Isoquine and Related Amodiaquine Analogues:  A New Generation of Improved 4-Aminoquinoline Antimalarials

O’Neill, Paul M.; Mukhtar, Amira; Stocks, Paul A.; Randle, Laura E.; Hindley, Stephen; Ward, Stephen A.; Storr, R. C.; Bickley, Jamie F.; O’Neil, Ian A.; Maggs, James L.; Hughes, Ruth H; Winstanley, Peter; Bray, Patrick G.; Park, B Kevin

doi:10.1021/jm030796n

Cited by 127 publications

(124 citation statements)

References 44 publications

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“…The organic solution was washed with water, dried over anhydrous sodium sulphate and then evaporated to dryness under reduced pressure to yield the crude product. The product was recrystallized from methanol [11,17] .…”

Section: General Procedures Of Synthesismentioning

confidence: 99%

Synthesis, Antimalarial Activity Evaluation and Drug likeness Study of Some New Quinoline-Lawsone Hybrids

Kashyap¹,

Chetia²,

Rudrapal³

2016

pharmaceutical-sciences

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Kashyap, et al.: Antimalarial Activity of Quinoline-Lawsone HybridsIn the present study, a new series of quinoline-lawsone hybrid compounds were synthesized and evaluated in vitro for their antimalarial effectiveness. Several aliphatic and aromatic/heteroaromatic diamines were used as connecting/bridge moiety between the 7-chloro-4-aminoquinoline and 3-amino-1, 4-naphthoquinone pharmacophoric scaffolds. The molecular properties of hybrid compounds were also studied in silico for drug-likeness assessment based on Lipinski's rule of five. Results of antimalarial activity reveal that all the tested compounds showed activity against both chloroquine sensitive (RKL-2) and chloroquine resistant (RKL-9) strains of Plasmodium falciparum which was considerably less as compared to the standard drug, chloroquine. All the compounds exhibited same degree of activity at the tested dose against sensitive strain with IC 50 values 0.391-1.033 µg/ml. Furthermore, four compounds which were additionally tested against resistant strain also showed activity with IC 50 values from 0.684 to 1.778 µg/ml at the same dose. The IC 50 values for CQ against sensitive and resistant strains of P. falciparum were found to be 0.0391 µg/ml and 0.305 µg/ml, respectively. From results it is apparent that the compound with a small alkyl bridge moiety diaminoethyl possesses better activity profile against both sensitive and resistant strains (IC 50 =0.391 and 0.684 µg/ml, respectively) than rest of the synthesized analogues. The results of drug-likeness studies showed that all newly designed quinoline-lawsone hybrids possess good drug-like properties, indicating their druglikeness behaviour is favourable for optimal antimalarial action. Assessment of drug-likeness score further implies the suitability of hybrid derivatives as drug-like molecules.Key words: Quinoline, lawsone, hybrid, bridge moiety, Plasmodium falciparum, resistant malariaOver the last few decades, the burden of malaria has increasingly become a serious health concern around the globe. The disease remains one of the most lethal infectious diseases of human beings affecting around 300-600 million people with about three million deaths per year globally [1] . Plasmodium falciparum is the most prevalent and deadly species among all malaria parasites, which causes severe complicated malaria such as cerebral malaria, and is responsible for most of the malaria-related deaths worldwide. Recent emergence of multidrug-resistant strains of P. falciparum has further complicated the issues of treating malaria using currently available antimalarial drugs [2][3][4] . However, with the development of novel and potent antimalarial agents the above challenging issue could be addressed.Chloroquine (CQ, fig. 1), a 4-aminoquinoline synthetic antimalarial, was once a highly potent drug against malaria. Literature reports suggest that 7-chloro-4-aminoquinoline nucleus of 4-aminoquinoline antimalarial drugs is responsible for their antimalarial action which could be attributed mainly due to the prevention o...

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Section: General Procedures Of Synthesismentioning

confidence: 99%

Synthesis, Antimalarial Activity Evaluation and Drug likeness Study of Some New Quinoline-Lawsone Hybrids

Kashyap¹,

Chetia²,

Rudrapal³

2016

pharmaceutical-sciences

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“…The resulting molecule isoquine (ISQ 1) 32 (Fig. 13) is more active against the chloroquine resistant K1 strain than amodiaquine 2 [175]. Unfortunately, as with AQ-13 31, the easy access of hydroxylating enzymes to the methylene groups in aposition of the nitrogen atom results in poor bioavailability.…”

Section: Tert-butyl-isoquinementioning

confidence: 99%

Antimalarial Drugs – What is in Use and What is in the Pipeline

Schlitzer¹

2008

Archiv der Pharmazie

129

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Malaria continues to be a potentially fatal threat to almost half of the world's population. In light of this threat, the armory to fight this disease is rather limited. Resistance against the most common and affordable antimalarials is widespread. Only few new drugs are in clinical development, most of them belong to long used classes of antimalarial drugs. This review will concisely cover the drugs which are currently in use, and describe the drug candidates which are in clinical evaluation.

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“…In contrast to AQ, IQ was excreted primarily as glucuronide, instead of glutathione conjugate. 10 Another promising compound from the class of the 4-aminoquinolines is tebuquine (TQ), which is a biaryl analogue of AQ with a p-chlorophenyl moiety substituted at the 5-position of the 4-hydroxyaniline side chain of AQ. TQ is significantly more active than AQ and CQ in both in vitro and in vivo tests.…”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Synthesis and Antimalarial Activity of New Isotebuquine Analogues

et al. 2007

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Amodiaquine (AQ) and tebuquine are 4-aminoquinoline antimalarials with Mannich base side chain and are highly effective against chloroquine (CQ)-resistant strains of Plasmodium falciparum. Clinical use of AQ has been severely restricted due to hepatoxicity and agranulocytosis side effects associated with its long term use. Lysosomal accumulation and bioactivation to generate reactive quinoneimine metabolite are implicated to be the cause of the observed AQ toxicities. To avoid the quinoneimine formation and thus the toxicity, a series of isotebuquine analogues and their N ω -oxides with hydroxy group meta to the amino rather than in para position of the aniline moiety were prepared. The new Mannich bases are highly active against both CQ-sensitive (D6) and -resistant (W2 and TM91C235) clones of P. falciparum with IC 50 in the range of 0.3-120 ng/mL. New compounds are1000-fold less toxic (IC 50 ) 0.7-6 µg/mL) to mouse macrophage cell line than to parasite cell lines. Mono-Mannich bases are more active than bis-Mannich bases. Mono-Mannich base 1a (IC 50 ) 0.3 ng/mL) is 20-fold more active than the corresponding trifluoromethyl analogue 1b. No appreciable difference in either toxicity or efficacy were observed between the new Mannich bases (m-hydroxyaniline derivatives) 1a or 2a and the corresponding p-hydroxyaniline derivatives. IntroductionMalaria is one of the most widespread diseases in many regions of the world, exposing millions of people to risk of infection and death. The 4-aminoquinolines such as chloroquine (CQ) are the most important and widely used class of drugs for treatment of malaria. Chloroquine has been the drug of choice for malaria treatment since the early 1950s, providing effective and safe treatment for millions of Plasmodium falciparum infected patients a year. Development of drug resistance to chloroquine in malaria has become a major health concern in malaria endemic areas, which has prompted a search for alternative antimalarials against the CQ-resistant strains. 1,2 As a result, several new classes of antimalarial drugs were developed; none has reached the same status of recognition as the drug of choice in malaria therapy as CQ.Amodiaquine (AQ), a new Mannich base 4-aminoquinoline, is effective against chloroquine-resistant strains of P. falciparum. 3 However, the clinical use of AQ has been severely restricted because of the hepatoxicity and agranulocytosis side effects associated with its long term use. 4,5 Recent reports indicate that AQ was metabolized by cytochrome P-450 oxidation to form reactive quinoneimine metabolite with subsequent conjugate addition of glutathione or cysteinyl function of the enzymes. 6,7 Lysosomal accumulation and bioactivation of reactive quinoneimine metabolite are implicated to be the cause of the observed AQ in vivo toxicity. 8,9 To avoid the quinoneimine metabolite formation, a series of isoquine and related analogues were reported in the literature. 10-12 Isoquine (IQ) is an analogue of AQ, in which the 4′-hydroxy group on the aniline ring of AQ is int...

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Isoquine and Related Amodiaquine Analogues: A New Generation of Improved 4-Aminoquinoline Antimalarials

Cited by 127 publications

References 44 publications

Synthesis, Antimalarial Activity Evaluation and Drug likeness Study of Some New Quinoline-Lawsone Hybrids

Synthesis, Antimalarial Activity Evaluation and Drug likeness Study of Some New Quinoline-Lawsone Hybrids

Antimalarial Drugs – What is in Use and What is in the Pipeline

Synthesis and Antimalarial Activity of New Isotebuquine Analogues

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