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Progress in Antimalarial Drug Discovery and Development
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Anna C.C. Aguiar, Wilian A. Cortopassi, Antoniana U. Krettli
During World War II, the Japanese had taken control of the Java region and thus the commerce of C. ledgeriana trees, which resulted in short supplies of quinine (5) worldwide and motivated the beginning of research programs that led to the first synthetic 4-aminoquinolines. Among them, CQ (3) was proven to be the least toxic and showed high efficacy against the fatal form of malaria caused by P. falciparum. This discovery opened new frontiers for the development of other synthetic 4-aminoquinoline compounds with antimalarial effect, e.g., amodiaquine (AQ, 6) (Olliaro et al. 1996).
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Amodiaquine is a 4-aminoquinoline derivative that has been widely used for treatment of malaria and is more active than the other 4-aminoquinoline, chloroquine, against Plasmodium falciparum parasites, which are moderately chloroquine resistant. Upon oral administration, amodiaquine is rapidly absorbed and extensively metabolized such that very little of the parent drug is detected in the blood. The main metabolite of amodiaquine is N-desethylamodiaquine with other minor metabolites being 2-hydroxyl-N-desethyl-amodiaquine and N-bis-desethylamodiaquine (Figure 3.87) (Churchill et al. 1985, 1986; Mount et al. 1986). The formation of N-desethylamodiaquine is rapid, while its elimination is very slow with a terminal half-life of more than 100 h (Laurent et al. 1993; Winstanley et al. 1987). Both amodiaquine and N-desethylamodiaquine have antimalarial activity, but amodiaquine is three times more active. Amodiaquine N-deethylation has been used as an alternative marker reaction for CYP2C8 because of its high affinity and high turnover rate (Km = 1.0 µM; Vmax = 2.6 pmol/min/pmol CYP2C8) (Li et al. 2002). N-Desethylamodiaquine is found to be CYP2C8 selective in the liver with a minor amount being formed by CYP2D6 and extrahepatic enzymes CYP1A1 and 1B1 (Li et al. 2002).
Treatment and prevention of malaria
Published in David A Warrell, Herbert M Gilles, Essential Malariology, 2017
David A Warrell, William M Watkins, Peter A Winstanley
The only 4-aminoquinoline in clinical use, other than chloroquine, is amodiaquine. It is rapidly and completely metabolized to desethyl-amodiaquine (DESAQ), which is equally active against the parasite. For these reasons, Churchill has suggested that amodiaquine should be considered a pro-drug for DESAQ. In many locations in Africa, amodiaquine is more effective than chloroquine for treating malaria, suggesting a possible difference in resistance mechanisms. However, it is now apparent that differences in efficacy between 4-aminoquinoline drugs and their metabolites largely reflect differences in liposolubility; the degree of cross-resistance correlates well with the octanol: water partition coefficient. Amodiaquine and chloroquine share the same resistance mechanism and, although the degree of cross-resistance to amodiaquine is relatively small, the degree of cross-resistance to DESAQ (the active moiety in vivo) is complete. Whether the greater efficacy of amodiaquine has significant operational usefulness is still an open question, given the dangers of severe toxic reactions associated with frequent dosage.
Heme metabolism as a therapeutic target against protozoan parasites
Published in Journal of Drug Targeting, 2019
Guilherme Curty Lechuga, Mirian C. S. Pereira, Saulo C. Bourguignon
The interference in heme crystallization is one of the mechanisms behind the activity of 4-aminoquinoline derivatives against Plasmodium spp. Chloroquine (CQ) and other quinolines form complexes with heme through π-π stacking interactions of the quinoline ring and the porphyrin system [85]. These interactions inhibit the formation of Hz crystals (Figure 3), increasing the levels of free heme that leads to oxidative stress and parasite damage. Ultrastructural analysis of P. falciparum treated with CQ demonstrated an efflux of free heme iron atoms from the digestive vacuole to the cytoplasm [87]. Additionally, quinolines are weak bases that accumulate in acidic vacuoles, this ion trap mechanism enhances drug activity [88]. Recently, we showed that exogenous addition of heme improves in vitro activity of 4-aminoquinoline-3-carbonitriles derivatives enhancing 8-fold the trypanocidal action against trypomastigotes of T. cruzi [89].
AQ-13 - an investigational antimalarial drug
Published in Expert Opinion on Investigational Drugs, 2019
Juliana Boex Mengue, Jana Held, Andrea Kreidenweiss
Malaria is caused by Plasmodium parasites. Amongst the five human pathogenic species, Plasmodium falciparum is the most deadly accounting for 445.000 deaths in 2016 alone – with more than 90% occurring in children in Africa [1]. Current options for falciparum malaria treatment are all based on combination therapies consisting of artemisinin and related derivatives combined to a long-acting partner drug (artemisinin-based combination therapy, ACT) [2]. It is very concerning that parasites with decreased sensitivity to artemisinins have emerged in South East Asia, and eventually also in Africa [3–5]. There is a great fear of losing artemisinins to P. falciparum resistance as it was the fate for many other antimalarials in the past, including chloroquine (CQ) and sulphadoxine-pyrimethamine [6]. In addition, resistance to ACT partner drugs such as mefloquine and piperaquine are also on the rise in South-East Asia, calling for new treatment options [7,8]. CQ, a synthetic 4-aminoquinoline, used from the 1940s on, was the mainstay of malaria treatment over about half a century. CQ was very potent, well tolerated and available at low costs [9]. With its extensive use, CQ-resistant P. falciparum independently appeared in South East Asia in the late 1950s, then in South America and between 1978 and 1988 resistant P. falciparum have emerged in all sub-Saharan African countries [10–12]. CQ resistance is also increasingly occurring in P. vivax, the dominant Plasmodium species outside Africa [13,14].
Design and synthesis of 4-piperazinyl quinoline derived urea/thioureas for anti-breast cancer activity by a hybrid pharmacophore approach
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Raja Solomon Viswas, Sheetal Pundir, Hoyun Lee
Chloroquine (CQ), which contains a 4-aminoquinoline scaffold (Figure 1), is a well-known antimalarial drug. Based on repurposing concept, we previously demonstrated that the combination of CQ with radiation or Akt inhibitors not only significantly increases antigrowth/cell-killing effects but also enhances the selectivity towards cancer over non-cancer cells1–3. CQ is well known for their lysosomotropic property and accrued in the lysosomes and elevates intra-lysosomal pH; and inhibits with autophagosome degradation in the lysosomes. This unique characteristic of CQ and its analogs may be imperative for the enhancement of cell-killing by cancer therapeutic agents in different tumor models4,5. Based on this interesting note, we synthesised several 4-aminoquinoline analogs (Figure 1, I) and examined their cytotoxic effects on breast cancer cell lines. We found that some of these compounds are very effective and show selective cytotoxic effects on cancer cells6,7. In continuation of our efforts to develop more effective CQ analogs (Figure 1, II and III) by merging 4-piperazinylquinoline ring structure with an isatin ring by a hybrid approach, and found that 4-piperazinylquinoline exhibited promising anti-breast cancer activity8–10.