Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies

Abstract

A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogs, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10 mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. KEYWORDS: amodiaquine, benzoxazole, antiplasmodial activity, antimalarial activity, malaria, reactive metabolite, 4-aminoquinolines; bioactivation; structure-activity relationship; β-hematin; quinone imine. INTRODUCTIONMalaria remains a leading cause of morbidity and mortality globally. In 2012, there were an estimated 207 million cases of malaria and 627 000 deaths worldwide, with 90% of all malaria deaths occurring in sub-Saharan Africa. 1 One of the biggest challenges facing malaria chemotherapy is the rapid emergence of resistance to existing antimalarial drugs. 2 This challenge underscores the need for the continued search for new antimalarials.Chloroquine (1) (structure shown in Figure 1), was undoubtedly one of the most successful antimalarials ever owing to its good efficacy and low cost which made it affordable especially in the developing countries with high malaria endemicity. 3 Chloroquine was replaced as first line therapy by the sulfonamide antimalarials and, later on, artemisinin combination therapy (ACT), following the development of widespread resistance against the drug by Plasmodium falciparum. 4An aromatic side chain analogue of chloroquine, amodiaquine (2), however, retains activity against chloroquine-resistant Plasmodium strains. 5 Besides, it is an established fact that resistance against these 4-aminoquinolines is not a result of target modification but is caused by impaired accumulation of the drug at the target. 6,7 Consequently, amodiaquine is an attractive lead compound in the search for new antimalarials. Despite the desirable antimalarial efficacy of amodiaquine, chronic use especially during prophylaxis has been found to precipitate severe hepatotoxicity, myelotoxicity and agranulocytosis. 8,9 This toxicity has been attributed to the bioactivation of amodiaquine to reactive quinone imine (3) and aldehyde quinone imine (4) metabolites (figure 1) which covalently bind to cellular macromolecules causing drug-induced toxicity and cell damage di...

Identification and SAR Evaluation of Hemozoin-Inhibiting Benzamides Active against Plasmodium falciparum

“…33, 35 The relationship was statistically significant with P < 0.0001. Furthermore, a moderately good r 2 value of 0.68 was observed for the correlation, which increased to r 2 = 0.84 upon removal of the point corresponding to compound 15i , which was an apparent outlier (Figure 7b).…”

Synthesis and Antimalarial Activity of 1,4-Disubstituted Piperidine Derivatives

“…Studies have shown that compounds with piperidine rings [4,8,[21][22][23][24][25][26] have good selectivity and activity for the P. falciparum strain. This prompted us to assess their antiplasmodial activity against the chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of P. falciparum as well as their cytotoxic activity against HUVEC cells (Tables 3 and 4).…”

“…The 4-arylaminopiperidine is a structural moiety found in many alkaloids [4][5][6][7][8][9][10][11] and pharmaceutical products such as fentanyl and structurally-related analgesic opioids or H1-antihistamines agents such as bamipine [12][13][14][15][16][17] and neurokinin 1 (NK1) receptor antagonists [18][19][20]. Studies have shown that compounds with piperidine rings [4,8,[21][22][23][24][25][26] have good selectivity and activity for the P. falciparum strain.…”

“…Research is being pursued for the discovery of new antimalarials with less side effects, a faster onset of action and a better rate of response [4,8,[21][22][23][24][25][26]. In the process of searching for new small molecules interacting with the P. falciparum strain, we have identified the target compounds A with various R1, R2 and R3 substituents ( Figure 1).…”

“…The residual was dissolved in 15 mL of ethyl acetate and (1N) of NaOH (15 mL), the aqueous phase was decanted and extracted twice with 15 mL of ethyl acetate. Combined organic phases were washed with water and brine, dried over MgSO4 and concentrated in vacuum. The crude product was purified by crystallisation (ether petroleum/ethyl acetate (8:2)).tert-Butyl 4-(2-(2-chlorophenoxy)-N-phenylacetamido) piperidine-1-carboxylate (9a).…”