A longer-chain acylated derivative of Dictyostelium differentiation-inducing factor-1 enhances the antimalarial activity against Plasmodium parasites.

The spread of malarial parasites resistant to first-line treatments such as artemisinin combination therapies is a global health concern. Differentiation-inducing factor 1 (DIF-1) is a chlorinated alkylphenone (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) hexan-1-one) originally found in the cellular slime mould Dictyostelium discoideum. We previously showed that some derivatives of DIF-1, particularly DIF-1(+2) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) octan-1-one), exert potent antimalarial activities. In this study, we synthesised DIF-1(+3) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) nonan-1-one). We then evaluated the effects of DIF-1(+3) in vitro on Plasmodium falciparum and in vivo over 7 days (50-100 mg/kg/day) in a mouse model of Plasmodium berghei. DIF-1(+3) exhibited a half-maximal inhibitory concentration of approximately 20-30 % of DIF-1(+2) in three laboratory strains with a selectivity index > 263, including in strains resistant to chloroquine and artemisinin. Parasite growth and multiplication were almost completely suppressed by treatment with 100 mg/kg DIF-1(+3). The survival time of infected mice was significantly increased (P = 0.006) with no apparent adverse effects. In summary, addition of an acyl group to DIF-1(+2) to prepare DIF-1(+3) substantially enhanced antimalarial activity, even in drug-resistant malaria, indicating the potential of applying DIF-1(+3) for malaria treatment.

[Progress of researches on antimalarial peptides].

Malaria remains a major global public health concern, and nearly half of the global populations are still at risk of malaria infection. However, continuous emergence and spread of drug-resistant malaria parasite strains lead to ineffectiveness of conventional antimalarials. Therefore, development of novel antimalarial agents is of urgent need for malaria elimination. As an important component of the host natural immune defense system, antibacterial peptides provide the first line of defense against pathogenic invasion, and the mechanism of preferentially attacking the cell membrane makes them difficult to develop drug resistance. Antimicrobial peptides are therefore considered as a promising candidate for novel antimalarial agents. This review summarizes the advances in researches on antimicrobial peptides with antimalarial actions and discusses the potential of antimalarial peptides as novel antimalarials.

Progress of researches on antimalarial peptides / 中国血吸虫病防治杂志

Malaria remains a major global public health concern, and nearly half of the global populations are still at risk of malaria infection. However, continuous emergence and spread of drug-resistant malaria parasite strains lead to ineffectiveness of conventional antimalarials. Therefore, development of novel antimalarial agents is of urgent need for malaria elimination. As an important component of the host natural immune defense system, antibacterial peptides provide the first line of defense against pathogenic invasion, and the mechanism of preferentially attacking the cell membrane makes them difficult to develop drug resistance. Antimicrobial peptides are therefore considered as a promising candidate for novel antimalarial agents. This review summarizes the advances in researches on antimicrobial peptides with antimalarial actions and discusses the potential of antimalarial peptides as novel antimalarials.

Integrated computational approach towards repurposing of antimalarial drug against SARS-CoV-2 main protease.

Huge vaccination drives are underway around the world for the ongoing COVID-19 pandemic. However, the search for antiviral drugs is equally crucial. As new drug discovery is a time-consuming process, repurposing of existing drugs or developing drug candidates against SARS-CoV-2 will make the process faster. Considering this, 63 approved and developing antimalarial compounds were selected to screen against main protease (Mpro) and papain-like protease (PLpro) of SARS-CoV-2 using in silico methods to find out possible new drug candidate(s). Out of 63 compounds, epoxomicin showed the best binding affinity against the Mpro with CDocker energy of - 57.511 kcal/mol without any toxic effect. This compound was further taken for molecular dynamic simulation study, where the Mpro-epoxomicin complex was found to be stable with binding free energy - 79.315 kcal/mol. The possible inhibitory potential of the selected compound was determined by 3D-QSAR analysis and found to be 0.4447 µM against SARS-CoV-2 Mpro. Finally, the structure activity relationship of the compound was analyzed and two fragments responsible for overall good binding affinity of the compound at the active site of Mpro were identified. This study suggests a safe antimalarial drug, namely epoxomicin, as a probable inhibitor of SARS-CoV-2 Mpro which needs further validation by in vitro/in vivo studies before clinical use. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-01916-0.

Derivatives of Dictyostelium differentiation-inducing factors suppress the growth of Plasmodium parasites in vitro and in vivo.

Malaria, which is caused by protozoa of the genus Plasmodium, remains a major endemic public health problem worldwide. Since artemisinin combination therapies are used as a first-line treatment in all endemic regions, the emergence of parasites resistant to these regimens has become a serious problem. Differentiation-inducing factor 1 (DIF-1) is a chlorinated alkylphenone originally found in the cellular slime mold Dictyostelium discoideum. DIF-1 and its derivatives exhibit a range of biological activities. In the present study, we investigated the effects of 41 DIF derivatives on the growth of Plasmodium falciparum in vitro using four laboratory strains and 12 field isolates. Micromolar concentrations of several DIF derivatives strongly suppressed the growth of the four laboratory strains, including strains that exhibited resistance to chloroquine and artemisinin, as well as strains that were susceptible to these drugs. In addition, DIF-1(+2), the most potent derivative, strongly suppressed the growth of 12 field isolates. We also examined the effects of DIF-1(+2) on the activity of the rodent malarial parasite Plasmodium berghei in mice. Intraperitoneal administration of DIF-1(+2) over 4 days (50 or 70 mg/kg/day) significantly suppressed the growth of the parasite in the blood with no apparent adverse effects, and a dose of 70 mg/kg/day significantly prolonged animal survival. These results suggest that DIF derivatives, such as DIF-1(+2), could serve as new lead compounds for the development of antimalarial agents.

A novel fungal metabolite inhibits Plasmodium falciparum transmission and infection.

BACKGROUND: Malaria transmission depends on infected mosquitoes and can be controlled by transmission-blocking drugs. The recently discovered FREP1-mediated malaria transmission pathway is an excellent target to screen drugs for limiting transmission. METHODS: To identify candidate small molecules, we used an ELISA-based approach to analyze extracts from a fungal library for inhibition of the FREP1-parasite interaction. We isolated and determined one active compound by chromatography and crystallography, respectively. We measured the effects of the bioactive compound on malaria transmission to mosquitoes through standard membrane-feeding assays (SMFA) and on parasite proliferation in blood by culturing. RESULTS: We discovered the ethyl acetate extract of the fungus Purpureocillium lilacinum that inhibited Plasmodium falciparum transmission to mosquitoes. Pre-exposure to the extract rendered Anopheles gambiae resistant to Plasmodium infection. Furthermore, we isolated one novel active compound from the extract and identified it as 3-amino-7,9-dihydroxy-1-methyl-6H-benzo[c]chromen-6-one, or "pulixin." Pulixin prevented FREP1 from binding to P. falciparum-infected cell lysate. Pulixin blocked the transmission of the parasite to mosquitoes with an EC50 (the concentration that gave half-maximal response) of 11 µM based on SMFA. Notably, pulixin also inhibited the proliferation of asexual-stage P. falciparum with an EC50 of 47 nM. The compound did not show cytotoxic effects at a concentration of 116 µM or lower. CONCLUSION: By targeting the FREP1-Plasmodium interaction, we discovered that Purpureocillium lilacinum extract blocked malaria transmission. We isolated and identified the bioactive agent pulixin as a new compound capable of stopping malaria transmission to mosquitoes and inhibiting parasite proliferation in blood culture.

Molecular modeling and design of some ß-amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles derivatives against chloroquine sensitive, 3D7 strain of Plasmodium falciparum.

Resistance nature of Plasmodium falciparum (P. falciparum) to the most effective antimalarial drug, Artemisinin, intimidate the global goal of total eradication of malarial. In an attempt to overcome this challenge, the research was aimed at designing derivatives of ß-amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles with improve activity against the P. falciparum through structural modifications of the most active compound (design template), and their activity determined using the developed theoretical predictive model. To achieve this, the geometries were optimized via density functional theory (DFT) using B3LYP/6-31G∗ basis set to generate molecular descriptors for model development. Analysis of the developed model and the descriptors mean effect lead to the design of derivatives with improved activity. Five (5) theoretical models were developed, where the model {pIC50 = 5.95067(SpMin5_Bhi) - 0.0323461(RDF45m) + 0.0203865 (RDF95e) + 0.0499285 (L1m) - 3.50822} with the highest coefficient of determination (R2) of 0.9367, cross-validated R2 (Q2cv) of 0.8242, and the external validated R2 (R2 pred) of 0.9462, selected as the best model. The mean effect analysis revealed descriptor SpMin5_Bhi as the most contributive. The descriptor encodes the first ionization potentials of the compounds and are influenced by electron-withdrawing/donating substituents. Hence, structural modifications of the compound with the highest activity (a design template) using electron-withdrawing substituents such as -NO2, -SO3H, -Br, -I, -CH2CH3, and -CH3 was done at a different positions, to obtain five (5) hypothetical novel compounds. The statistical results, shows the robustness, excellent prediction power, and validity of the selected model. Descriptor analysis revealed the first ionization potential (SpMin5_Bhi) to play a significant role in the activity of ß-amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles derivatives. The five design derivatives of ß-amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles with higher activities revealed compound 21C to have an antimalarial activity of pIC50 = 6.7573 higher than it co-designed compounds and even the standard drug. This claim could be verified through molecular docking to determine their interaction with the target protein.

Discovery of a natural fluorescent probe targeting the Plasmodium falciparum cysteine protease falcipain-2.

The Plasmodium falciparum cysteine protease falcipain-2 (FP-2) is an attractive antimalarial target. Here, we discovered that the natural compound NP1024 is a nonpeptidic inhibitor of FP-2 with an IC50 value of 0.44 µmol L-1. The most exciting finding is that both in vitro and in vivo, NP1024 directly targets FP-2 in malaria parasite-infected erythrocytes as a natural fluorescent probe, thereby paving the way for an integration of malaria diagnosis and treatment.

Drug Interactions With the Ca2+-ATPase From Sarco(Endo)Plasmic Reticulum (SERCA).

The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is an intracellular membrane transporter that utilizes the free energy provided by ATP hydrolysis for active transport of Ca2+ ions from the cytoplasm to the lumen of sarco(endo)plasmic reticulum. SERCA plays a fundamental role for cell calcium homeostasis and signaling in muscle cells and also in cells of other tissues. Because of its prominent role in many physiological processes, SERCA dysfunction is associated to diseases displaying various degrees of severity. SERCA transport activity can be inhibited by a variety of compounds with different chemical structures. Specific SERCA inhibitors were identified which have been instrumental in studies of the SERCA catalytic and transport mechanism. It has been proposed that SERCA inhibition may represent a novel therapeutic strategy to cure certain diseases by targeting SERCA activity in pathogens, parasites and cancer cells. Recently, novel small molecules have been developed that are able to stimulate SERCA activity. Such SERCA activators may also offer an innovative and promising therapeutic approach to treat diseases, such as heart failure, diabetes and metabolic disorders. In the present review the effects of pharmacologically relevant compounds on SERCA transport activity are presented. In particular, we will discuss the interaction of SERCA with specific inhibitors and activators that are potential therapeutic agents for different diseases.

Changing antimalarial agents after inefficacy or intolerance in patients with cutaneous lupus erythematosus: A multicenter observational study.

BACKGROUND: Changing from one antimalarial (AM) agent to another is often recommended in cutaneous lupus erythematosus (CLE) when the first AM agent is ineffective or poorly tolerated. OBJECTIVE: To evaluate the effect on cutaneous response of a switch from hydroxychloroquine to chloroquine, or the reverse, after failure of the first AM agent. METHODS: We conducted a retrospective observational study between 1997 and September 2015. The overall cutaneous response rate and reasons for failure of the switch were assessed for up to 48 months. Kaplan-Meier survival curves were used to assess the risk for failure of the second AM agent. RESULTS: A total of 64 patients with CLE (78% were women) were included; for 48 patients, the switch was for inefficacy, and for 16, it was for adverse events. Median follow-up was 42 months (range, 3-171). Of the patients changed because of inefficacy, 56% were responders at month 3; however, the response decreased over time, with a median duration before failure of the second AM agent of 9 months (95% confidence interval, 6-24). For patients switched because of adverse events, the second AM agent was well tolerated in 69% of cases. LIMITATIONS: Retrospective design and subjective evaluation of cutaneous response. CONCLUSION: A change of AM agent should be considered in patients with CLE when the first AM agent is ineffective or poorly tolerated.

More Consistent Antimalarial Intake in First 5 Years of Disease Is Associated with Better Prognosis in Patients with Systemic Lupus Erythematosus.

OBJECTIVE: To examine whether more consistent use of antimalarial agents (AM) leads to better results in systemic lupus erythematosus (SLE). METHODS: From a longitudinal cohort study, we identified inception patients with a minimum of 5 years of followup. They were divided into 3 groups: patients who took AM > 60% of the time (group A), those who took AM < 60% of the time (group B), and those who did not receive AM (group C) during the first 5 years of followup. Outcomes included increase in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), flare, achieving low disease activity (LDA), adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000, cumulative doses of steroids (CMS), and AM-related retinal toxicity. Regression analysis models were constructed to identify predictors of the outcomes. RESULTS: There were 459 patients identified: 236 (51.4%) in group A, 88 (19.2%) in group B, and 135 (29.4%) in group C. The changes in SDI, flare event, and CMS were significantly lower in group A, which more often achieved LDA. Multivariable analysis revealed that the patients in group A had a lower risk of increasing SDI and were more likely to achieve LDA at Year 5 compared to the patients in group C. Patients taking AM had lower CMS over the 5 years of followup. There was only 1 patient with AM-related retinal toxicity in each group. CONCLUSION: More consistent use of an AM over the first 5 years of SLE is associated with better outcomes.

Carbon-14 radiolabeling and tissue distribution evaluation of MMV390048.

The antimalarial compound MMV390048 ([14 C]-11) was labeled with carbon-14 isotope via a 3-step synthesis. It was obtained in a 15.5% radiochemical overall yield from carbon-14 labeled methyl iodide with a radiochemical purity of >99%. After single oral administration of [14 C]-11 to albino and pigmented rats its tissue distribution profile was studied. Tissue distribution results showed high local exposure in the GI tract and excretory organs but low exposure of all other tissues. The radioactivity uptake was higher in the eyes of the pigmented rats than in the eyes of the albino rats at all-time points. The highest accumulation reached in the eyes of the pigmented rats was 0.46% at 6 hours. However, these levels are still very low as compared to the other organs studied. There was very little radioactivity from MMV390048 ([14 C]-11) present in the skin of both the albino and pigmented rats. The results obtained are supportive of further development of MMV390048 as a potential antimalarial compound.

Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid.

5-Nor stemmadenine alkaloids, isolated from the genus Tabernaemontana, display a range of bioactivity. 16-Hydroxy-16,22-dihydroapparicine, the active component of an extract from the Tabernaemontana sp. (dichotoma, elegans, and divaricate), exhibited potent antimalarial activity, representing the first such report of the antimalarial property of 5-nor stemmadenine alkaloids. We, therefore, decided to attempt the total synthesis of the compound to explore its antimalarial activity and investigate structure and bioactivity relationships. As a result, we completed the first total synthesis of 16-hydroxy-16,22-dihydroapparicine, by combining a phosphine-mediated cascade reaction, diastereoselective nucleophilic addition of 2-acylindole or methylketone via a Felkin-Anh transition state, and chirality transferring intramolecular Michael addition. We also clarified the absolute stereochemistries of the compound. Furthermore, we evaluated the activity of the synthetic compound, as well as that of some intermediates, all of which showed weak activity against chloroquine-resistant Plasmodium falciparum (K1 strain) malaria parasites.

In vivo evaluation of isolated triterpenes and semi-synthetic derivatives as antimalarial agents.

The triterpenes balsaminoside B (1) and karavilagenin C (2) were isolated from the African medicinal plant Momordica balsamina L. Karavoates B (3) and D (4) were synthesized by diacylation of 2 with acetic and propionic anhydrides, respectively. In previous work, derivatives 3 and 4 exhibited submicromolar median inhibitory concentrations (IC50) in vitro against Plasmodium falciparum Welch (human malaria parasite) strains 20 to 25 times lower than those of natural product 2. The main objective of the present study was to explore structure-in vivo antimalarial activity relationships (SAR) for compounds 1-4 in Plasmodium berghei Vincke and Lips NK65-infected mice in the 4 day suppressive test. Semi-synthetic derivatives 3 and 4 exhibited greater in vivo antimalarial activity than isolates 1 and 2. Orally and subcutaneously administered karavoate B exhibited the greatest in vivo antimalarial activity (55.2-58.1% maximal suppression of parasitemia at doses of 50 mg kg(-1) day(-1)). Diacylation of natural isolate 2 with short chain carboxylic acid moieties yielded derivatives with enhanced maximal in vivo parasitemia suppression for both routes of administration. Maximal in vivo parasite suppression by diacetyl derivative 3 was roughly double that of natural precursor 2.

Chloroquine-based hybrid molecules as promising novel chemotherapeutic agents.

Chloroquine (CQ) has a broad spectrum of pharmacological activities including anticancer and anti-inflammatory, in addition to its well-known antimalarial activity. This very useful property of CQ may be rendered through a variety of different molecular and cellular mechanisms, including the induction of apoptosis, necrosis and lysosomal dysfunction. CQ alone may not be as effective as many well-known anticancer drugs; however, it often shows synergisticts when combined with other anticancer agents, without causing substantial ill-effects. To increase its pharmacological activity, scientists synthesized many different chloroquine derivatives by a repositioning approach, some of which show higher activities than the parental CQ. To further improve anticancer activity, medicinal chemists have recently been focusing on generating CQ hybrid molecules by joining, directly or through a linker, 4-aminoquinoline and other pharmacologically active phamarcophore(s). Indeed, some CQ hybrid molecules substantially improved anticancer activity while maintaining desirable CQ property, providing an excellent opportunity of developing effective and safe novel anticancer agents. Since the approach of developing CQ hybrid molecules has advanced much more in the antimalarial drug research, it can provide an excellent template for anticancer drug development. This review provides an overview of CQ-based hybrid molecules by focusing on: (1) the potential advantage of the hybrid approach in developing effective and safe anticancer agents; (2) what we can learn from the CQ hybrid approach used in the development of effective antimalarial agents; and (3) CQ hybrid molecules as potential anticancer agents in different categories classified based on their chemical compositions.

Development and Validation of Reversed-Phase High Performance Liquid Chromatographic Method for Hydroxychloroquine Sulphate.

In the present work new, simple reversed-phase high performance liquid chromatographic method was developed and validated for the determination of hydroxychloroquine sulphate in blood plasma. Chloroquine sulphate was used as an internal standard. The chromatographic separation was achieved with octadecyl silane Hypersil C18 column (250×6 mm, 5 µm) using water and organic (acetonitrile:methanol: 50:50, v/v) mobile phase in 75:25 v/v ratio, with sodium 1-pentanesulfonate and phosphoric acid. This organic phase was maintained at pH 3.0 by orthophosphoric acid. The flow rate of 2.0 ml/min(.) with detection at 343 nm was used in the analysis. The calibration curve of standard hydroxychloroquine sulphate was linear in range 0.1-20.0 µg/ml. The method was validated with respected to linearity, range, precision, accuracy, specificity and robustness studies according to ICH guidelines. The method was found to be accurate and robust to analyze the hydroxychloroquine sulphate in plasma samples.

Research Progress of Artemisinins-based Antimalarial Agents / 中国中医药信息杂志

Artemisinin is the antimalarial active ingredient, which is discovered by Chinese scientists in 1970s. The chemical structure of artemisinin is modified or altered to obtain a series of analogues to satisfy the medication requirements. According to the physicochemical properties of medicines and actual clinical necessities, the preparations of artemisinins are developed and the common preparations include tablet, suppository, injection, etc.. With the developing of technology, researchers have conducted a large number of studies on the artemisinins nanoparticles injection, transdermal drug delivery systems, mucosal drug delivery systems and etc. This article systematically collected and discussed the recent studies on the antimalarial preparations of artemisinins in line with different administration routes.

Evaluation of the antimalarial potential of Icacina senegalensis Juss (Icacinaceae).

OBJECTIVE: To evaluate in vivo antimalarial activity of methanol leaf extract of Icacina senegalensis. METHODS: The extract was investigated for activity against early and established malaria infections using Swiss albino mice infected with Plasmodium berghei at dose levels of 25, 50 and 100 mg/kg. Chloroquine (10 mg/kg) was used as positive control. RESULTS: A dose dependent chemo-suppression of the parasites was observed at different dose levels of the extract tested with a considerable mean survival time. CONCLUSIONS: The results support further investigation on components of traditional medicines as potential new antimalarial agents.

Identification of novel phenyl butenonyl C-glycosides with ureidyl and sulfonamidyl moieties as antimalarial agents.

A new series of C-linked phenyl butenonyl glycosides bearing ureidyl(thioureidyl) and sulfonamidyl moieties in the phenyl rings were designed, synthesized, and evaluated for their in vitro antimalarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains. Among all the compounds screened the C-linked phenyl butenonyl glycosides bearing sulfonamidyl moiety (5a) and ureidyl moiety in the phenyl ring (7d and 8c) showed promising antimalarial activities against both 3D7 and K1 strains with IC50 values in micromolar range and low cytotoxicity offering new HITS for further exploration.

Evaluation of the antimalarial potential of Icacina senegalensis Juss (Icacinaceae)

Objective: To evaluate in vivo antimalarial activity of methanol leaf extract of Icacina senegalensis. Methods: The extract was investigated for activity against early and established malaria infections using Swiss albino mice infected with Plasmodium berghei at dose levels of 25, 50 and 100 mg/kg. Chloroquine (10 mg/kg) was used as positive control. Results: A dose dependent chemo-suppression of the parasites was observed at different dose levels of the extract tested with a considerable mean survival time. Conclusions: The results support further investigation on components of traditional medicines as potential new antimalarial agents.