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Background: Malaria represents the major parasitic disease in tropical regions, and the development of new potent drugs is of pivotal importance. In this study, a series of hybrid molecules were designed by linking the 7-chloroquinoline core of chloroquine to different fluorinated flavonoid-related scaffolds. Materials & methods: Compounds were prepared by exploiting the click chemistry approach, allowing the introduction of a 1,2,3-triazole, a privileged structural motif in antiparasitic dug discovery. Results: Compounds 1b and 1c were the most interesting and were endowed with the highest in vitro activity, mainly against a resistant Plasmodium falciparum strain. They also inhibited hemozoin formation, and 1c was more effective than chloroquine against stage V gametocytes. Conclusion: The homoisoflavone core is a new, promising antimalarial scaffold that deserves further investigation.

A library of quinoline-based hydrazones bearing 1H-1,2,3-triazole core was designed, synthesized, and evaluated for their antiplasmodial activity against the drug-resistant Plasmodium falciparum W2 strain. The inclusion of pyrazine-2-carboxylic acid with a flexible propyl spacer afforded the most active scaffold with an IC

Malaria is the most lethal parasitic infections in the world. To address the emergence of drug resistance to current antimalarials, here we report the design and synthesis of new series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide hybrids by using multicomponent Petasis reaction as the key step and evaluated in vitro for their antimalarial effectiveness. The structure of all the compounds were confirmed by NMR Spectroscopy and mass spectrometry. Most of the compounds showed potent antimalarial activity against both CQ-sensitive (3D7) and CQ-resistant (W2) strains. A8, A5, and A4 are the most potent compounds that showed excellent anti-plasmodial activity against CQ-resistant strain in the nanomolar range with IC

Artemisinin resistance may facilitate selection of Plasmodium falciparum resistant to combination therapy partner drugs. We evaluated 99 P. falciparum isolates collected in 2021 from northern Uganda, where resistance-associated PfK13 C469Y and A675V mutations have emerged, and eastern Uganda, where these mutations are uncommon. With the ex vivo ring survival assay, isolates with the 469Y mutation (median survival 7.3% for mutant, 2.5% mixed, and 1.4% wild type) and/or mutations in Pfcoronin or falcipain-2a, had significantly greater survival; all isolates with survival > 5% had mutations in at least one of these proteins. With ex vivo growth inhibition assays, susceptibility to lumefantrine (IC50 14.6 vs. 6.9 nM, p 50 > 20 nM (p = 0.0002). Targeted sequencing of 819 isolates from 2015-21 identified multiple polymorphisms associated with altered drug susceptibility, notably decreased susceptibility to lumefantrine with PfK13 469Y (p = 6x10− 8) and chloroquine with PfCRT mutations (p = 1x10− 20). Our results raise concern regarding activity of artemether-lumefantrine, the first-line antimalarial in Uganda.

Effective chemotherapy is essential for controlling malaria. However, resistance of Plasmodium falciparum to existing antimalarial drugs has undermined attempts to control and eventually eradicate the disease. In this study, a series of 2-((substituted)(4-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)methyl)-6-substitutedphenol derivatives were prepared using Petasis reaction with a view to evaluate their activities against P. falciparum. The development of synthesized compounds (F1-F16) was justified through the study of H1 NMR, C13 NMR, mass spectra. Compound F1 and F2 were also structurally validated by single crystal X-ray diffraction analysis. All the compounds were evaluated for their in vitro antiplasmodial assessment against the W2 strain (chloroquine-resistant) of P. falciparum IC50 values ranging from 0.74-6.4 μM. Two compounds, F4 and F16 exhibited significant activity against W2 strain of P. falciparum with 0.75 and 0.74 μM. The compounds (F3-F6 and F16) were also evaluated for in vitro cytotoxicity against two cancer cell lines, human lung (A549) and cervical (HeLa) cells, which demonstrated non-cytotoxicity with significant selectivity indices. In addition, in silico ADME profiling and physiochemical properties predicts drug-like properties with a very low toxic effect. Thus, all these results indicate that tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine scaffolds may serve as models for the development of antimalarial agents.

Protease inhibitors represent a promising therapeutic option for the treatment of parasitic diseases such as malaria and human African trypanosomiasis. Falcitidin was the first member of a new class of inhibitors of falcipain-2, a cysteine protease of the malaria parasite Plasmodium falciparum. Using a metabolomics dataset of 25 Chitinophaga strains for molecular networking enabled identification of over 30 natural analogues of falcitidin. Based on MS/MS spectra, they vary in their amino acid chain length, sequence, acyl residue, and C-terminal functionalization; therefore, they were grouped into the four falcitidin peptide families A-D. The isolation, characterization, and absolute structure elucidation of two falcitidin-related pentapeptide aldehyde analogues by extensive MS/MS spectrometry and NMR spectroscopy in combination with advanced Marfey’s analysis was in agreement with the in silico analysis of the corresponding biosynthetic gene cluster. Total synthesis of chosen pentapeptide analogues followed by in vitro testing against a panel of proteases revealed selective parasitic cysteine protease inhibition and, additionally, low-micromolar inhibition of α-chymotrypsin. The pentapeptides investigated here showed superior inhibitory activity compared to falcitidin.

[Image: see text] A series of 25 conjugates has been synthesized to evaluate their antiplasmodial potency and cytotoxicity against the chloroquine resistant (CQR) W2 strain of P. falciparum and Vero kidney cell lines, respectively. Most of the compounds showed IC(50) values in the lower nM range and proved to be many fold more active than chloroquine (CQ). The studies were extended to decipher modes of action using techniques including UV–vis absorption, NMR titrations, and mass spectrometry, and conclusions were strengthened by docking and density functional theory (DFT) simulations. The most active compound, with IC(50) 15 nM and selectivity index >4000, proved to be an interesting template for antimalarial drug discovery. To the best of our knowledge this is the first report of a potent naphthalimide based antiplasmodial conjugate.

© 2022 Published by Elsevier Masson SAS., Malaria remains a prevalent infectious disease in developing countries. The first-line therapeutic options are based on combinations of fast-acting artemisinin derivatives and longer-acting synthetic drugs. However, the emergence of resistance to these first-line treatments represents a serious risk, and the discovery of new effective drugs is urgently required. For this reason, new antimalarial chemotypes with new mechanisms of action, and ideally with activity against multiple parasite stages, are needed. We report a new scaffold with dual-stage (blood and liver) antiplasmodial activity. Twenty-six spirooxadiazoline oxindoles were synthesized and screened against the erythrocytic stage of the human malaria parasite P. falciparum. The most active compounds were also tested against the liver-stage of the murine parasite P. berghei. Seven compounds emerged as dual-stage antimalarials, with IC50 values in the low micromolar range. Due to structural similarity with cipargamin, which is thought to inhibit blood-stage P. falciparum growth via inhibition of the Na + efflux pump PfATP4, we tested one of the most active compounds for anti-PfATP4 activity. Our results suggest that this target is not the primary target of spirooxadiazoline oxindoles and further studies are ongoing to identify the main mechanism of action of this scaffold., This work was supported by FCT (Fundação para a Ciência e a Tecnologia, I.P.) through iMed.ULisboa (UID/DTP/04138/2019), project PTDC/QUI-QOR/29664/2017, and PhD fellowship SFRH/BD/137544/2018 (E. Lopes). The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project Nº 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). Financial support from FCT and Portugal 2020 to the Portuguese Mass Spectrometry Network (Rede Nacional de Espectrometria de Massa – RNEM; LISBOA-01-0145-FEDER-402-022125) is also acknowledged.

Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84–99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children., Intermittent preventive treatment with dihydroartemisinin-piperaquine (DP) is protective in children against malaria. Here, the authors analyze plasma drug concentration, malaria incidence, and drug resistance markers from a clinical trial in Uganda and determine the optimal DP dosing regimen.

Effective chemotherapy is essential for controlling malaria. However, resistance of Plasmodium falciparum to existing antimalarial drugs has undermined attempts to control and eventually eradicate the disease. In this study, a series of 2-((substituted)(4-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)methyl)-6-substitutedphenol derivatives were prepared using Petasis reaction with a view to evaluate their activities against P. falciparum. The development of synthesized compounds (F1–F16) was justified through the study of H(1) NMR, C(13) NMR, mass spectra. Compound F1 and F2 were also structurally validated by single crystal X-ray diffraction analysis. All the compounds were evaluated for their in vitro antiplasmodial assessment against the W2 strain (chloroquine-resistant) of P. falciparum IC(50) values ranging from 0.74–6.4 μM. Two compounds, F4 and F16 exhibited significant activity against W2 strain of P. falciparum with 0.75 and 0.74 μM. The compounds (F3–F6 and F16) were also evaluated for in vitro cytotoxicity against two cancer cell lines, human lung (A549) and cervical (HeLa) cells, which demonstrated non-cytotoxicity with significant selectivity indices. In addition, in silico ADME profiling and physiochemical properties predicts drug-like properties with a very low toxic effect. Thus, all these results indicate that tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine scaffolds may serve as models for the development of antimalarial agents.

Quinoline-isoniazid-phthalimide triads have been synthesised to assess their antiplasmodial efficacy and cytotoxicity against chloroquine-resistant W2 strain of P. falciparum and Vero cells, respectively. Most of the synthesized compounds displayed IC50 in lower nM range and appeared to be approximately five to twelve fold more active than chloroquine. Heme-binding studies were also carried out to delineate the mode of action. The promising compounds with IC50s in range of 11–30 nM and selectivity index >2800, may act as promising template for the design of new antiplasmodials.

The present paper describes the synthesis, anti-plasmodial, and cytotoxic evaluation of 7-chloroquinoline-based conjugates with isatins/indoles/ nitroimidazoles, obtained via Cu-promoted 1,3-dipolar cycloadditions. On contemplating SAR of the synthesized series, the inclusion of indole and nitroimidazole-core improved the anti-plasmodial activities while the isatin seemed to have a lesser effect. The conjugate with a nitroimidazole-core and hexyl chain length as a spacer between the two pharmacophores was found to be most potent among the synthesized series and displayed an IC50 of 0.12 µM and a selectivity index of 1748.

Benzoxaboroles are under study as potential new drugs to treat malaria. One benzoxaborole, AN13762, has potent activity and promising features, but its mechanisms of action and resistance are unknown. To gain insights into these mechanisms, we cultured malaria parasites with nonlethal concentrations of AN13762 and generated parasites with varied levels of resistance. Parasites with low-level resistance had mutations in PfPARE, which processes AN13762 into an active metabolite; PfPARE mutations prevented this processing. Parasites with high-level resistance had mutations in any of a number of enzymes, mostly those involved in stress responses. Parasites selected for AN13762 resistance were not resistant to other antimalarials, suggesting novel mechanisms of action and resistance for AN13762, a valuable feature for a new class of antimalarial drugs., New antimalarial drugs are needed. The benzoxaborole AN13762 showed excellent activity against cultured Plasmodium falciparum, against fresh Ugandan P. falciparum isolates, and in murine malaria models. To gain mechanistic insights, we selected in vitro for P. falciparum isolates resistant to AN13762. In all of 11 independent selections with 100 to 200 nM AN13762, the 50% inhibitory concentration (IC50) increased from 18–118 nM to 180–890 nM, and whole-genome sequencing of resistant parasites demonstrated mutations in prodrug activation and resistance esterase (PfPARE). The introduction of PfPARE mutations led to a similar level of resistance, and recombinant PfPARE hydrolyzed AN13762 to the benzoxaborole AN10248, which has activity similar to that of AN13762 but for which selection of resistance was not readily achieved. Parasites further selected with micromolar concentrations of AN13762 developed higher-level resistance (IC50, 1.9 to 5.0 μM), and sequencing revealed additional mutations in any of 5 genes, 4 of which were associated with ubiquitination/sumoylation enzyme cascades; the introduction of one of these mutations, in SUMO-activating enzyme subunit 2, led to a similar level of resistance. The other gene mutated in highly resistant parasites encodes the P. falciparum cleavage and specificity factor homolog PfCPSF3, previously identified as the antimalarial target of another benzoxaborole. Parasites selected for resistance to AN13762 were cross-resistant with a close analog, AN13956, but not with standard antimalarials, AN10248, or other benzoxaboroles known to have different P. falciparum targets. Thus, AN13762 appears to have a novel mechanism of antimalarial action and multiple mechanisms of resistance, including loss of function of PfPARE preventing activation to AN10248, followed by alterations in ubiquitination/sumoylation pathways or PfCPSF3.

Aim: WHO Malaria report 2017 estimated 216 million cases of malaria and 445,000 deaths worldwide, with 91% of deaths affecting the African region. Results/methodology: Microwave promoted the synthesis of cycloalkyl amine substituted isoindoline-1,3-dione-4-aminoquinolines was urbanized for evaluating their antiplasmodial activities. Compound with the optimum combination of propyl chain length and hydroxyethyl piperazine proved to be the most potent among the synthesized scaffolds against chloroquine-resistant W2 strain of Plasmodium falciparum with an IC50 value of 0.006 μM. Heme-binding along with density functional theory studies were further carried out in order to delineate the mechanism of action of the most active compound. Conclusion: The synthesized scaffold can act as a therapeutic template for further synthetic modifications toward the search for a new antimalarial agent., Graphical abstract

Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg−1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target., Benzoxaboroles have been shown to be active against different pathogens. Here, the authors show that the benzoxaborole AN3661 inhibits Plasmodium falciparum in vitro and in mouse models, and identify a homologue of a mammalian cleavage and polyadenylation specificity factor as a drug target.

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 β-alanine as a spacer and secondary amine as substituent displayed good anti-plasmodial activities. Compound 7j, with an optimum combination of β-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.