Synthesis and antiplasmodial activity of new heteroaryl derivatives of 7-chloro-4-aminoquinoline

Casagrande, Manolo; Barteselli, A.; Basilico, Nicoletta; Taramelli, Donatella; Sparatore, Anna

doi:10.1016/j.bmc.2012.07.040

Cited by 28 publications

(26 citation statements)

References 33 publications

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“…The chloroquine (CQ)-sensitive (D10) and the CQ-resistant (W2) strains of P. falciparum were maintained at 5% hematocrit (human type A-positive red blood cells [RBCs]) in RPMI 1640 (EuroClone) medium supplemented with 1% AlbuMax II (lipid-rich bovine serum albumin) (Invitrogen), 0.01% hypo-xanthine (Sigma), 20 mM HEPES (EuroClone), and 2 mM glutamine (EuroClone). All the cultures were maintained at 37°C in a standard gas mixture consisting of 1% O 2 , 5% CO 2 , and 94% N 2 (11).…”

Section: Methodsmentioning

confidence: 99%

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Parapini

Olliaro

Navaratnam

et al. 2015

Antimicrob Agents Chemother

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f Artemisinins are peroxidic antimalarial drugs known to be very potent but highly chemically unstable; they degrade in the presence of ferrous iron, Fe(II)-heme, or biological reductants. Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying to in vitro testing and clinical situations. Dihydroartemisinin (DHA) is studied here because it is an antimalarial drug on its own and the main metabolite of other artemisinins. The behaviors of DHA in phosphate-buffered saline, plasma, or erythrocyte lysate at different temperatures and pH ranges were examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay on Plasmodium falciparum, and the extent of decomposition of DHA was established through use of high-performance liquid chromatography with electrochemical detection analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide (CO). A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3 h and almost completely abolished after 24 h. Serum-enriched media also affected DHA activity. Effects were temperature and pH dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpreting in vitro studies, prone as their results are to experimental and drug storage conditions. Disorders such as fever, hemolysis, or acidosis associated with malaria severity may contribute to artemisinin instability and reduce their clinical efficacy.A rtemisinin derivatives have been the most potent antimalarials available to date; they are highly active against all Plasmodium species and parasite stages, including young gametocytes, and constitute the backbone of malaria case management for severe and uncomplicated malaria (as a component of artemisinin combination therapy [ACT]) (1). The emergence and spread of artemisinin resistance in Southeast Asia is, therefore, a serious threat to malaria control (2, 3).All artemisinin derivatives share a distinctive 1,2,4-trioxane pharmacophore, which confers their antimalarial activity (the corresponding acyclic analogues lacking the endoperoxide bridge are inactive) (4, 5) but also makes these molecules particularly highly reactive and thus difficult to quantify in plasma or blood. Of the various artemisinin-type compounds in use, dihydroartemisinin (DHA), the reduced lactol derivative of artemisinin, is an antimalarial compound on its own (currently coformulated with piperaquine) and the main bioactive metabolite of artesunate and artemether. DHA itself is chemically fragile and displays a marked propensity to undergo ring opening of the lactol and rearrangement under neutral conditions, leading to a new, biologically active peroxide, which in turn rapidly decays to the inert end product deoxyartemisi...

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Section: Methodsmentioning

confidence: 99%

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Parapini

Olliaro

Navaratnam

et al. 2015

Antimicrob Agents Chemother

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“…Azoles are an important class of nitrogen containing heterocyclic compounds laced with various biological activities [25, [61][62][63][64][65][66][67][68][69][70][71][72][73][74]. Inclusion of such heterocyclic molecules is often known to enhance the biological activities and malaria is not the exception of it.…”

Section: Modification At N-alkyl Amino Side Chainmentioning

confidence: 99%

Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: A review

Mushtaque¹,

Shahjahan²

2015

European Journal of Medicinal Chemistry

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“…It appears that the heme detoxification pathway is not directly involved in CQ resistance; it has been reported that CQ resistance is related to mutations in drug transporters (PfCRT, Pgh1, and PfMRP) that affect drug accumulation in the parasite by reducing drug uptake, or increasing drug efflux, or both. 7,8 Recent research to develop novel ACQ-based compounds that bypass CQ resistance is resulting in the synthesis of potentially promising new antimalarial agents, including 2 0 ,2 0 -dimethyldiamines, 9 ACQ heteroaryl derivatives, 10 4-aminoquinoline/clotrimazole-based hybrids, 11 aminoquinoline-pyrimidine hybrids, 12 aminoquinoline-tetrazole combinations, 13 and quinoline-pyrimidine hybrids. 14 recently reported with excellent in vitro potencies against CQR W2 and CQS 3D7 P.f.…”

Section: Introductionmentioning

confidence: 99%

Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice

Opsenica

Verbić

Tot

et al. 2015

Bioorganic & Medicinal Chemistry

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Synthesis and antiplasmodial activity of new heteroaryl derivatives of 7-chloro-4-aminoquinoline

Cited by 28 publications

References 33 publications

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: A review

Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice

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