Chloroquine-sensitive Strain Of Plasmodium Falciparum Research Articles

A promising class of Antiprotozoal agents, design and synthesis of novel Pyrimidine–Cinnamoyl Hybrids

Malaria, caused by parasitic protozoans of the Plasmodium genus, continues to be one of the greatest global health crises, especially in Africa. The emergence of antimalarial drug resistance continues to be a health problem necessitating an urgent need for alternative and cost-effective antimalarials. Using a molecular hybridization approach, we report the design and synthesis of an efficacious novel class of antiprotozoal agents; (E)-1-(4-(4,6-diphenylpyrimidin-2-yl)piperazin-1-yl)-3-phenyl prop-2-en-1-one derivatives (8a-r). The in vitro inhibitory activity of the synthesized compounds was evaluated against the NF54 chloroquine-sensitive strain of Plasmodium falciparum. From the antiprotozoal screening, three compounds displayed propitious activity with IC50 values (0.18-0.21μM), using quinine and chloroquine as standard antimalarials. Compounds 8o and 8l emerged as the most potent candidates with IC50 values of 0.18 ± 0.02 μM and 0.21 ± 0.001 μM with an associated good safety index of 18.59 and 16.75 to human kidney epithelial (HEK293) cells, respectively. The synthesized analogues present a new chemical architecture structurally unrelated to the current regime of antimalarial drugs, representing a valid strategy to combat resistance in P. falciparum species to current commercial drugs. We further investigated the binding affinities of the compounds against recombinant forms of two P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z, both of which are essential and promising druggable candidates. Compound 8l exhibited the highest binding affinity for both PfHsp70s. Furthermore, molecular docking revealed that compounds 8k, 8l, 8m, and 8o exhibited better fitness to PfHsp70-1, with compounds 8l and 8o showing the highest binding affinity of 10.5 kcal/mol and 10.1 kcal/mol, respectively. Therefore, it can be speculated that PfHsp70-1 may be a possible target of some of the inhibitors tested in this study. The presence of electron-donating groups on the phenyl ring of 4,6-pyrimidine moiety and cinnamoyl group demonstrated a positive correlation between the observed computational data and the biological activity. Taken together, this paper demonstrates the importance of using the molecular hybridization approach in the development of newer cinnamoyl clubbed with 4,6-diphenyl pyrimidine hybrids as potential antiprotozoal agents.

Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides.

A series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102 highlighted that 23 compounds possessed IC50 < 30 µM. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC50 = 1.6 µM was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 µM. A good correlation between the experimental logk and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated N-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an 'averaged' selection-driven interaction pattern was produced based in namely 'pseudo-consensus' 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds.

Unveiling antiplasmodial alkaloids from a cumulative collection of Strychnos extracts by multi-informative molecular networks.

Malaria, a disease known for thousands of years and caused by parasites of the Plasmodium genus, continues to cause many deaths throughout the world today, particularly due to the emergence of parasite resistance to the current therapeutic arsenal. Plants of the Strychnos genus, remarkable due to their multiple traditional uses as well as their alkaloid content, are promising candidates to develop new antimalarial treatments. Indeed, previous research on this plant group has shown promising (≤ 5 µg/ml) or good (between 5 and 15 µg/ml) antiplasmodial activities. Using the chloroquine-sensitive strain of Plasmodium falciparum (3D7), and artemisinin as positive control, a screening of antiplasmodial activities from 43 crude methanolic extracts from 28 species of the Strychnos genus was carried out in three independent assays. A total of 12 extracts had good (6 extracts) or promising (6 extracts) antiplasmodial activities. These results allowed both to confirm known activities but also to detect new ones. These extracts were then analyzed by HPLC-ESI(+)-Q/TOF, and the processed MS/MS data allowed to generate a molecular network in which the antiplasmodial activities were implemented as metadata. The exploration of the molecular network revealed the presence of alkaloids still unknown, and potentially active against malaria, in particular alkaloids close to usambarensine and its derivatives. This study shows that the emergence of molecular networking offers new leads for identifications of alkaloids from the Strychnos genus. The presence of unknown alkaloids potentially active against malaria confirms all the interest to continue in studying the Strychnos genus. Bioassay- and mass-guided fractionations as well as various dereplication tools would allow to identify and characterize these interesting alkaloids further.

Quebrachitol from Putranjiva roxburghii Wall. (Putranjivaceae) a potent antimalarial: Pre-clinical efficacy and its interaction with PfLDH

Researchers are exploring natural resources in search of a new and effective anti-malarial compound to address the challenges in malarial treatment due to emerging incidences of drug-resistant strains. Following background knowledge of traditional medicine, we evaluated the in-vitro and in-vivo anti-malarial efficacy of Putranjiva P. roxburghii (Putranjivaceae) twigs ethanol extracts and fraction (PRT). In-vitro parasite-specific lactate dehydrogenase (pLDH) assay was performed using a chloroquine-sensitive Plasmodium falciparum strain. The results of the in-vitro study were further validated by in-vivo anti-malarial studies on P. berghei Keyberg 173 (K173) infected mice. The crude ethanol extract of the PRT showed the most moderate antiparasitic activity (IC50 = 15.51 μg/mL). In contrast, its butanol fraction extract showed potent activity (IC50 = 5.14 μg/mL) with a selectivity index (SI) of 28.87. Two phytochemicals, viz. 2, 4 dihydroxy-5-(hydroxymethyl) benzoic acid (DHMBA), and quebrachitol (QBC), were identified with anti-parasitic activity (IC50 = 5.01 μg/mL and 0.87 μg/mL) and selectivity index (SI) of 45 and 158. The in-vivo studies confirmed the significant anti-malarial activity of QBC at the dose of 30 and 60 mg/kg body weight with chemo-suppression values of 73.26% and 61.88%, respectively. The present study demonstrates the bioactive marker-based standardization of P. roxburghii twig, the antiplasmodial potential of PRT, and the role of QBC in suppressing parasitemia. The findings of the study support QBC as a prospective lead for a natural product-based adjunct remedy to conventional antiparasitic agents for malarial infectious.

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities.

A series of 26 novel 1-(7-chloroquinolin-4-yl)-4-nitro-1H-pyrazoles bearing a dichloromethyl and an amino or thio moiety at C3 and C5 has been prepared in yields up to 72% from the reaction of 1,1-bisazolyl-, 1-azolyl-1-amino-, and 1-thioperchloro-2-nitrobuta-1,3-dienes with 7-chloro-4-hydrazinylquinoline. A new way for the formation of a pyrazole cycle from 3-methyl-2-(2,3,3-trichloro-1-nitroallylidene)oxazolidine (6) is also described. In addition, the antimalarial activity of the synthesized compounds has been evaluated in vitro against the protozoan malaria parasite Plasmodium falciparum. Notably, the 7-chloro-4-(5-(dichloromethyl)-4-nitro-3-(1H-1,2,4-triazol-1-yl)-1H-pyrazol-1-yl)quinoline (3b) and 7-chloro-4-(3-((4-chlorophenyl)thio)-5-(dichloromethyl)-4-nitro-1H-pyrazol-1-yl)quinoline (9e) inhibited the growth of the chloroquine-sensitive Plasmodium falciparum strain 3D7 with EC50 values of 0.2 ± 0.1 µM (85 ng/mL, 200 nM) and 0.2 ± 0.04 µM (100 ng/mL, 200 nM), respectively. Two compounds (3b and 10d) have also been tested for anti-SARS-CoV-2, antibacterial, and cytotoxic activity.

Total phenolic and flavonoid contents, antioxidant, antidiabetic and antiplasmodial activities of Garcinia forbesii King: A correlation study

Garcinia forbesii King belongs to Clusiaceae is a source of secondary metabolites especially xanthones with various biological activities. G. forbesii King is also known for its empirical use for malaria and diabetes. This study investigated the total phenolic and flavonoid contents, in vitro antioxidant, antidiabetic and antiplasmodial activities of four extracts attained from the stem bark of G. forbesii King. The total phenolic and flavonoid contents were determined by spectrophotometric methods and antioxidant activity was evaluated by DPPH, ABTS, FRAP assays. In vitro antidiabetic activity was assessed by α-glucosidase and α-amylase assays and antiplasmodial activity was studied against chloroquine sensitive Plasmodium falciparum strain 3D7. The highest value of total phenolic (187.37 ± 0.06 mg GAE/g) and flavonoid (35.97 ± 0.02 mg QE/g) contents were recorded in n-hexane and methanolic extracts. n-Hexane extract showed the highest DPPH activity with IC50 of 8.12 ± 0.02 μg/mL. Ethyl acetate extract exhibited better scavenging ability for ABTS with IC50 of 3.88 ± 0.04 μg/mL. The FRAP assay showed better activity in methanol extract with an inhibition value of 73.68 ± 3.66 µM Fe2+/g. The strong inhibition against α-glucosidase and α-amylase were displayed by dichloromethane extract with IC50 of 35.13 ± 2.01 μg/mL and 4.83 ± 0.20 μg/mL. n-Hexane and methanol extracts showed significant antiplasmodial activity with IC50 of 0.23 ± 0.01 μg/mL and 0.73 ± 0.01 μg/mL, respectively. The correlation analysis indicated a positive relationship of total phenolic and flavonoid contents with antiplasmodial activity. The results revealed that n-hexane and methanol extracts could be used as a potential natural antiplasmodial, while dichloromethane extract is a promising natural antidiabetic.

Biological Activity Evaluation and In Silico Studies of Polyprenylated Benzophenones from Garcinia celebica.

This study aimed to isolate polyprenylated benzophenones from the rootbark of Garcinia celebica and assess their activities in vitro and in silico. The antioxidant activity was evaluated by the DPPH, ABTS, and FRAP methods. The cytotoxicity was evaluated against HeLa, MCF-7, A549, and B16 cancer cell lines. The antiplasmodial activity was performed against the chloroquine-sensitive Plasmodium falciparum strain 3D7. Molecular docking was analyzed on alpha-estrogen receptor (3ERT) and P. falciparum lactate dehydrogenase enzyme (1CET). The prediction of ADMET for the compounds was also studied. For the first time, (-)-cycloxanthochymol, isoxanthochymol, and xanthochymol were isolated from the root bark of Garcinia celebica. The antioxidant and cytotoxicity evaluation showed that all benzophenones exhibited antioxidant activity compared to gallic acid and quercetin as positive controls and also exhibited strong activity against HeLa, MCF-7, A549, and B16 cell lines compared to cisplatin as the positive control. The antiplasmodial evaluation showed that isoxanthochymol exhibited activity against the chloroquine-sensitive P. falciparum strain 3D7. In addition, the in silico molecular docking study supported in vitro activities. The ADMET analysis also indicated the isolated benzophenones are potential oral drug candidates.

Short Communication: In vitro antimicrobial and antimalarial screening of a crude extract of Streptomyces sp. AB8 isolated from Lapindo Mud Volcano Area, Sidoarjo, Indonesia

Abstract. Arifiyanto A, Setyaningrum E, Nukmal N, Aeny TN. 2021. Short Communication: In vitro antimicrobial and antimalarial screening of a crude extract of Streptomyces sp. AB8 isolated from Lapindo Mud Volcano Area, Sidoarjo, Indonesia. Biodiversitas 22: 2817-2823. Streptomyces is a potential bacterial genus that has been investigated extensively as a source of natural microbial compounds. Its potential metabolites have been widely developed for pharmaceutical, pathogen control, and other applications in agriculture. This study aimed to determine the ability of the Streptomyces sp AB8 crude extract in inhibiting Plasmodium and pathogenic microbes. Streptomyces was cultured on Gause synthetic media for 10 days. The fermented broth culture media has dissolved in a 1:1 mixture of ethyl acetate and methanol. Biochemical characterization of this isolate has carried out using the standard methods. In-vitro antimalarial activity assay was performed using a chloroquine-sensitive Plasmodium falciparum strain 3D7. Fresh type O-positive human erythrocytes were suspended at 4 percent hematocrit in a complete medium to maintain culture. The inhibitory concentration (IC50) was determined using probit analysis. The results showed the extract of Streptomyces sp. AB8 contains phenolic and alkaloids. Streptomyces sp. AB8 extract can inhibit Dickeya zeae N-Unila 5, Dickeya zeae N-Unila 10, Aspergillus sp IK3, and Escherichia coli growth. The results also showed that the ICs0 value of extract against P. falciparum 3D7 was 17.56 ug/mL. Further research was needed to determine the types of purified bioactive compounds and their bioactivity.

3-Hydroxy-propanamidines, a New Class of Orally Active Antimalarials Targeting Plasmodium falciparum.

3-Hydroxypropanamidines are a new promising class of highly active antiplasmodial agents. The most active compound 22 exhibited excellent antiplasmodial in vitro activity with nanomolar inhibition of chloroquine-sensitive and multidrug-resistant parasite strains ofPlasmodium falciparum (with IC50 values of 5 and 12 nM against 3D7 and Dd2 strains, respectively) as well as low cytotoxicity in human cells. In addition, 22 showed strong in vivo activity in thePlasmodium berghei mouse model with a cure rate of 66% at 50 mg/kg and a cure rate of 33% at 30 mg/kg in the Peters test after once daily oral administration for 4 consecutive days. A quick onset of action was indicated by the fast drug absorption shown in mice. The new lead compound was also characterized by a high barrier to resistance and inhibited the heme detoxification machinery in P. falciparum.

Design, synthesis and biological evaluation of mono- and bisquinoline methanamine derivatives as potential antiplasmodial agents

Several classes of antimalarial drugs are currently available, although issues of toxicity and the emergence of drug resistant malaria parasites have reduced their overall therapeutic efficiency. Quinoline based antiplasmodial drugs have unequivocally been long-established and continue to inspire the design of new antimalarial agents. Herein, a series of mono- and bisquinoline methanamine derivatives were synthesised through sequential steps; Vilsmeier-Haack, reductive amination, and nucleophilic substitution, and obtained in low to excellent yields. The resulting compounds were investigated for in vitro antiplasmodial activity against the 3D7 chloroquine-sensitive strain of Plasmodium falciparum, and compounds 40 and 59 emerged as the most promising with IC50 values of 0.23 and 0.93 µM, respectively. The most promising compounds were also evaluated in silico by molecular docking protocols for binding affinity to the {001} fast-growing face of a hemozoin crystal model.

Synthesis and Antiplasmodial Activity of 1,2,3-Triazole-Naphthoquinone Conjugates.

A series of 34 1,2,3-triazole-naphthoquinone conjugates were synthesized via copper-catalyzed cycloaddition (CuAAC). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and against three different tumor cell lines (SKBr-3, MCF-7, HEL). The most active antimalarial compounds showed a low antiproliferative activity. Simplified analogues were also obtained and some structure–activity relationships were outlined. The best activity was obtained by compounds 3s and 3j, having IC50 of 0.8 and 1.2 μM, respectively. Molecular dockings were also carried on Plasmodium falciparum enzyme dihydroorotate dehydrogenase (PfDHODH) in order to rationalize the results.

Study of the antimalarial activity of 4-aminoquinoline compounds against chloroquine-sensitive and chloroquine-resistant parasite strains

This study is concerned with identifying features of 4-aminoquinoline scaffolds that can help pinpoint characteristics that enhance activity against chloroquine-resistant parasites. Statistically valid predictive models are reported for a series of 4-aminoquinoline analogues that are active against chloroquine-sensitive (NF54) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Quantitative structure activity relationship techniques, based on statistical and machine learning methods such as multiple linear regression and partial least squares, were used with a novel pruning method for the selection of descriptors to develop robust models for both strains. Inspection of the dominant descriptors supports the hypothesis that chemical features that enable accumulation in the food vacuole of the parasite are key determinants of activity against both strains. The hydrophilic properties of the compounds were found to be crucial in predicting activity against the chloroquine-sensitive NF54 parasite strain, but not in the case of the chloroquine-resistant K1 strain, in line with previous studies. Additionally, the models suggest that ‘softer’ compounds tend to have improved activity for both strains than do ‘harder’ ones. The internally and externally validated models reported here should also prove useful in the future screening of potential antimalarial compounds for targeting chloroquine-resistant strains.Graphical Predictive models reveal linear relationships for activity of 4-aminoquinoline analogues active against chloroquine-sensitive strains of Plasmodium falciparum

Antimicrobial and antiprotozoal activities of twenty-four Nigerian medicinal plant extracts

Medicinal plants exploration has become an important tool in the discovery of bioactive natural substances capable of inhibiting the mechanisms of microbial and protozoal activity. The aim of this study was to determine the antimicrobial and antiprotozoal activities of medicinal plants extracts used for the treatment of various illnesses in southwestern Nigeria.Twenty-four medicinal plant extracts were screened for antimicrobial activity against three fungal and six bacterial strains; and antiprotozoal activities against chloroquine-sensitive strains of Plasmodium falciparum (antiplasmodial assay), a culture of Leishmania donovani promastigotes and axenic amastigotes (antileishmanial activity) and two-days old culture of Trypanosoma brucei brucei (antitrypanosomal assay).Five extracts exhibited strong antifungal activity against Cryptococcus neoformans, with Ricinodendron heudelotii (Baill.) Heckel, Terminalia ivorensis A.Chev and Macaranga barteri Müll. Arg, having an IC50 of 31.73, 32.10 and 75.63 μg/mL, respectively. Ten of the extracts were active against T. brucei, with Eleusine indica displaying the most significant activity (IC50 and IC90 of 8.26 and 10.14 μg/mL). None of the extracts displayed any significant antiplasmodial and antileishmanial activities. In addition, none of the extracts displayed cytotoxicity on transformed human monocytic (THP1) cells.The study revealed that M. barteri had the broadest spectrum of activity, with activity against C. neoformans, P. aeruginosa, vancomycin resistant Enterococci faecalis (VRE) and T. brucei. M. barteri could be exploited for broad spectrum antimicrobial and antitrypanosomal activity, while Eleusine indica could be subjected to bioassay guided fractionation and isolation of antitrypanosomal constituents. This study suggests that the evaluated plants are potential sources of novel anti-infective agents.

Bastimolide B, an Antimalarial 24-Membered Marine Macrolide Possessing a tert-Butyl Group.

We reported previously the discovery of the potent antimalarial 40-membered macrolide bastimolide A (1) from the tropical marine cyanobacterium Okeania hirsute. Continued investigation has led to the discovery of a new analogue, bastimolide B (2), a 24-membered polyhydroxy macrolide with a long aliphatic chain and unique terminal tert-butyl group. Its complete structure was determined by a combination of extensive spectroscopic methods and comparative analysis of its methanolysis products with those of bastimolide A. A methanolysis mechanism for bastimolide A is proposed, and one unexpected isomerization product of the C2-C3 double bond, 2-(E)-bastimolide A (3), was obtained. Bastimolide B (2) showed strong antimalarial activity against chloroquine-sensitive Plasmodium falciparum strain HB3. A preliminary investigation of the structure-activity relationship based on six analogues revealed the importance of the double bond as well as the 1,3-diol and 1,3,5-triol functionalities.

Synthesis and antimalarial evaluation of artesunate-polyamine and trioxolane-polyamine conjugates

A series of artesunate-polyamine and trioxolane-polyamine conjugates have been prepared. The conjugates were evaluated for antimalarial activity towards the K1 dual drug resistant and NF54 chloroquine-sensitive strains of Plasmodium falciparum (Pf) and for cytotoxicity towards the rat myoblast cell line L6. (Bis)-Boc-(bis)-artesunate-polyamine and (tetra)-artesunate-polyamine conjugates exhibited potent in vitro activity towards both strains of Pf, with IC50 values in the range of 0.3–1.1 nM, comparable to the parent artesunate. Cytotoxicity within this series of analogues typically increased with polyamine (PA) chain length, identifying the PA3-4-3 (spermine), and to some extent the PA3-7-3 series, as being highly selective towards the parasite. The corresponding series of (bis)-Boc-(bis)-trioxolane and (tetra)-trioxolane-polyamine conjugates were less active as antimalarials than the parent trioxolane acid, highlighting the limitation of using this warhead for drug-conjugate studies. Preliminary in vivo evaluation of two artesunate-polyamine conjugates 11 and 16 demonstrated 95.5–99.8% reduction in parasitaemia with maximal 30 day survival rates (ip delivery). Oral testing of 11 proved less efficacious, with 95.7% activity and inconsistent survival rates of 16–30 days. In contrast, trioxolane-polyamines were substantially less effective (ip delivery), exhibiting only modest reductions in parasitaemia and modest to no increase in survival rates.

Isolation, structural elucidation and antiplasmodial activity of fucosterol compound from brown seaweed, Sargassum linearifolium against malarial parasite Plasmodium falciparum

The brown seaweed, Sargassum linearifolium (Turner) C. Agardh, 1820 is commonly available along the south-east coast of India. Its compound fucosterol was isolated and confirmed through spectral characterisation and chemical transformation methods. The antiplasmodial effect of the isolated fucosterol was investigated against the 3D7 chloroquine sensitive Plasmodium falciparum strain, parasitaemia percentage was determined at 48 h and morphological change was studied through microscopic examination after Giemsa staining. A perceptible antiplasmodial effect was produced by fucosterol compound against the P. falciparum and positive control, chloroquine with the IC50 values (μg/mL) of 7.48 and 12.81, respectively. Fucosterol showed higher antiplasmodial activity as compared to chloroquine. It is inferred that both the fucosterol and chloroquine could have inhibited the schizont stage of the parasite during the intra-erythrocyte asexual development. The findings underline the usefulness of the seaweed-based fucosterol and further studies are warranted.

Ferrocenyl and organic novobiocin derivatives: Synthesis and their in vitro biological activity

A focused series of novobiocin derivatives containing a ferrocene unit together with their corresponding organic novobiocin analogues have been synthesized in modest to good yields. These compounds were screened for biological activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) and human breast cancer cell line (HCC38). With the exception of compounds 5c and 5d, the general trend observed is that incorporation of the ferrocene moiety into novobiocin scaffold resulted in compounds 6a–d/6f showing enhanced activity compared to organic analogues 5a–b and 5e–f.

Antiplasmodial activity of Mezoneuron benthamianum leaves and identification of its active constituents

Ethnopharmacological relevanceDecoctions of the leaves of M. benthamianum Baill. are used by traditional healers in Guinea to treat malaria and this use was validated by a preliminary clinical assay. Aim of the studyTo evaluate the in vitro antiplasmodial activity and to identify active compounds from extracts of M. benthamianum leaves. Material and methodsAntiplasmodial activity of extracts, fractions and pure compounds was evaluated in vitro against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) using the measurement of the plasmodial lactate dehydrogenase activity. Selectivity of extracts and purified compounds for Plasmodium parasites was evaluated by using WST-1 test on HeLa human cells. Compounds were isolated using normal phase silica gel column chromatography and prepHPLC and their structures elucidated using extensive spectroscopic analysis. ResultsHydroethanolic extracts (70% v/v) of M. benthamianum leaves showed a moderate in vitro activity against P. falciparum 3D7, with IC50 in the range 22.5 – 32.6µg/mL, depending on the batch; while a dark precipitate formed during ethanol evaporation showed higher activity (IC50 =6.5µg/mL). The fractionation was performed on this most active fraction and was followed by in vitro antiplasmodial assay. Active compounds (5, 7, 8) belong to several phytochemical classes, contributing together to the global antiplasmodial activity of the hydroethanolic extract against P. falciparum parasite. This study finally allowed the isolation of three diterpenes including two new compounds named Mezobenthamic acids A (1) and B (2) and neocaesalpin H (3), as well as quercetin (4), kaempferol (7), resveratrol (6), gallic acid (9) and its ethylester (5), β-sitosterol glucoside (10) and 13b-hydroxy-pheophorbide a (8). ConclusionThis study gives some concrete evidence to support the ethnopharmacological use of Mezoneuron benthamianum leaves extract in the management of malaria. The active compounds can be further studied for their antiplasmodial potential, as well as their suitability to be used as quality markers for the standardization of this herbal drug from the Guinean traditional pharmacopeia.

Synthesis of an organo-ruthenium aminoquinoline-trioxane hybrid and evaluation of its activity against Plasmodium falciparum and its toxicity toward normal mammalian cells

A new hybrid compound 5 containing a ruthenocene, a 4-aminoquinoline, and a 1,2,4-trioxane within a single molecular structure has been synthesized and evaluated for antimalarial potential. In order to ascertain the role of each component of hybrid 5, its antimalarial activity has been measured against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum in comparison with those of chloroquine, artemisinin, a ruthenocene-trioxane compound 9 not containing an aminoquinoline, the precursor trioxane ketone 4, and a trioxane dimer 10. Hybrid 5 displays high antimalarial activity, in the mid to low nanomolar IC50 range, and low cytotoxicity toward healthy mammalian cells, which translates into good selectivity indexes. The potency of 5 is consistently higher than those of chloroquine, the parent metal-free trioxane, and compound 9, the structural intermediate featuring a ruthenocene moiety bound to the trioxane but lacking the aminoquinoline. These results validate our hypothesis that it is the combination of the aminoquinoline, the ruthenocenyl moiety, and the trioxane in a single molecule that provides the enhanced antiplasmodial activity, and highlight the concept of hybrid compounds as a strategy that deserves further attention.

New antiprotozoal agents: Synthesis and biological evaluation of different 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives

In an endeavor to develop efficacious antiprotozoal agents 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives (5–14) were synthesized, characterized and biologically evaluated for antiprotozoal activity. The compounds were screened in vitro against the HM1: IMSS strain of Entamoeba histolytica and NF54 chloroquine-sensitive strain of Plasmodium falciparum. Among the synthesized compounds six exhibited promising antiamoebic activity with IC50 values (0.14–1.26μM) lower than the standard drug metronidazole (IC50 1.80μM). All nine compounds exhibited antimalarial activity (IC50 range: 1.42–19.62μM), while maintaining a favorable safety profile to host red blood cells. All the compounds were less effective as an antimalarial and more toxic (IC50 range: 14.67–81.24μM) than quinine (IC50: 275.6±16.46μM) against the human kidney epithelial cells. None of the compounds exhibited any inhibitory effect on the viability of Anopheles arabiensis mosquito larvae.