Sitamaquine as a putative antileishmanial drug candidate: from the mechanism of action to the risk of drug resistance

Open Access

Review

Table I

Physico-chemical and biological properties of sitamaquine, an antileishmanial agent active against visceral leishmaniasis.

Physico-chemical and biological properties of sitamaquine
Chemical formula	C₂₁H₃₃N₃O.2HCl (dihydrochloride)

Physical properties	Octanol/water partition coefficient: LogP = 5.84

	Molecular weight: 342.51 g 415.43 g (dihydrochloride)

Solubility	Dihydrochloride: water soluble (> 100 mg/ml at 25 °C)
	Ethanol soluble

Chemical characteristics	Weak base pKa = 4.2 (quinoline nitrogen) 10.4 (amine side chain)

Behaviour in biological fluids	Affinity for proteins (Duenas et al., 2007)

Interaction with host cell / parasite	Affinity for negative phospholipids (Duenas et al., 2007)
	Morphology alteration of Leishmania (Langreth et al., 1983)

Uptake and accumulation in	Electrical gradient diffusion (Duenas et al., 2007)

Leishmania donovani promastigotes	No affinity for sterols (Soares et al., 2010)
	No transporter suspected (López-Martín et al., 2008)
	Energy dependent efflux (Soares et al., 2010)

Intracellular targets	Accumulation in acidocalcisomes (Vercesi et al., 2000)
	Rapid collapse of the mitochondrial inner-membrane potential (Vercesi et al., 2002)
	Sitamaquine susceptibility not related to accumulation into acidocalcisomes (López-Martín et al., 2008)

Bioavailability	Plasma half-life: 26.1 hr
	4-CH₂OH as major urinary metabolite (Theoharides et al., 1987)

Clinical trials Phase II	High efficacy rate at doses 1.5-3 mg/kg/day × 28 by oral route
	Trials in India (Jha et al., 2005)
	Trials in kenya (Wasunna et al., 2005)

Toxicity / adverse effects (% of patients)	Vomiting Abdominal pains Headache (10 %) Methemoglobinemia (3 %) Cyanosis (3 %) Renal adverse effects: if doses > 2.5 mg/kg Nephritic syndrome (3 %) Glomerulonephritis (2 %)	(Jha et al., 2005)
	No methemoglobinemia in Kenya (Wasunna et al., 2005)

Resistance	At risk: obtained in vitro (Bories et al., 2008)

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