Design and synthesis of new antimalarial agents from 4-aminoquinoline (original) (raw)
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Synthesis and Antimalarial Activity of Side Chain Modified 4-Aminoquinoline Derivatives
Journal of Medicinal Chemistry, 2007
A new series of side-chain modified 4-aminoquinolines have been synthesized and found active against P. falciparum in vitro and P. yoelli in vivo. Compounds 6, 11, 12, and 19 exhibited superior in vitro activity compared to chloroquine. Selected compounds 6, 12, and 19 exhibited significant suppression in the in vivo assay. These analogs form a complex with hematin and inhibit the -hematin formation, suggesting that this class of compounds act on a heme polymerization target.
Synthesis and Evaluation of 7-Substituted 4-Aminoquinoline Analogues for Antimalarial Activity
Journal of Medicinal Chemistry, 2011
We previously reported that substituted 4-aminoquinolines with a phenylether substituent at the 7position of the quinoline ring and the capability of intramolecular hydrogen bonding between the protonated amine on the side chain and a hydrogen bond acceptor on the amine's alkyl substituents exhibited potent antimalarial activity against the multi-drug resistant strain P. falciparum W2. We employed a parallel synthetic method to generate diaryl ether, biaryl, and alkylaryl 4-aminoquinoline analogs, in the background of a limited number of side chain variations that had previously afforded potent 4-aminoquinolines. All subsets were evaluated for their antimalarial activity against the chloroquine-sensitive strain 3D7 and the chloroquineresistant K1 and cytotoxicity mammalian cell lines. While all three arrays showed good antimalarial activity, only the biaryl-containing subset showed consistently good potency against the drug-resistant K1strain good selectivity with regard to mammalian cytotoxicity. Overall, our data indicate that the biaryl-containing series contains promising candidates for further study.
Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.
Synthesis and in Vitro and in Vivo Antimalarial Activity of New 4-Anilinoquinolines †
Journal of Medicinal Chemistry, 2001
A new series of 4-aminoquinoline Mannich base derivatives were prepared by selectively modifying the aliphatic diethyl amino function of isoquinewith different aliphatic/aromatic heterocyclic primary amino moieties at Mannich side chain. The synthesized compounds were characterized by their physical,analytical and spectral data, and screened for in vitro antimalarial activity against a chloroquine-sensitive 3D7 strain of Plasmodium falciparum. All the compounds showed in vitro antimalarial activity at the tested dose; which, however, was considerably less than that of the standard reference drug, chloroquine. Among the synthesized compounds, compounds with cyclohexyl (2f), methyl (2c) substitutions showed comparatively better activity than other compounds with n-octyl (2a), propyl (2b), 3-aminopropyl (2d) and furan-2-ylmethyl (2e) substitutions at aminomethyl side chain. The results clearly demonstrate that compound with saturated cycloalkylmoiety (cyclohexyl) exhibitedto some extentmore activity as compared to the compound with heterocyclicmoiety (furan-2-ylmethyl); and compounds with short chain alkyl substitutions (methyl, propyl etc.) were found to be more potent than that of compounds with long chain alkyl substitution (n-octyl).
Journal of medicinal chemistry, 2017
Emergence of drug resistant Plasmodium falciparum including artemisinin-tolerant parasites highlights the need for new antimalarials. We have previously shown that dibemequines, 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains, are efficacious. In this study, analogues in which the terminal phenyl group of the dibemethin was replaced with a 2-pyridyl group and in which the 4-amino-7-chloroquinoline was either maintained or replaced with a 4-aminoquinoline-7-carbonitrile were synthesized in an effort to improve druglikeness. These compounds exhibited significantly improved solubility and decreased lipophilicity and were potent against chloroquine-sensitive (NF54) and -resistant (Dd2 and 7G8) P. falciparum strains with 5/6 having IC< 100 nM against the NF54 strain. All inhibited both β-hematin (synthetic hemozoin) formation and hemozoin formation in the parasite. Parasitemia was reduced by over 90% in P. berghei infected mice in 3/6 derivatives following...
Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities
Bioorganic & Medicinal Chemistry Letters, 2005
A simple two-step synthesis method was used to make 51 B-ring-substituted 4-hydroxyquinolines allowing analysis of the effect of ring substitutions on inhibition of growth of chloroquine sensitive and resistant strains of Plasmodium falciparum, the dominant cause of malaria morbidity. Substituted quinoline rings other than the 7-chloroquinoline ring found in chloroquine were found to have significant activity against the drug-resistant strain of P. falciparum W2.
Antimicrobial agents and chemotherapy, 1999
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 falciparum clones 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 growt...
New 4-aminoquinolines as moderate inhibitors of P. falciparum malaria
Synthesis of novel aminoquinoline derivatives has been accomplished and their activity against malaria strains has been examined. The compounds showed moderate in vitro antimalarial activity against two P. falciparum strains, 3D7 (CQ susceptible clone) and Dd2 (CQ resistant clone). Three aminoquinolines were further examined for antimalarial efficacy in a mouse model using a modified Thompson test. In this model, mice were infected with P. berghei-infected red blood cells, and drugs were administered orally. Antimalarial 3 was found toxic at a dose of 320 (mg/kg)/day in 3/6 mice, however, 2/6 mice of the same group survived through day 31, and one of them was cured.
Bioorganic & Medicinal Chemistry, 2015
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.
II 196 4-aminoquinolines as Antimalarial Drugs
2016
Malaria is a widespread parasitic infection with high mortality rates and a distribution which happens to correlate with the distribution of poverty. The class of drugs known as the 4-aminoquinolines has shown promise in treating malaria, especially infection by the Plasmodium falciparum parasite. While drugs such as chloroquine heralded the start of 4-aminoquinoline prophylaxis, resistance soon developed and became widespread. By investigating the structureactivity relationships of chloroquine, it was possible for medicinal chemists to devise novel compounds such as amodiaquine and isoquine for treatment of chloroquine-resistant strains of the parasite. These structural alterations ranged from compounds which could undergo bioactivation into toxic metabolites, to fluorinated alternatives and structural isomers. The present review aims to discuss the chemical investigation into chloroquine and its alternatives, and to examine the prospects of future antimalarial drugs of the 4-amino...