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Ceramicines are a series of limonoids which were isolated from the barks of Malaysian Chisocheton ceramicus (Meliaceae), and were known to show various biological activity. Six new limonoids, ceramicines U–Z ( 1 – 6 ), with a cyclopentanone[α]phenanthrene ring system with a β-furyl ring at C-17 were isolated from the barks of C. ceramicus . Their structures were determined on the basis of the 1D and 2D NMR analyses, and their absolute configurations were investigated by CD spectroscopy. Ceramicine W ( 3 ) exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC 50 value of 1.2 µM. In addition, the structure–antimalarial activity relationship (SAR) of the ceramicines was investigated to identify substituent patterns that may enhance activity. It appears that ring B and the functional groups in the vicinity of rings B and C are critical for the antimalarial activity of the ceramicines. In particular, bulky ester substituents with equatorial orientation at C-7 and C-12 greatly increase the antimalarial activity. Graphical Abstract

The abietane-type diterpenoids are significant bioactive compounds exhibiting a varied range of pharmacological properties. In this study, the first synthesis and biological investigation of the new abietane-diterpenoid (+)-4-epi-liquiditerpenoid acid (8a) together with several of its analogs are reported. The compounds were generated from the readily available methyl callitrisate (7), which was obtained from callitrisic acid present in Moroccan Sandarac resin. A biological evaluation was conducted to determine the effects of the different functional groups present in these molecules, providing basic structure–activity relationship (SAR) elements. In particular, the ferruginol and sugiol analogs compounds 10–16 were characterized by the presence of a phenol moiety, higher oxidization states at C-7 (ketone), and the hydroxyl, methyl ester or free carboxylic acid at C19. The biological profiling of these compounds was investigated against a panel of six human solid tumor cell lines (HBL-100, A549, HeLa, T-47D, SW1573 and WiDr), four parasitic Leishmania species (L. donovani, L. infantum, L. guyanensis and L. amazonensis) and two malaria strains (3D7 and K1). Furthermore, the capacity of the compounds to modulate gamma-aminobutyric acid type A (GABAA) receptors (α1β2γ2s) is also described. A comparison of the biological results with those previously reported of the corresponding C18-functionalized analogs was conducted.

Proteases of the malaria parasite Plasmodium falciparum have long been investigated as drug targets. The P. falciparum genome encodes 10 aspartic proteases called plasmepsins, which are involved in diverse cellular processes. Most have been studied extensively but the functions of plasmepsins IX and X (PMIX and PMX) were unknown. Here we show that PMIX is essential for erythrocyte invasion, acting on rhoptry secretory organelle biogenesis. In contrast, PMX is essential for both egress and invasion, controlling maturation of the subtilisin-like serine protease SUB1 in exoneme secretory vesicles. We have identified compounds with potent antimalarial activity targeting PMX, including a compound known to have oral efficacy in a mouse model of malaria.

M5717 is the first plasmodium translation elongation factor 2 inhibitor to reach clinical development as an antimalarial. We aimed to characterise the safety, pharmacokinetics, and antimalarial activity of M5717 in healthy volunteers. This first-in-human study was a two-part, single-centre clinical trial done in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants were enrolled into one of nine dose cohorts (50, 100, 200, 400, 600, 1000, 1250, 1800, or 2100 mg) and randomly assigned (3:1) to M5717 or placebo. A sentinel dosing strategy was used for each dose cohort whereby two participants (one assigned to M5717 and one assigned to placebo) were initially randomised and dosed. Randomisation schedules were generated electronically by independent, unblinded statisticians. Part two was an open-label, non-randomised volunteer infection study using the Plasmodium falciparum induced blood-stage malaria model in which participants were enrolled into three dose cohorts. Healthy men and women of non-childbearing potential aged 18–55 years were eligible for inclusion; individuals in the volunteer infection study were required to be malaria naive. Safety and tolerability (primary outcome of the single ascending dose study and secondary outcome of the volunteer infection study) were assessed by frequency and severity of adverse events. The pharmacokinetic profile of M5717 was also characterised (primary outcome of the volunteer infection study and secondary outcome of the single ascending dose study). Parasite clearance kinetics (primary outcome of the volunteer infection study) were assessed by the parasite reduction ratio and the corresponding parasite clearance half-life; the incidence of recrudescence up to day 28 was determined (secondary outcome of the volunteer infection study). Recrudescent parasites were tested for genetic mutations (exploratory outcome). The trial is registered with ClinicalTrials.gov (NCT03261401). Between Aug 28, 2017, and June 14, 2019, 221 individuals were assessed for eligibility, of whom 66 men were enrolled in the single ascending dose study (eight per cohort for 50–1800 mg cohorts, randomised three M5717 to one placebo, and two in the 2100 mg cohort, randomised one M5717 to one placebo) and 22 men were enrolled in the volunteer infection study (six in the 150 mg cohort and eight each in the 400 mg and 800 mg cohorts). No adverse event was serious; all M5717-related adverse events were mild or moderate in severity and transient, with increased frequency observed at doses above 1250 mg. In the single ascending dose study, treatment-related adverse events occurred in three of 17 individuals in the placebo group; no individual in the 50 mg, 100 mg, or 200 mg groups; one of six individuals in each of the 400 mg, 1000 mg, and 1250 mg groups; two of six individuals in the 600 mg group; and in all individuals in the 1800 mg and 2100 mg groups. In the volunteer infection study, M5717-related adverse events occurred in no participants in the 150 mg or 800 mg groups and in one of eight participants in the 400 mg group. Transient oral hypoesthesia (in three participants) and blurred vision (in four participants) were observed in the 1800 mg or 2100 mg groups and constituted an unknown risk; thus, further dosing was suspended after dosing of the two sentinel individuals in the 2100 mg cohort. Maximum blood concentrations occurred 1–7 h after dosing, and a long half-life was observed (146–193 h at doses ≥200 mg). Parasite clearance occurred in all participants and was biphasic, characterised by initial slow clearance lasting 35–55 h (half-life 231·1 h [95% CI 40·9 to not reached] for 150 mg, 60·4 h [38·6 to 138·6] for 400 mg, and 24·7 h [20·4 to 31·3] for 800 mg), followed by rapid clearance (half-life 3·5 h [3·1 to 4·0] for 150 mg, 3·9 h [3·3 to 4·8] for 400 mg, and 5·5 h [4·8 to 6·4] for 800 mg). Recrudescence occurred in three (50%) of six individuals dosed with 150 mg and two (25%) of eight individuals dosed with 400 mg. Genetic mutations associated with resistance were detected in four cases of parasite recrudescence (two individuals dosed with 150 mg and two dosed with 400 mg). The safety, pharmacokinetics, and antimalarial activity of M5717 support its development as a component of a single-dose antimalarial combination therapy or for malaria prophylaxis. Wellcome Trust and the healthcare business of Merck KGaA, Darmstadt, Germany.

Malaria is a deadly parasitic disease, having a high rate of incidence and mortality across the world. The spread and development of resistance against chemical insecticides is one of the major problems associated with malaria treatment and control. Hence, plant based formulations may serve as an alternative source towards development of new drugs for treatment of malaria. The present study was aimed to evaluate the in vitro antiplasmodial activities of leaf, stem and flower of Calotropis gigantea against chloroquine-sensitive Plasmodium falciparum (3D7 strain) and its cytotoxicity against THP-1 cell lines. The plant extract which showed highest potency, in the in vitro antimalarial activity was further tested in vivo against P. berghei (ANKA strain) for validating its efficacy. The crude extracts of methanol, ethyl acetate and chloroform from leaves, stem and flowers of C. gigantea were prepared using Soxhlet apparatus. These extracts were screened for in vitro antimalarial activity against P. falciparum 3D7 strain. The cytotoxicity studies of crude extracts were conducted against THP-1 cell line. Phytochemical analysis of these extracts was carried out by following the standard methods. The damage to erythrocytes due to the plant extracts was tested. The in vivo study was conducted in P. berghei (ANKA) infected BALB/c albino mice by following the 4-day suppressive test. The phytochemical screening of the crude extracts showed the presence of alkaloids, flavonoids, triterpenes, tannins, carbohydrates, phenols, coumarins, saponins, phlobatannins and steroids. Out of all the extracts, the methanolic extract of leaves showed highest antimalarial activity with IC50 value of 12.17 μg/ml. In cytotoxicity evaluation, none of the crude extracts, showed cytotoxicity on THP-1 cell line. Since, methanolic leaf extract of C. gigantea showed good antimalarial activity in vitro, it was tested in vivo. In the in vivo results, the methanolic leaf extract of C. gigantea exhibited an excellent activity against P. berghei malaria parasite, wherein the decrement of parasite counts was moderately low and dose-dependent (p < 0.05) in comparison to the P. berghei infected control group, which showed a daily increase of parasitaemia unlike the chloroquine-treated group. The methanolic leaf extract of C. gigantea may act as potent alternative source for development of new medicines or drugs for the treatment of drug-resistant malaria. Thus, further research is needed to characterize the bioactive molecules of the extracts of C. gigantea that are responsible for inhibition of malaria parasite.

With the emergence and spread of artemisinin resistance, new therapies for malaria are needed. This study shows that the imidazolopiperazine KAF156, a new antimalarial compound, has in vivo antimalarial activity. Expanding artemisinin resistance and worsening partner-drug resistance in Southeast Asia threaten the global control of Plasmodium falciparum malaria. 1 – 5 New drugs are needed. KAF156 represents a new class of antimalarial agents (imidazolopiperazines) 6 identified by high-throughput phenotypic screening. KAF156 has potent in vitro activity against both asexual and sexual blood stages and the preerythrocytic liver stages of the malarial parasite. 7 The mechanism of antimalarial action is unknown, but drug resistance, mediated by mutations in the P. falciparum cyclic amine resistance locus ( PfCARL ) gene, which encodes a protein of unknown function, can be selected. 7 In a study of 70 healthy . . .

DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity. Healthy participants aged 18–55 years were enrolled in a two-part study: part 1, a single ascending dose (25–1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2). In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (Cmax) ranged between 1310 ng/mL and 34 800 ng/mL and was reached in a median time (tmax) between 1·5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log10 parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1·55 (95% CI 1·42–1·67) and in the mefloquine (10 mg/kg) group was 2·34 (2·17–2·52), corresponding to a parasite clearance half-life of 9·4 h (8·7–10·2) and 6·2 h (5·7–6·7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552–1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0·0001). The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment. Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.

Background & objectives: Due to the rapid increase of drug resistance in Plasmodium parasites, there is a pressing need of developing new antiplasmodial drugs. In this study, new amodiaquine (AQ) analogs were synthesized, followed by an evaluation of their antiplasmodial activity. Methods: A new series of quinoline derivatives containing N-alkyl (piperazin-1-yl)methyl benzamidine moiety was synthesized by reacting 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzonitrile with appropriate primary amines. The synthesized compounds were investigated for inhibitory activity by inhibition test of heme detoxification (ITHD). Their antiplasmodial activity was then evaluated using the classical 4-day suppressive test (Peter's test) against Plasmodium berghei-infected mice (ANKA strain). Results: The results showed that the percentage of heme detoxification inhibition in the active compounds was 90%. The most promising analogs, N-butyl-4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzamidine (compound 1e), and 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl)]-N-(4-methylpentan-2-yl)benzamidine (compound 1f) displayed 97.65 and 99.18% suppressions at the doses of 75 and 50 mg/kg/day, respectively. Further, the mean survival time of the mice treated with these compounds was higher than that of the negative control group. Interpretation & conclusion: The newly synthesized amodiaquine analogs presented sufficient antiplasmodial activity with excellent suppressions and high in vitro heme detoxification inhibition. Higher mean survival time of the mice treated with synthetic compounds further confirmed the in vivo antimalarial activity of these new AQ analogs. Therefore, these compounds have the potential to replace common drugs from 4-aminoquinoline class. However, further investigations such as pharmacokinetic evaluations, cytotoxicity, toxicity, and formulation seem to be necessary.

Antimalarial drug resistance has thrown a spanner in the works of malaria elimination. New drugs are required for ancillary support of existing malaria control efforts. Plasmodium falciparum requires host glucose for survival and proliferation. On this basis, P . falciparum hexose transporter 1 ( Pf HT1) protein involved in hexose permeation is considered a potential drug target. In this study, we tested the antimalarial activity of some compounds against Pf HT1 using computational techniques. We performed high throughput virtual screening of 21,352 small-molecule compounds against Pf HT1. The stability of the lead compound complexes was evaluated via molecular dynamics (MD) simulation for 100 nanoseconds. We also investigated the pharmacodynamic, pharmacokinetic and physiological characteristics of the compounds in accordance with Lipinksi rules for drug-likeness to bind and inhibit Pf HT1. Molecular docking and free binding energy analyses were carried out using Molecular Mechanics with Generalized Born and Surface Area (MMGBSA) solvation to determine the selectivity of the hit compounds for Pf HT1 over the human glucose transporter (hGLUT1) orthologue. Five important Pf HT1 inhibitors were identified: Hyperoside (CID5281643); avicularin (CID5490064); sylibin (CID5213); harpagoside (CID5481542) and quercetagetin (CID5281680). The compounds formed intermolecular interaction with the binding pocket of the Pf HT1 target via conserved amino acid residues (Val314, Gly183, Thr49, Asn52, Gly183, Ser315, Ser317, and Asn48). The MMGBSA analysis of the complexes yielded high free binding energies. Four (CID5281643, CID5490064, CID5213, and CID5481542) of the identified compounds were found to be stable within the Pf HT1 binding pocket throughout the 100 nanoseconds simulation run time. The four compounds demonstrated higher affinity for Pf HT1 than the human major glucose transporter (hGLUT1). This investigation demonstrates the inhibition potential of sylibin, hyperoside, harpagoside, and avicularin against Pf HT1 receptor. Robust preclinical investigations are required to validate the chemotherapeutic properties of the identified compounds.

Malaria is one of the major health problems in developing countries. The disease kills a large number of people every year and also affects financial status of many countries. Resistance of the plasmodium parasite, the causative agent, to the existing drugs, including chloroquine, mefloquine, and artemisinin based combination therapy (ACT), is a serious global issue in malaria treatment and control. This warrants an urgent quest for novel compounds, particularly from natural sources such as medicinal plants. Alkaloids have over the years been recognized as important phytoconstituents with interesting biological properties. In fact, the first successful antimalarial drug was quinine, an alkaloid, which was extracted from Cinchona tree. In the present review work, the alkaloids isolated and reported recently (2013 till 2019) to possess antimalarial activity are presented. Several classes of alkaloids, including terpenoidal, indole, bisindole, quinolone, and isoquinoline alkaloids, were identified with a promising antimalarial activity. It is hoped that the reports of the review work will spur further research into the structural modification and/or development of the interesting compounds as novel antimalarial drugs.