Synthesis, and anti-malarial screening, of 1-diethylamino-4- (dihydroartemisinin-10-yl)amino pentane

Abstract

Artemisinin and its derivatives have become antimalarial drugs of choice because they are effective against most stages in the life cycle of  plasmodium and are safe for all, including pregnant women. World Health Organisation (WHO) has nevertheless recommended artemisinin based combination therapy (ACT) to guard against possible development of resistance, as observed with chloroquine. In this study we coupled dihydroartemisinin with 2-amino- 5-diethyl aminopentane (the chloroquine handle) by using the Mitsunobu coupling (an SN2 reaction). This involves
the use of diisopropylazodicarboxylate (DIAD), triphenyl phosphine (Ph3P), 2-amino-5-diethylaminopentane and dihydroartemisinin (DHA) at room temperature to synthesize the target compound, 1-diethylamino-4-
(dihydroartemisinin-10-yl)amino pentane {coded: DHA-CQ; IUPAC Name: N1,N1-diethyl-N4-(3,6,9- trimethyldecahydro- 3,12-epoxy[1,2]dioxepino[4,3-i] isochromen-10-yl) pentane-1,4-diamine}. The structure of DHA-CQ was determined from spectroscopic data (IR, 1H & 13C NMR, MS). The compound was screened at three dose levels of 3 mg/kg, 10 mg/kg and 30 mg/kg, for in vivo curative antimalarial activity against mice infected with Plasmodium berghei berghei. The target  compound also had an LD50 of 330 mg/kg in mice by the oral route. A
single dose kinetics study was carried out and three different metabolites were identified.

Keywords: Artemisinin; Chloroquine; Dihydroartemisinin; Plasmodium berghei berghei; Mitsunobu coupling