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In this work, a series of nineteen novel pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids were synthesized as potent antimalarial agents by covalently linking the scaffolds of 4-aminoquinoline and pyrano[2,3-c]pyrazoles via an ethyl linker and characterized using Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR). Molecular docking was used to test each hybrid's and standard chloroquine's ability to bind to Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH), an important enzyme in the parasite's glycolytic pathway. The hybrid compounds had a stronger binding affinity than the standard chloroquine (CQ). The schizontical antimalarial test of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrid compound shows that all nineteen hybrid compounds were potent with the IC50 values ranging from 0.0151 to 0.301 µM against the CQ-sensitive 3D7 P. falciparum strain, and were active against the CQ-resistant K1 P. falciparum strain with the IC50 values ranging from 0.01895 to 2.746 µM. All the tested hybrid compounds were less potent than the standard drug chloroquine dipaspate (CQDP) against the CQ-sensitive 3D7 strain. In contrast, nine of the nineteen hybrids (16d, 16g, 16h, 16i, 16l, 16n, 16o, 16r, and 16s) displayed superior antimalarial activity than the CQDP against the CQ-resistant K1 P. falciparum strain. Among all the tested hybrids, 16c against the 3D7 strain and 16h against the K1 strain were the most promising antimalarial agents with 0.0151 and 0.01895 µM of IC50 values, respectively. In addition, the compounds were selective, showing moderate to low cytotoxic activity against a human normal liver WRL68 cell line. The synthesis of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids introduces new chemical entities that have the potential to exhibit potent antimalarial activity. It could address the ongoing challenge of drug resistance in malaria treatment.

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Malaria tropica, caused by the parasite Plasmodium falciparum (P. falciparum), remains one of the greatest public health burdens for humankind. Due to its pivotal role in parasite survival, the energy metabolism of P. falciparum is an interesting target for drug design. To this end, analysis of the central metabolite adenosine triphosphate (ATP) is of great interest. So far, only cell-disruptive or intensiometric ATP assays have been available in this system, with various drawbacks for mechanistic interpretation and partly inconsistent results. To address this, we have established fluorescent probes, based on Förster resonance energy transfer (FRET) and known as ATeam, for use in blood-stage parasites. ATeams are capable of measuring MgATP2- levels in a ratiometric manner, thereby facilitating in cellulo measurements of ATP dynamics in real-time using fluorescence microscopy and plate reader detection and overcoming many of the obstacles of established ATP analysis methods. Additionally, we established a superfolder variant of the ratiometric pH sensor pHluorin (sfpHluorin) in P. falciparum to monitor pH homeostasis and control for pH fluctuations, which may affect ATeam measurements. We characterized recombinant ATeam and sfpHluorin protein in vitro and stably integrated the sensors into the genome of the P. falciparum NF54attB cell line. Using these new tools, we found distinct sensor response patterns caused by several different drug classes. Arylamino alcohols increased and redox cyclers decreased ATP; doxycycline caused first-cycle cytosol alkalization; and 4-aminoquinolines caused aberrant proteolysis. Our results open up a completely new perspective on drugs' mode of action, with possible implications for target identification and drug development.

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Amongst heterocyclic compounds, quinoline and its derivatives are advantaged scaffolds that appear as a significant assembly motif for developing new drug entities. Aminoquinoline moiety has gained significant attention among researchers in the 21stcentury. Considering the biological and pharmaceutical importance of aminoquinoline derivatives, herein, we review the recent developments (since 2019) in various biological activities of the 4-aminoquinoline scaffold hybridized with diverse heterocyclic moieties such as quinoline, pyridine, pyrimidine, triazine, dioxine, piperazine, pyrazoline, piperidine, imidazole, indole, oxadiazole, carbazole, dioxole, thiazole, benzothiazole, pyrazole, phthalimide, adamantane, benzochromene, and pyridinone. Moreover, by gaining knowledge about SARs, structural insights, and molecular targets, this review may help medicinal chemists design cost-effective, selective, safe, and more potent 4-aminoquinoline hybrids for diverse biological activities.

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Objectives: The ongoing fight against endemic diseases is necessary due to the growing resistance of malarial parasites to widely accessible medications. Thus, there has been an ongoing search for antimalarial medications with improved efficacy. The goal of this study was to develop derivatives of benzoheterocyclic 4-aminoquinolines with enhanced activities and better binding affinities than the original compounds. Methods: Thirty-four derivatives of benzoheterocyclic 4-aminoquinolines were docked (using a model of dihydrofolate reductase-thymidylate synthase [DRTS] protein) with Molegro software to identify the compound with the minimum docking score as a design template. The generated quantitative structure-activity model was employed to estimate the activity of the designed derivatives. The derivatives were also docked to determine the most stable derivatives. Furthermore, the designed derivatives were tested for their drug-likeness and pharmacokinetic properties using SwissADME software and pkCSM web application, respectively. Results: Compound H-014, (N-(7-chloroquinolin-4-yl)-2-(4-methylpiperazin-1-yl)-1,3-benzoxazol-5-amine) with the lowest re-rank score of -115.423 was employed as the design template. Then 10 derivatives were further designed by substituting -OH, -OCH3, -CHO, -F, and -Cl groups at various positions of the template. We found that the designed derivatives had improved activities compared to the template. The docking scores of the designed derivatives were lower than those of the original derivatives. Derivative h-06 (7-methoxy-4-((2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)amino)quinolin-6-ol) with four hydrogen bonds was identified as the most stable due to its lowest re-rank score (-163.607). While all of the designed derivatives satisfied both the Lipinski and Verber rules, some derivatives such as h-10 (cytochrome P450 1A2 [CYP1A2]); h-05, h-08, h-09, and h-10 [CYP2C19]; and h-03, h-07, h-08, and h-10 [renal organic cation transporter 2 substrate]) showed poor absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Conclusion: Ten derivatives of benzoheterocyclic 4-aminoquinolines were designed with improved efficacies. Derivatives that follow Lipinski and Verber rules and are mostly non-toxic and non-sensitive to the skin can be utilized in the development of effective antimalarial medications.

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Malaria is the fifth most lethal parasitic infection in the world. Antimalarial medications have played a crucial role in preventing and eradicating malaria. Numerous heterocyclic moieties have been incorporated into the creation of effective antimalarial drugs. The 4-aminoquinoline moiety is favoured in antimalarial drug discovery due to the diverse biological applications of its derivative. Since the 1960s, 4-aminoquinoline has been an important antimalarial drug due to its low toxicity, high tolerability, and rapid absorption after administration. This review focused on the antimalarial efficacy of the 4-aminoquinoline moiety hybridised with various heterocyclic scaffolds developed by scientists since 2018 against diverse Plasmodium clones. It could aid in the future development of more effective antimalarial agents.

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The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named MG3, against P. falciparum drug-resistant parasites. Here, we report the optimized and safer synthesis of MG3, now suitable for a scale-up, and its additional in vitro and in vivo characterization. MG3 is active against a panel of P. vivax and P. falciparum field isolates, either alone or in combination with artemisinin derivatives. In vivo MG3 is orally active in the P. berghei, P. chabaudi, and P. yoelii models of rodent malaria with efficacy comparable, or better, than that of CQ and of other quinolines under development. The in vivo and in vitro ADME-Tox studies indicate that MG3 possesses a very good pre-clinical developability profile associated with an excellent oral bioavailability, and low toxicity in non-formal preclinical studies on rats, dogs, and non-human primates (NHP). In conclusion, the pharmacological profile of MG3 is in line with those obtained with CQ or the other quinolines in use and seems to possess all the requirements for a developmental candidate.

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BACKGROUND: Polypharmacology means drugs having interactions with multiple targets of a unique disease or many disease pathways. This concept has been greatly appreciated against complex diseases, such as oncology, CNS disorders, and anti-infectives. METHODS: The integration of diverse compounds available on public databases initiates polypharmacological drug discovery research. Immunocompromised patients may suffer from complex diseases. Multiple-component drug formulations may produce side effects and resistance issues due to unintended drug-target interactions. RESULTS: Polypharmacology remains a novel avenue to propose a more effective and less toxic treatment. The 4-amino quinoline scaffold has become an important construction motif for the development of new drugs against lifestyle diseases like cancer and infectious diseases like tuberculosis and malaria. CONCLUSION: The present study is an attempt to explore the polypharmacological effects of 4- aminoquinoline drugs to combat malaria, cancer, and tuberculosis.

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The development of sub-type selective α1 adrenoceptor ligands has been hampered by the high sequence similarity of the amino acids forming the orthosteric binding pocket of the three α1 adrenoceptor subtypes, along with other biogenic amine receptors. One possible approach to overcome this issue is to target allosteric sites on the α1 adrenoceptors. Previous docking studies suggested that one of the quinoline moieties of a bis(4-aminoquinoline), comprising a 9-carbon methylene linker attached via the amine groups, could interact with residues outside of the orthosteric binding site while, simultaneously, the other quinoline moiety bound within the orthosteric site. We therefore hypothesized that this compound could act in a bitopic manner, displaying both orthosteric and allosteric binding properties. To test this proposition, we investigated the allosteric activity of a series of bis(4-aminoquinoline)s with linker lengths ranging from 2 to 12 methylene units (designated C2-C12). A linear trend of increasing [3H]prazosin dissociation rate with increasing linker length between C7 and C11 was observed, confirming their action as allosteric modulators. These data suggest that the optimal linker length for the bis(4-aminoquinoline)s to occupy the allosteric site of the α1A adrenoceptor is between 7 and 11 methylene units. In addition, the ability of C9 bis(4-aminoquinoline) to modulate the activation of the α1A adrenoceptor by norepinephrine was subsequently examined, showing that C9 acts as a non-competitive antagonist. Our findings indicate that the bis(4-aminoquinolines) are acting as allosteric modulators of orthosteric ligand binding, but not efficacy, in a bitopic manner.

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The tumor microenvironment contains high concentrations of TGFß, a crucial immunosuppressive cytokine. TGFß stimulates immune escape by promoting peripheral immune tolerance to avoid tumoricidal attack. Small-molecule inhibitors of TGFßR1 are a prospective method for next-generation immunotherapies. In the present study, we identified selective 4-aminoquinoline-based inhibitors of TGFßR1 through structural and rational-based design strategies. This led to the identification of compound 4i, which was found to be selective for TGFßR1 with the exception of MAP4K4 in the kinase profiling assay. The compound was then further optimized to remove MAP4K4 activity, since MAP4K4 is vital for proper T-cell function and its inhibition could exacerbate tumor immunosuppression. Optimization efforts led to compound 4s that inhibited TGFßR1 at an IC50 of 0.79 ± 0.19 nM with 2000-fold selectivity against MAP4K4. Compound 4s represents a highly selective TGFßR1 inhibitor that has potential applications in immuno-oncology.

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OBJECTIVE: The antimalaria 4-aminoquinoline drugs chloroquine and HCQ are used in the treatment of a wide range of CTDs. Data to inform on the safety of their use in pregnancy are limited. METHODS: In a Danish nationwide cohort study from 1996 through 2016, we identified 4-aminoquinoline-exposed pregnancies from a cohort of 1 240 875 pregnancies to investigate the associated risks of major birth defects, preterm birth, and small size for gestational age (SGA). Distinct study cohorts of propensity-score-matched 4-aminoquinoline-exposed and unexposed pregnancies (in a 1:1 ratio) were established for each outcome analysis. The association with the outcomes was assessed by prevalence odds ratios (ORs) estimated through logistic regression. The associated risks for chloroquine and HCQ were individually assessed through additional analyses. RESULTS: A total of 1487 pregnancies exposed to 4-aminoquinolines (1184 chloroquine- and 303 HCQ-exposed) were identified. Among the 983 pregnancies exposed to 4-aminoquinolines in the first trimester, 34 infants (3.5%) were diagnosed with major birth defects as compared with 36 (3.7%) among the matched unexposed pregnancies (prevalence OR, 0.94; 95% CI: 0.59, 1.52). Exposure to 4-aminoquinolines in pregnancy was neither associated with an increased risk of preterm birth (prevalence OR, 0.97; 95% CI: 0.73, 1.28) or SGA (prevalence OR, 1.18; 95% CI: 0.93, 1.50), compared with unexposed pregnancies. No significant associations between exposure to chloroquine or HCQ individually and risk of the outcomes were identified. CONCLUSION: Among pregnancies exposed to 4-aminoquinolines (chloroquine and HCQ), no increased risk of major birth defects, preterm birth, or SGA was identified.

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Aim: Cysteine proteases are important molecular targets involved in the replication, virulence and survival of parasitic organisms, including Trypanosoma and Leishmania species. Methodology & results: Analogs of the 7-chloro-N-[3-(morpholin-4-yl)propyl]quinolin-4-amine were synthesized and their inhibitory activity against the enzymes cruzain and rhodesain as well as against promastigotes forms of Leishmania species and epimastigotes forms of Trypanosoma cruzi were evaluated. Five compounds showed activity against both enzymes with half maximal inhibitory concentration (IC50) values ranging from 23 to 123 µM. Among these, compounds 3 and 4 displayed leishmanicidal activity; compound 4 was the most promising with IC50 values <10 µM and no cytotoxicity for uninfected cells. Conclusion: The results obtained indicate that cysteine proteases are likely to be the molecular target of compounds 3 and 4.

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Malaria is a life threatening disease caused by microscopic parasites called Plasmodium that are transmitted to human beings by mosquitoes. Single celled Eukaryotic plasmodium parasite is responsible to cause malaria in human beings and is transmitted by bite of Anopheles species mosquitoes. Resurgence of malaria towards the end of 20th Century is due to failure of its eradication completely. Parasite recurrence occurs due to high densities of parasite, low immunity and non opimized drug concentration. The ineffective eradications strategies were due to indefinable complex life cycle of Plasmodium and emergence of drugs resistant strains of Plasmodium falciparum (Pf) including Artemisinin and Artemisinin based combination therapy (ACT). The vector of the disease i.e. mosquitoes became resistive towards Pyrethroids, which are only class of insecticides recommended for vector control. Artemisinin based combination therapy gained acceptance as an effective approach to counter the spread of disease resistance to chloroquine, sulfadoxine, pyrimethamine and other anti malarial drugs. Understanding the underlying molecular basis of the pathogenesis led to the development of some new diagnostic, drugs and insecticides. Reports on the use of new combination therapies reduced the burden of disease worldwide. Some of the new combination therapies are in clinical stage of development that have efficacy against drug resistant parasites and the potential to use in single dose regimens to improve compliance. The current review represents the recent anti-malarial research carried out globally especially in the class of synthesis of small molecule and natural product derivatives as potent anti-malarial drugs. The review also covers the advancement in the anti-malarial vaccine development although goal for vaccine development still remains elusive.

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Synthesis of C-5-substituted 1,3-dioxoisoindoline-4-aminoquinolines having amide group as a spacer was developed with an intent to evaluate their antiplasmodial activities. The synthesized dioxoisoindoline-aminoquinolines tethered with ß-alanine as a spacer and secondary amine as substituent displayed good anti-plasmodial activities. Compound 7j, with an optimum combination of ß-alanine and an ethyl chain length as linker along with diethylamine as the secondary amine counterpart at dioxoisoindoline proved to be most potent and non-cytotoxic with IC50 of 0.097 µM against W2 strain of P. falciparum and a selective index of >2000.

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A new class of quinoline derivatives, bearing amino chains at C-4 and a styryl group at C-2, were tested on Leishmania donovani promastigotes and axenic and intracellular Leishmania pifanoi amastigotes. The introduction of the C-4 substituent improves the activity, which is due to interference with the mitochondrial activity of the parasite and its concomitant bioenergetic collapse by ATP exhaustion. Some compounds show a promising antileishmanial profile, with low micromolar or submicromolar activity on promastigote and amastigote forms and a good selectivity index.

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Alzheimer's disease (AD) is one of the most common age-related neurodegenerative disorders. Aggregation of amyloid-ß peptide into extracellular plaques with incorporation of metal ions, such as Cu2+, and reduction of the neurotransmitter acetylcholine levels are among the factors associated to the AD brain. Hence, a series of 7-chloro-4-aminoquinoline Schiff bases (HLa-e) were synthesized and their cytotoxicity and anti-cholinesterase activity, assessed for Alzheimer's disease. The intrinsic relationship between Cu2+ and the amyloidogenic plaques encouraged us to investigate the chelating ability of HLa-e. Dimeric tetracationic compounds, [Cu2(NHLa-e)4]Cl4, containing quinoline protonated ligands were isolated from the reactions with CuCl2·2H2O and fully characterized in the solid state, including an X ray diffraction study, whereas EPR data showed that the complexes exist as monomers in DMSO solution. The inhibitory activity of all compounds was evaluated by Ellman's spectrophotometric method in acetylcholinesterase (AChE) from Electrophorus electricus and butyrylcholinesterase (BChE) from equine serum. HLa-e and [Cu(NHLd)2]Cl2 were selective for AChE (IC50 = 4.61-9.31 µM) and were not neurotoxic in primary brain cultures. Docking and molecular dynamics studies of HLa-e inside AChE were performed and the results suggested that these compounds are able to bind inside AChE similarly to other AChE inhibitors, such as donepezil. Studies of the affinity of HLd for Cu2+ in DMSO/HEPES at pH 6.6 and pH 7.4 in µM concentrations showed formation of analogous 1:2 Cu2+/ligand complexes, which may suggest that in the AD-affected brain HLd may scavenge Cu2+ and the complex, also inhibit AChE.

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Analogues of 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]indol-4-amine 1, a known cruzain inhibitor, were synthesized using a molecular simplification strategy. Five series of analogues were obtained: indole, pyrimidine, quinoline, aniline and pyrrole derivatives. The activity of the compounds was evaluated against the enzymes cruzain and rhodesain as well as against Trypanosoma cruzi amastigote and trypomastigote forms. The 4-aminoquinoline derivatives showed promising activity against both enzymes, with IC50 values ranging from 15 to 125µM. These derivatives were selective inhibitors for the parasitic proteases, being unable to inhibit mammalian cathepsins B and S. The most active compound against cruzain (compound 5a; IC50=15µM) is considerably more synthetically accessible than 1, while retaining its ligand efficiency. As observed for the original lead, compound 5a was shown to be a competitive enzyme inhibitor. In addition, it was also active against T. cruzi (IC50=67.7µM). Interestingly, the pyrimidine derivative 4b, although inactive in enzymatic assays, was highly active against T. cruzi (IC50=3.1µM) with remarkable selectivity index (SI=128) compared to uninfected fibroblasts. Both 5a and 4b exhibit drug-like physicochemical properties and are predicted to have a favorable ADME profile, therefore having great potential as candidates for lead optimization in the search for new drugs to treat Chagas disease.

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BACKGROUND: Until 2006, the Mauritanian Ministry of Health recommended chloroquine and sulfadoxine-pyrimethamine for first- and second-line treatment of uncomplicated malaria, respectively. This study assessed the clinical efficacy of sulfadoxine-pyrimethamine in Kobeni as first-line treatment. MATERIALS AND METHODS: This study included 55 patients with Plasmodium falciparum infections, who were treated with sulfadoxine-pyrimethamine and followed up for 28 days. Isolates were genotyped to distinguish between recrudescence and reinfection. Treatment success rates and survival were analysed per protocol to evaluate drug efficacy. RESULTS: After inclusion, 2 patients were excluded for protocol violations, and 3 patients were lost to follow-up. Of the remaining 50 patients (per protocol population), 43 (86%) had adequate clinical and parasitological responses. Of the 7 patients with treatment failure, 5 (10%) were early failures, while 2 (4%) had initially responded and had late clinical failure on day 7, associated with recrudescence. With the exception of one adult weighing 91 kg, all treatment failures occurred in children aged from 7 to 12 years. CONCLUSIONS: Sulfadoxine-pyrimethamine monotherapy was moderately effective but insufficiently reliable in view of the relatively high rate of early treatment failure. The high prevalence of chloroquine resistance found in earlier studies and the results of the present study on sulfadoxine-pyrimethamine justify the change in national policy and systematic use of artemisinin-based combination therapy for first-line treatment of P. falciparum malaria in Mauritania.

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Current drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivatives with submicromolar potencies against T. brucei. Among these compounds, the guanidinononyltacrine analogue 15e exhibits a 5-fold increased antitrypanosomal potency, 10-fold increased selectivity, and 100-fold decreased anticholinesterasic activity relative to the parent huprine Y. Its biological profile, lower molecular weight relative to dimeric compounds, reduced lipophilicity, and ease of synthesis, make it an interesting anti-HAT lead, amenable to further optimization to eliminate its remaining anticholinesterasic activity.

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A diverse set of highly substituted 4-aminoquinolines was synthesized from ynamides, triflic anhydride, 2-chloropyridine, and readily accessible amides in a mild one-step procedure.

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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 analogues, 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 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively.

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