Recent developments in 8-aminoquinoline antimalarials

Bhat, Bilal A.; Seth, M.; Bhaduri, A. P.

doi:10.1007/978-3-0348-7118-1_6

Cited by 6 publications

(4 citation statements)

References 91 publications

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“…As reviewed by Nodiff et al (27) and Bhat et al (9), substantial efforts have been made to identify an 8-aminoquinoline with a better therapeutic index than that of primaquine and with activity against blood stages of malaria. A potential primaquine replacement, WR 238605 (32) (Fig.…”

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8-Aminoquinolines Active against Blood Stage Plasmodium falciparum In Vitro Inhibit Hematin Polymerization

Vennerstrom

Nuzum

Miller

et al. 1999

Antimicrob Agents Chemother

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From the Walter Reed Army Institute of Research (WRAIR) inventory, thirteen 8-aminoquinoline analogs of primaquine were selected for screening against a panel of seven Plasmodium falciparumclones and isolates. Six of the 13 8-aminoquinolines had average 50% inhibitory concentrations between 50 and 100 nM against these P. falciparum clones and were thus an order of magnitude more potent than primaquine. However, excluding chloroquine-resistant clones and isolates, these 8-aminoquinolines were all an order of magnitude less potent than chloroquine. None of the 8-aminoquinolines was cross resistant with either chloroquine or mefloquine. In contrast to the inactive primaquine prototype, 8 of the 13 8-aminoquinolines inhibited hematin polymerization more efficiently than did chloroquine. Although alkoxy or aryloxy substituents at position 5 uniquely endowed these 13 8-aminoquinolines with impressive schizontocidal activity, the structural specificity of inhibition of both parasite growth and hematin polymerization was low.

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confidence: 99%

8-Aminoquinolines Active against Blood Stage Plasmodium falciparum In Vitro Inhibit Hematin Polymerization

Vennerstrom

Nuzum

Miller

et al. 1999

Antimicrob Agents Chemother

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“…It is a potent antimalarial agent, an analogue of PQ, but safer than PQ, and causes only one third as much as methemoglobinemia [3,4]. It has shown curative and causal prophylactic activities against sporozoite-induced P. cynomolgi infection in rhesus monkeys and is also safe in subacute toxicity studies in rats and rhesus monkeys with no teratogenic action [5].…”

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confidence: 98%

In Vitro and In Vivo pharmacokinetic studies of bulaquine (analogue of primaquine), a novel antirelapse antimalarial, in rat, rabbit and monkey—highlighting species similarities and differences

Mehrotra

Lal

Puri³

et al. 2007

Biopharm & Drug Disp

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Bulaquine (BQ) is a potent antirelapse antimalarial developed by CDRI, India. Bulaquine was rapidly absorbed in rats and rabbits with no distinct absorption phase while in monkeys a variable irregular absorption profile was observed. BQ was extensively converted to primaquine (PQ) after oral administration and the conversion was maximum in rats and minimum in rabbits, which is possibly due to the species difference. Clearance was higher in rats (3.2 l/h/kg) than in rabbits and monkeys (1.2 l/h/kg) and it was found be negligibly excreted in rat urine and feces. The elimination half-life in rats and rabbits was comparable after both oral and i.v. administration ($1.2 h). In all three species, PQ was resident in the body for a period longer than BQ. PQ, being the major active metabolite of BQ, might be responsible for the extended therapeutic effect of BQ. The oral bioavailability of BQ was 3.12%, 5.3% and 12% in rats, rabbits and monkeys, respectively, which could be mainly due to the high instability of BQ at acidic pH as demonstrated from a simulated gastric fluid stability study. Protein binding in various species was in the range 50-65% while the partition coefficient between RBCs and plasma (K rbc/pl ) was between 0.75 and 1, indicating significant RBC uptake.

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“…However, persistent use of primaquine as the leading therapeutic armor is limited because of its well-documented adverse effects, namely, methaemoglobinaemia and cyanosis, haemolytic anaemia in G6PD-deficient individuals, hepatotoxicity, gastrointestinal distress, epigastric discomfort, anorexia, vomiting, nausea, headache, and so on [2]. Furthermore, primaquine is contraindicated in pregnant females and is not recommended for infants [3].The consequent search for a safer and potent antimalarial has resulted in the development of bulaquine ([N 1 -(3-acetyl-4-5-dihydro-2-furanyl)-N 4 -(6-methoxy-8-quinolinyl)-1,4-pentanediamine], CDRI 80/53) at the Central Drug Research Institute, Lucknow, India [4,5]. It is a potent antimalarial analogue of primaquine that causes only one-third of methaemoglobinaemia, as compared to primaquine thus proving to be three to four times safer for human consumption [6].…”

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“…The consequent search for a safer and potent antimalarial has resulted in the development of bulaquine ([N 1 ‐(3‐acetyl‐4‐5‐dihydro‐2‐furanyl)‐N 4 ‐(6‐methoxy‐8‐quinolinyl)‐1,4‐pentanediamine], CDRI 80/53) at the Central Drug Research Institute, Lucknow, India [4,5]. It is a potent antimalarial analogue of primaquine that causes only one‐third of methaemoglobinaemia, as compared to primaquine thus proving to be three to four times safer for human consumption [6].…”

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Identification of Differentially Expressed Genes after Acute Exposure to Bulaquine (CDRI 80/53) in Mice Liver

Noel

Sharma

Shankar

et al. 2008

Basic Clin Pharma Tox

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Therapeutic agents derived from 8-aminoquinoline possess potent activity against hepatic stages of plasmodia. Bulaquine (CDRI 80/53), an enamine analogue of primaquine and a relatively new derivative of 8-aminioquinoline, synthesized at the Central Drug Research Institute, Lucknow, India, has shown promising activity against hypnozoites of Plasmodium vivax and Plasmodium ovale . Moreover, it has been found to be three to four times safer than primaquine in pre-clinical studies. In this study, global gene profiling using 22,827 probes was carried out in the livers of male Swiss mice to identify affected genes and cellular pathways at 6, 12 and 24 hr after a single oral dose of bulaquine (40 mg/kg). Present gene expression analysis revealed perturbation in 11 probes (P < 0.01 and 2-fold), including those corresponding to protein synthesis, cell division, protein ubiquitination, transcription regulation and steroid biosynthesis. Large numbers of probes (>100) corresponding to transcription, protein biosynthesis and intracellular signalling showed >2-fold differential expression at one of the time-points. Furthermore, 60 Gene Ontology terms were affected significantly (z score > 2). Conversely, serum biochemistry and histological evaluation of hepatic tissue showed no signs of stress. These gene expression alterations provide the first report of early hepatic response after an acute dose of bulaquine in mice liver; however, absence of traditional markers of hepatic stress might suggest a general hepatic response inherent in these transcriptional changes. Interestingly, the total number of affected probes was less as compared to that previously reported for primaquine.Malaria is a major health problem in areas where infection is endemic and in travellers returning to non-endemic areas. The infection caused by four species of Plasmodium in human beings results in approximately 2.7 million deaths worldwide each year [1]. Of these, Plasmodium falciparum led cerebral infection is the most life-threatening, whereas Plasmodium vivax and Plasmodium ovale led frequent relapses result in much suffering and temporary disability in a large number of infected individuals. Tissue schizonticides can act on the hepatic forms of the parasite to prevent the development of erythrocytic stage and consequent relapses. Chemotherapeutic agents of the 8-aminoquinoline group are particularly important in this regard, as they possess excellent tissue schizonticidal activity (causal prophylactic and radical curative) against persistent liver stages of the P. vivax and P. ovale responsible for the malarial relapses. Of all the important 8-aminoquinoline derivatives, synthesized primaquine is the only clinically used antirelapse antimalarial. However, persistent use of primaquine as the leading therapeutic armor is limited because of its well-documented adverse effects, namely, methaemoglobinaemia and cyanosis, haemolytic anaemia in G6PD-deficient individuals, hepatotoxicity, gastrointestinal distress, epigastric discomfort, anorexia,...

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Recent developments in 8-aminoquinoline antimalarials

Cited by 6 publications

References 91 publications

8-Aminoquinolines Active against Blood Stage Plasmodium falciparum In Vitro Inhibit Hematin Polymerization

8-Aminoquinolines Active against Blood Stage Plasmodium falciparum In Vitro Inhibit Hematin Polymerization

In Vitro and In Vivo pharmacokinetic studies of bulaquine (analogue of primaquine), a novel antirelapse antimalarial, in rat, rabbit and monkey—highlighting species similarities and differences

Identification of Differentially Expressed Genes after Acute Exposure to Bulaquine (CDRI 80/53) in Mice Liver

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