoxythiophenol in DMF containing potassium carbonate gave the 4-[(arylthio)ethyl]-6-methoxy-8-nitroquinolines 8, X = F and OCH3, respectively.…”

8‐Aminoquinolines with an Aminoxyalkyl Side Chain Exert in vitro Dual‐Stage Antiplasmodial Activity

“…Methyl substitution at position 4 of the quinoline ring has been reported to enhance radical curative antimalarial activity. Introduction of phenoxy substituents at position 5 to prevent the formation of 5‐hydroxymetabolites and their oxidative products has also led to increased radical curative and blood schizontocidal antimalarial activity accompanied by lower toxicity . Combining both structural features has given rise to highly effective radical curative and suppressive analogues.…”