Discovery of a Bulky 2-tert-Butyl Group Containing Primaquine Analogue That Exhibits Potent Blood-Schizontocidal Antimalarial Activities and Complete Elimination of Methemoglobin Toxicity

Abstract

To eliminate an unwarranted metabolic pathway of the quinoline ring, a set of two compounds, where C-2 position of the antimalarial drug primaquine is blocked by metabolically stable bulky alkyl group are synthesized. Compound 2 [R = C(CH(3))(3)] of the series has produced excellent antimalarial efficacy against P. berghei and highly virulent multidrug-resistant P. yoelii nigeriensis strain in vivo. Compound 2 was also evaluated for methemoglobin (MetHb) toxicity. This study describes the discovery of a highly potent blood-schizontocidal antimalarial analogue 2, completely devoid of MetHb toxicity.

Primaquine revisited six decades after its discovery

“…Moreover, the anti-malarial activity of 2-tert-butylprimaquine was demonstrated against P. berghei, Plasmodium yoelii nigeriensis (in vivo) and P. falciparum (in vitro), exhibiting attributes of a new potent blood-schizontocidal. These are remarkable findings, as PQ itself is not a blood-schizontocide [165]. A latest report upholds that the remarkable blood-schizontocidal activity of 2-tert-butylprimaquine may be due to a disturbance of the heme catabolism pathways in the malarial parasite.…”

“…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].…”

“…[164] 41a -C(CH 3 ) 3 [164,165,167] 42a -1-adamantyl [165] [163] 57a -CH 3 , -O-C 6 H 3 (3-CF 3 , 4-F) (pos. 5)…”

Benzotriazole as a Synthetic Auxiliary

“…50,51 Synthetic pathways towards PQ derivatives using benzotriazole as a synthetic auxiliary could be divided into two major routes. The first was the one in which PQ reacted with BtcCl yielding PQ benzotriazolide 58, 52 which was the starting material for the preparation of PQ ureas 59, 52 carbamates 60 53 and polymer-PQ conjugates 61.…”

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.…”