Modifications of primaquine as antimalarials. 3. 5-Phenoxy derivatives of primaquine

Abstract

and 5% methanol, v/v). Commercial Raney nickel was purchased from W.R. Grace Co. (no. 30). Silica gel was purchased from EM .5-Hydroxy-6-methoxy-4-methyl-8-nitroquinoline (2). 4-Methyl-5,6-dimethoxy-8-nitroquinoline4 (6.21 g, 25 mmol) was dissolved in EtOH (100 mL) containing concentrated HC1 (4.7 mL). The mixture was heated under reflux for 21 h, cooled to 10 °C, and filtered. The solid was washed with cold (10 °C) EtOH (18 mL), followed by petroleum ether (15 mL), and air-dried to yield 5.41 g (92%) of the title compound, mp 253-257 °C dec.Anal. (CuH10N2O4) C, , N.5-Chloro-6-methoxy-4-methyl-8-nitroquinoline (3). A solution of the above 5-hydroxyquinoline (5.25 g, 0.022 mol) in P0C13 (75 mL) was heated at 80 °C for 2 h. The reaction mixture was poured onto ice and basified with excess NH4OH. The tan solid was filtered to give 5.8 g of crude product. This material was purified via column chromatography over silica gel and eluted with CHC13. The fast-moving yellow band was collected and concentrated to give 3.9 g (69%) of the title compound, mp 167-169 °C. Anal. (CUH9C1N203) C, H, Cl, N.6-Methoxy-4-methyl-8-nitro-5-[3-(trifluoromethyl)phenoxyjquinoline (4a). To a solution of 3-(trifluoromethyl)phenol (4.1 g) in 2-ethoxyethanol (45 mL) containing KOH (1.37 g) was added the above 5-chloroquinoline (5.7 g, 0.023 mol). The mixture was heated at reflux for 8 h and allowed to cool overnight. The solid was filtered and washed well with cold EtOH to give 5.9 g (69%) of the title compound, mp 206-208 6C. An analytical

Antimalarial activity and inhibition of monoamine oxidases A and B by exo‐erythrocytic antimalarials

“…Comparison of the optical isomers 1A and 1B of primaquine, favouring here the (-) isomer 1B as the less toxic compound, is offset by earlier reports showing that the (+) isomer 1A had a better therapeutic index in rhesus monkeys [16], with both 1A and 1B similarly inhibiting drug metabolism [17]. In view of the appearance of new and much improved antimalarials for radical cure and clearing of tissue parasites, such as 4 [12] or its 4-methyl-substituted analogues [18], further development of either (-)-primaquine (1B) or its (+) isomer 1A does in our opinion not seem warranted. However, the question regarding differences in activity and toxicity of optical isomers of the new generation of analogues should be pursued.…”

“…Chosen for this study were (+)-and (-)-primaquine (IA and 1B), the two optical isomers of primaquine of still unknown configuration [9], (+)-N-ethoxyacetylprimaquine 2 [10], an Nacylated primaquine resembling the bacterial metabolite (+_)-N-acetylprimaquine [2], (___)-carboxy-metabolite 3 obtained by total synthesis [11], and (___)-5-(m-trifluorophenoxy)primaquine (4), a representative of a superior class of primaquine-related antimalarials [12]. as discs of 5 mm diameter [6,14].…”

Primaquine revisited six decades after its discovery

“…Monosubstituted derivatives with phenoxy groups on C-5 were reasonably active, some of them having lower toxicity than PQ. Also in this case, introduction of a methyl group on C-3 or C-4 of several 5-phenoxyprimaquines drastically increased the blood-schizontocidal activity [168].…”

“…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].…”

8-Aminoquinoline Therapy for Latent Malaria

“…WR242511 stood alone as a 5-arlyoxy derivative among 5-phenoxy peers in late preclinical development. The 5-aryloxy series, first reported in 1982 (198), offered WR242511 as having conspicuously superior blood and hepatic schizontocidal as well as hypnozoitocidal activities relative to primaquine, other 5-aryloxy derivatives (199), and the 5-phenoxy derivatives (200). However, the peak methemoglobinemia levels in beagles were 2.7-, 4.0-, or 7.6-fold higher for tafenoquine, WR225448, and WR242511, respectively, than the level induced by primaquine in the same model (197).…”