Chloroquine-sensitive Strains 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.

Antiplasmodial specialised compounds from the leaves of Guarea glomerulata Harms (Meliaceae)

To the best of our knowledge, this is the first chemical study of Guarea glomerulata that led to the isolation and characterisation of nine distinct compounds from its methanolic leaves extract including one new trinortriterpenoid glomerulatin along with eight known compounds amongst which five compounds namely azadirone, oleanolic acid, sericoside, cleomiscosin D and griffonin reported for the first time from the genus Guarea. All the isolated compounds have been evaluated in vitro for their antiplasmodial potency against the chloroquine-sensitive strain P. falciparum 3D7. The results showed that glomerulatin and azadirone were the most active compounds with IC50 values of 1.02 ± 0.2 μM and 1.48 ± 0.4 μM, respectively. This study enriches the chemistry of the genus Guarea and further supports the identification of Meliaceae plants as a good source of antiplasmodial candidates for the development of new potent drugs against malaria.

Structure and Biosynthesis of Perochalasins A-C, Open-Chain Merocytochalasans Produced by the Marine-Derived Fungus Peroneutypa sp. M16.

Novel open-chain merocytochalasans, perochalasins A-C (1-3), containing an unusual N-O six-membered heterocyclic moiety, were isolated from cultures of the marine-derived Peroneutypa sp. M16 fungus, along with cytochalasin Z27 (4), cytochalasin Z28 (5), [12]-cytochalasin (6), and phenochalasin B (7). The structures of compounds 1-3 were established by analysis of the spectroscopic data. Full genome sequencing of Peroneutypa sp. M16 enabled the identification of a cytochalasan biosynthetic gene cluster and a proposal for the biosynthetic assembly of perochalasins. The proposal is supported by the nonenzymatic conversion of phenochalasin B (7) into 1-3, based on isotope-labeled hydroxylamine (15NH2OH and ND2OD) feeding studies in vivo and in vitro. In contrast to other merocytochalasans, these are the first cytochalasans confirmed to arise via nucleophilic addition and at a distinct location from the reactive macrocycle olefin, potentially expanding further the range of merocytochalasans to be discovered or engineered. Cytochalasin Z27 (4) exhibited antiplasmodial activities in the low micromolar range against the chloroquine-sensitive Plasmodium falciparum 3D7 strain as well as against resistant strains of the parasite (Dd2, TM90C6B, and 3D7r_MMV848).

Tetrahydropyridine appended 8-aminoquinoline derivatives: Design, synthesis, in silico, and in vitro antimalarial studies

Antimalarial drug resistance is a major obstacle in the ongoing quest against malaria. The disease affects half of the world’s population. The majority of them are toddlers and pregnant women. Needed a potent compound to act on drug-resistant Pf at appropriate concentrations without endangering the host. Envisaged solving this issue through rational drug design by creating a novel hybrid drug possessing two pharmacophores that can act on two marvellous and independent aims within the cell. Synthesized a new series of substituted 4-phenyl-1,2,3,6-tetrahydropyridine (THP) 8-Aminoquinoline-based hybrid analogs which have been integrated with quinoline, chloroquine, pamaquine, and primaquine, which exhibited antimalarial activity against Pf. Out of thirteen 4-phenyl-1,2,3,6-THP appended 8-Aminoquinoline derivatives, the compounds 1j, 1e, 1b, and 1l have exhibited good antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-9) strain with the minimum inhibitory concentration. Compound 1b was the most effective and showed consistently good potency against the drug-resistant (RKL-9) strain, although all other arrays showed good antimalarial efficacy. Additional docking and molecular dynamics studies were carried out at several targeting sites to quantify the structural parameters necessary for the activity.

In vitro antimalarial therapeutic interventions using various combinations of antibiotics and standard antimalarials against multi drug resistant Indian field isolates of Plasmodium falciparum

Resistance to antimalarials is considered to be major cause of increased malaria morbidity and mortality. Present study was undertaken to explore an effective drug combination against selected mutant parasite various combinations using standard antimalarials {Chloroquine diphosphate (CQ), Quinine (QUIN), Mefloquine (MQ), Piperaquine (PPQ), Artemether (ARTM), Arteether (ARTE), Dihydro-artemisinin (DHA), Lumefantrine (LUME)and Atovaquone (ATQ)} belonging to three different classes and two antibiotics, Azithromycin (AZI) and Doxycycline (DOXY) have been tried against K1 (chloroquine-resistant) and 3D7 (chloroquine-sensitive) strains as well as selected arteether torelant parasite (MZRI-R) and field isolates (MZRI & MZRII) of P. falciparum. SYBR Green I fluorescence (MSF) assay was used to determine IC50 values. Results of present studies highlighted that all the combinations used exhibited additive effect with varying intensity depending upon the drug ratios used. We also observed that combination of ARTM plus LUME was more advantageous than DOXY plus DHA/CQ and AZI plus CQ/ATQ for treatment of multidrug resistant parasites whereas combinations of LUME plus PPQ, ATQ plus DOXY/AZI can be used for treatment of CQ resistant parasite.

Chemical profiling of citrus fruit-peel and stem extracts by modified UHPLC-TOF-MS and their antiplasmodial, antioxidant and antimicrobial activities

Citrus jambhiri (Lush) and paradisi (Macf.) have wide usage as food spices. Therefore, the presence of profiled phytochemicals, the antioxidant, antimicrobial and anti-plasmodial activities of the stem and fruit-peel extracts were studied. The citrus stem and fruit-peel extracts were analyzed using ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-qTOF/MS) and anti-plasmodial activities against chloroquine-sensitive (CQS) strain of Plasmodium falciparum, antimicrobial against Gram-positive and Gram-negative bacterial strains as well as antioxidant potentials were determined in triplicate. Metabolite fingerprinting of C. jambhiri stem and C. paradisi fruit-peel extracts revealed rutamarin and spicatin respectively. The stem and fruit-peel of C. jambhiri showed moderate antimalarial activity. C. paradisi stem revealed a weak activity; however, C. paradisi fruit-peel showed no antimalarial activity (IC50 >100 μg/mL). C. paradisi and C. jambhiri extracts exhibited lower inhibition concentration (IC50: 3.0–7.0 µgmL−1), than ascorbic acid (IC50: 9.0 µgmL−1). C. paradisi stem DCM/methanol extract showed a reducing value of EC50: 8.00 µgmL−1 whereas reference compound used, (ascorbic acid) had EC50: 11.00 µgmL−1. Furthermore, C. jambhiri stem extract showed the best antimicrobial activity against the clinical isolates with high inhibition zones ≥ 15 mm. There is a paucity of information on the identification and importance of rutamarin and spicatin from Citrus extracts as a functional food ingredient with a promising compound implicated in the development of antimalarial drugs. Overall result however showed that the two citrus plants contain antioxidant constituents whereas C. jambhiri could be important source of antimicrobial agents. The study profiled two new compounds from the citrus extract and showed the potentials of the plant as source of antimalaria drug.

Evaluation of the antiplasmodial and anti-Toxoplasma activities of several Indonesian medicinal plant extracts

Ethnopharmacological relevanceMalaria, caused by Plasmodium parasites, remains a significant global health challenge, particularly in tropical and subtropical regions. At the same time, the prevalence of toxoplasmosis has been reported to be 30% worldwide. Traditional medicines have long played a vital role in discovering and developing novel drugs, and this approach is essential in the face of increasing resistance to current antimalarial and anti-Toxoplasma drugs. In Indonesian traditional medicine, various plants are used for their therapeutic properties. This study focuses on eleven medicinal plants from which nineteen extracts were obtained and screened for their potential medicinal benefits against malaria and toxoplasmosis. Aims of the studyThe aim of this study was to evaluate the efficacy of extracts from Indonesian medicinal plants to inhibit Plasmodium falciparum, a parasite responsible for malaria, and Toxoplasma gondii, an opportunistic parasite responsible for toxoplasmosis. MethodsNineteen extracts from eleven plants were subjected to in vitro screening against P. falciparum 3D7 (a chloroquine-sensitive strain) and the T. gondii RH strain. In vitro treatments were conducted on P. falciparum 3D7 and K1 (multidrug-resistant strains) using the potent extracts, and in vivo assessments were carried out with mice infected with P. yoelii 17XNL. LCMS analysis was also conducted to identify the main components of the most effective extract. ResultsSeven extracts showed significant antiplasmodial activity (>80% inhibition) at a concentration of 100 μg/ml. These extracts were obtained from Dysoxylum parasiticum (Osbeck) Kosterm., Elaeocarpus glaber (Bl.) Bijdr., Eleutherine americana Merr., Kleinhovia hospita L., Peronema canescens Jack, and Plectranthus scutellarioides (L.) R.Br. Notably, the D. parasiticum ethyl acetate extract exhibited high selectivity and efficacy both in vitro and in vivo. Herein, the key active compounds oleamide and erucamide were identified, which had IC50 values (P. falciparum 3D7/K1) of 17.49/23.63 μM and 32.49/51.59 μM, respectively. ConclusionsThe results of this study highlight the antimalarial potential of plant extracts collected from Indonesia. Particularly, extracts from D. parasiticum EtOH and EtOAc stood out for their low toxicity and strong antiplasmodial properties, with the EtOAc extract emerging as a notably promising antimalarial candidate. Key compounds identified within this extract demonstrate the complexity of extracts' action against malaria, potentially targeting both the parasite and the host. This suggests a promising approach for developing new antimalarial strategies that tackle the multifaceted challenges of drug resistance and disease management. Future investigations are necessary to unlock the full therapeutic potential of these extracts.

Design, in silico study, synthesis and evaluation of hybrid pyrazole substituted 1,3,5-triazine derivatives for antimalarial activity

ObjectivesMalaria is a significant global health challenge, particularly in Africa, Asia, and Latin America, necessitating immediate investigation into innovative and efficacious treatments. This work involves the development of pyrazole substituted 1,3,5-triazine derivatives as antimalarial agent. MethodsIn this study, ten compounds 7(a-j) were synthesized by using nucleophilic substitution reaction, screened for in silico study and their antimalarial activity were evaluated against 3D7 (chloroquine-sensitive) strain of P. falciparum. Key findingThe present work involves the development of hybrid trimethoxy pyrazole 1,3,5-triazine derivatives 7 (a–j). Through in silico analysis, four compounds were identified with favorable binding energy and dock scores. The primary focus of the docking investigations was on the examination of hydrogen bonding and the associated interactions with certain amino acid residues, including Arg A122, Ser A108, Ser A111, Ile A164, Asp A54, and Cys A15. The IC50 values of the four compounds were measured in vitro to assess their antimalarial activity against the chloroquine sensitive 3D7 strain of P. falciparum. The IC50 values varied from 25.02 to 54.82 μg/mL. ConclusionAmong the ten derivatives, compound 7J has considerable potential as an antimalarial agent, making it a viable contender for further refinement in the realm of pharmaceutical exploration, with the aim of mitigating the global malaria load.

Mechanism of antimalarial action and mitigation of infection-mediated mitochondrial dysfunction by phyto-constituents of Andrographis paniculata ((Burm f.) Wall. ex Nees) in Plasmodium berghei-infected mice

Ethnopharmacological relevanceAndrographis paniculata (AP) ((Burm f.) Wall. ex Nees) is a medicinal plant, documented for its folkloric use in the treatment of malaria. AimThis study was designed to determine the potency of extract and fractions of A. paniculata (AP) as a curative, both for susceptible and resistant malaria and to also determine the plant's mechanism of action. This study was also designed to determine whether AP extract and its most potent fraction will mitigate infection-mediated mitochondrial dysfunction, and to assess the phytochemical constituents of the most potent fraction. Materials and methodsn-Hexane, dichloromethane, ethylacetate and methanol were used to partition the methanol extract of A. paniculata. Graded doses of these extract and fractions were used to treat mice infected with chloroquine-sensitive strain of P. berghei in a curative model. The most potent fraction was used to treat mice infected with resistant (ANKA strain) P. berghei. Inhibition of hemozoin formation, reversal of mitochondrial dysfunction and antiinflammatory potentials were determined. A combination of ultraperformance liquid chromatography-quadrupole time of flight-mass spectrometry and nuclear magnetic resonance spectroscopy were used for chemical analysis. ResultsMicroscopy revealed that the dichloromethane fraction decreased the parasite burden the most, and inhibition of the hemozoin formation is one of its mechanisms of action. The dichloromethane fraction reversed parasite-induced mitochondrial pore opening in the host, enzyme-dependent ATP hydrolysis and peroxidation of host mitochondrial membrane phospholipids as well as its antiinflammatory potentials. The UPLC-qTOF-MS report and NMR fingerprints of the dichloromethane fraction of A. paniculata yielded fourteen compounds of which sibiricinone C was identified from the plant for the first time. ConclusionFractions of A. paniculata possess antiplasmodial effects with the dichloromethane fraction having the highest potency. The potent effect of this fraction may be attributed to the phytochemicals present because it contains terpenes implicated with antimalarial and antiinflammatory activities.

Antimalarial potential of Kerala Ayurvedic Water "Pathimugam".

The persistent threat of drug resistant malaria demands new cures. Low prevalence of malaria in the Indian state of Kerala compared with other proximal states led us to explore if there is any traditional practice in Kerala which may confer protection against malaria. In this context, our attention was drawn to "Pathimugam" i.e., Ceasalpinia sappan whose heartwood is used to prepare a red aqueous extract which is a uniquely popular drink all over Kerala. Aqueous and methanolic extracts of various organs of C. sappan were prepared and tested against Plasmodium falciparum grown in vitro culture using SYBR Green-I assay. The cytotoxicity of active extracts/fractions was studied using mammalian HeLa cell line. In vivo efficacy was determined using Plasmodium berghei ANKA infected mice. The highest antiplasmodial activities in the alcoholic and aqueous extracts were observed in leaf methanolic extract (IC 2 μg/ml) and heartwood aqueous extract (IC 12.5 μg/ml). C. sappan extracts were equipotent against both chloroquine sensitive Pf3D7 and resistant Pf INDO strains and showed suppression of % parasitemia in P. berghei infected mice. Activity guided chromatographic fractionation of aqueous wood extract led to the fortification of antiplasmodial activity (IC 5 μg/ml). Our results establish the antiplasmodial potential of C. sappan and suggest that its regular use might have prophylactic or curative actions that may assist in keeping check on malaria in the Indian state of Kerala.

In vitro and in vivo antimalarial activities of the ethanol extract of Erythrina sigmoidea stem bark used for the treatment of malaria in the Western Region of Cameroon

BackgroundMalaria is one of the leading causes of morbidity and/or mortality in tropical Africa. The spread and development of resistance to chemical antimalarial drugs and the relatively high cost of the latter are problems associated with malaria control and are reasons to promote the use of plants to meet healthcare needs to treat malaria. The aim of this study was to evaluate antiplasmodial activities of extracts of Erythrina sigmoidea (Mah quat), which is traditionally used for the treatment of malaria in the western region of Cameroon.Material and methodsThe ethanol extract of E. sigmoidea stem bark was obtained through the maceration process using 95% ethanol, while the aqueous extract was prepared by infusion. The in vitro antiplasmodial effect of extracts against P. falciparum chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains was determined using the Trager and Jensen method. On the other hand, the in vivo antimalarial activity of the extract was evaluated in mice infected with Plasmodium berghei strain NK65 using the Peters’ 4-day suppressive test and Ryley test (curative test). A total of 36 mice were used, subdivided into six groups of six mice each: one normal control, a negative control, a positive control, and three other groups for the tested product. Blood samples were collected on the 10th day of each test for hematological parameters.ResultsThe aqueous extract had an in vitro antiplasmodial activity against the chloroquine-sensitive strain with an IC50 of 29.51 ± 3.63 µg/mL and against the chloroquine-resistant strain with an IC50 of 35.23 ± 3.17 µg/mL. The highest in vitro antiplasmodial activity was observed with the ethanol extract against the chloroquine-sensitive strain with an IC50 of 6.44 ± 0.08 µg/mL and against the chloroquine-resistant strain with an IC50 of 7.53 ± 0.22 µg/mL. The ethanol extract demonstrated suppressive activity in vivo with reduction rates of 87.69%, 86.79%, and 81.08% at doses of 500 mg/kg, 250 mg/kg, and 125 mg/kg, respectively; and curative activity in vivo with reduction rates of 80%, 78.5%, and 77.5% at doses of 500 mg/kg, 250 mg/kg, and 125 mg/kg, respectively. The number of white blood cells in the negative control (44.55 ± 5.02 103/µL) was higher compared to the other groups. As for the red blood cells, we observed a massive destruction of the latter in the infected and untreated group (5.82 ± 1.50 106/µL) compared to the infected and ethanol extract-treated groups (8.74 ± 1.57 106/µL for 500 mg/kg, 7.54 ± 1.77 106/µL for 250 mg/kg, and 8.9 ± 1.50 106/µL for 125 mg/kg).ConclusionThis study provides scientific data on the use of E. sigmoidea by the local population for the treatment of malaria. It shows that E. sigmoidea has antiplasmodial activity, and we also see that there are differences between the parameters that we have in the treated groups and those of the untreated group. However, toxicity tests are necessary to assess its safety.

Antiplasmodial activity and toxicity of the leaves, stem and roots of Parinari robusta Oliv [CHRYSOBALANACEAE] in animal model

Malaria continues to wreak havoc on various populations as a result of the mortality and economic burden associated with the disease. Progress made in the therapeutics of the disease is threatened by the emerging parasite resistance to currently used first line treatment drugs. This has prompted the search for new, effective, and safe antimalarial agents. Parinari robusta is one plant in use with inadequate evidence about its efficacy. This study therefore aimed to assess the in vivo and in vitro antimalarial potential, and the safety of the leaves, stem and roots of the plant. Acute toxicity was carried out according to OECD guidelines. In vivo antimalarial activity of the hydroethanolic extracts were assessed using the Peter's 4-day suppressive and Rane's curative tests. In vitro antiplasmodial activity of the hydroethanolic crude extracts were evaluated using the SYBR Green I fluorescence assay on the chloroquine sensitive (3D7) and chloroquine resistant (Dd2) strains of P. falciparum. P. robusta was safe with the lethal dose above 3000 mg/kg. All the extracts significantly (p < 0.001) suppressed parasitaemia in the Peter's suppressive and Rane's curative test in a dose dependent manner. The extracts showed highly to weakly active in vitro antiplasmodial activity with an IC50 between 2.629 μg/ml to 30.320 μg/ml against 3D7 and Dd2 strain of P. falciparum. Leaf and stem extract gave the most superior activity against the Dd2 and 3D7 P. falciparum strains. The findings of this study provide scientific evidence supporting the traditional use of P. robusta in the treatment of malaria.

Antiplasmodial activity, in silico ADME and mammalian cell cytotoxicity of a synthetic protoberberine alkaloid, coralyne

Coralyne is a synthetic protoberberine alkaloid with anticancer activity and selectivity superior to that of berberine, its congener. As berberine is gifted with antiplasmodial activity, this study assessed the antiplasmodial activity of coralyne against erythrocytic stages of the malaria parasite in culture. Parasites were cultured by adopting the method described by Trager and Jensen in 1976. Following this, parasites were exposed at ring stage to increasing doses of coralyne to enable us compute the IC50. Further, given that berberine is a substrate of the efflux transporter permeability glycoprotein (P-gp), in silico techniques were used to study the pharmacokinetics of oral coralyne. Coralyne showed excellent potency (IC50Pf3D7: 0.52 µg/ml) against chloroquine sensitive strain and a little less potency (IC50PfINDO: 1.15 µg/ml) against the chloroquine resistant malaria parasite strain (Resistance index: 2.21). Further, with CC50HEK: &gt;100 µg/ml, it was non-toxic to mammalian cells. However, in silico absorption, distribution, metabolism and excretion (ADME) studies predicts that like berberine, coralyne may also have poor oral bioavailability thus limiting its usefulness as an orally deliverable antimalarial agent. Given the negative impact of low bioavailability in the development of protoberberine alkaloids as antimalarials, synthesizing analogues of coralyne with nanomolar potency against the malaria parasite and improved oral pharmacokinetics may be a good strategy for the future.

A lupeol derivative and other isolates with antiplasmodial activity from the stem root of Rauvolfia mannii Stapf. (Apocynaceae)

Rauvolfia mannii is a plant from western and eastern areas of African continent and is widely used in folk medicine for the treatment of various diseases including malaria. Herein, one previously undescribed acylated triterpene (1), together with five already published natural products (2-6) were removed from its roots. The chemical structures of these compounds were determined by spectroscopic and spectrometric means (NMR, HRESIMS, IR and UV). In addition to the isolated triterpenoids, components 5 and 6 are also newly reported from the genus Rauvolfia. Moreover, some constituents were further tested against the chloroquine-sensitive strain of P. falciparum (3D7). It has been found that 3 and 4 showed a moderate antiplasmodial activity with IC50 values of 46.25 and 39.79 µM respectively.

New antimalarial iromycin analogs produced by Streptomyces sp. RBL-0292.

Two new antimalarial compounds, named prenylpyridones A (1) and B (2), were discovered from the actinomycete cultured material of Streptomyces sp. RBL-0292 isolated from the soil on Hamahiga Island in Okinawa prefecture. The structures of 1 and 2 were elucidated as new iromycin analogs having α-pyridone ring by MS and NMR analyses. Compounds 1 and 2 showed moderate in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with IC50 values ranging from 80.7 to 106.7 µM.

Akedanones A-C, In Vitro and In Vivo Antiplasmodial 2,3-Dihydronaphthoquinones Produced by Streptomyces sp. K20-0187.

Three new antiplasmodial compounds, named akedanones A (1), B (2), and C (3), were discovered from the cultured material of Streptomyces sp. K20-0187 isolated from a soil sample collected at Takeda, Kofu, Yamanashi prefecture in Japan. The structures of compounds 1-3 were elucidated as new 2,3-dihydronaphthoquinones having prenyl and reverse prenyl groups by mass spectrometry and nuclear magnetic resonance analyses. Compound 1 and the known furanonaphthoquinone I (4) showed potent in vitro antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with half-maximal inhibitory concentration values ranging from 0.06 to 0.3 μM. Compounds 1 and 4 also displayed potent in vivo antiplasmodial activity against drug-sensitive rodent malaria Plasmodium berghei N strain, with inhibition rates of 47.6 and 43.1%, respectively, on intraperitoneal administration at a dose of 5 mg kg-1 day-1 for 4 days.

Phytochemical profiling of Striga asiatica; characterisation and anti-microbial assessment of the isolates

One undescribed compound, striasinol (1), and twelve previously described compounds were isolated from the aerial parts of Striga asiatica. Structure elucidation of isolated compounds was achieved by the interpretation of 1D and 2D NMR and HRESIMS data. The absolute configuration (1S,5S) of 1 was ascertained based on GIAO NMR calculations, DP4+ probability analysis, and a comparison of the experimental and calculated specific rotation values. The isolated compounds were evaluated for their antimalarial action, and none was found to be effective against the chloroquine-sensitive (D6) or chloroquine-resistant (W2) strains of Plasmodium falciparum. The isolates were found non-toxic to the Vero cell line as well. Subsequent testing of these metabolites for antimicrobial activities against various bacterial and fungal strains (up to 20 µg/mL), revealed that compounds 6 (chryseriol) and 7 (apigenin) showed a reasonable activity towards methicillin-resistant Staphylococcus aureus ATCC 1708 (MRSA), with IC50 values of 5.81 and 3.60 μg/mL, respectively.

N-Substituted Phenylhydrazones Kill the Ring Stage of Plasmodium falciparum.

Antimalarial resistance has hampered the effective treatment of malaria, a parasitic disease caused by Plasmodium species. As part of our campaign on phenotypic screening of phenylhydrazones, a library of six phenylhydrazones was reconstructed and evaluated for their in vitro antimalarial and in silico receptor binding and pharmacokinetic properties. The structures of the phenylhydrazone hybrids were largely confirmed using nuclear magnetic resonance techniques. We identified two compounds which exhibited significant antimalarial potential against the ring stage (trophozoite) of 3D7 chloroquine-sensitive (CS) strain and DD2 chloroquine-resistant (CR) strains of Plasmodium falciparum with monosubstituted analogs bearing meta or para electron-donating groups showing significant activity in the single-digit micromolar range. Structure activity relationship is presented showing that electron-donating groups on the substituent hydrophobic pharmacophore are required for antimalarial activity. Compounds PHN6 and PHN3 were found to be the most potent with pIC50s (calculated form in vitro IC50s) of 5.37 and 5.18 against 3D7 CS and DD2 CR strains, respectively. Our selected ligands (PHN3 and PHN6) performed better when compared to chloroquine regarding binding affinity and molecular stability with the regulatory proteins of Plasmodium falciparum, hence predicted to be largely responsible for their in vitro activity. Pharmacokinetic prediction demonstrated that the phenylhydrazones may not cross the blood-brain barrier and are not P-glycoprotein (P-gp) substrates, a good absorption of 62% to 69%, and classified as a category IV compound based on toxicity grading.

Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors

The rapid emergence of resistance to existing frontline antimalarial drugs emphasizes a need for the development of target-oriented molecules with novel modes of action. Given the importance of a plant-like Calcium-Dependent Protein Kinase 1 (PfCDPK1) as a stand-alone multistage signalling regulator of P. falciparum, we designed and synthesized 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a–s) and 9) directed towards PfCDPK1. This was accomplished by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4-azido-7-chloroquinoline, respectively via a ‘click’ reaction. The selected CQTrICh-analogs: 7l and 7r inhibited the growth of chloroquine-sensitive 3D7 strain and -resistant RKL-9 isolate of Plasmodium falciparum, with IC50 values of 2.4 μM &1.8 μM (7l), and 3.5 μM &2.7 μM (7r), respectively, and showed no apparent hemolytic activity and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. 7l and 7r were found to stably interact with the catalytically active ATP-binding pocket of PfCDPK1 via energetically favourable H-bonds. The interaction was confirmed in vitro by microscale thermophoresis and kinase assays, which demonstrated that the active hybrids interact with PfCDPK1 and inhibit its kinase activity which is presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating their selectivity for the parasite kinase. We report the antiplasmodial potential of novel kinase-targeting bio-conjugates, a step towards developing pan-kinase inhibitors which is a prerequisite for multistage anti-malarial protection.

SAR Guided Synthesis of Potent, Selective and Artemisinin Synergistic New Imidazole Derivatives with Promising In Vitro Antiplasmodial and In Vivo Antimalarial Activities

AbstractGuided by Structural Activity Relationship (SAR), a series of synthetic tri‐ and tetra‐substituted imidazoles were studied for in vitro antiplasmodial activities against erythrocytic stages of chloroquine sensitive and resistant strains of Plasmodium falciparum using SYBR green I assay. This led to the identification of three potent (IC50 μM) derivatives : Im2 (0.75), Im5 (0.75) and Im22 (0.5). These three lead molecules present unique structural features with a common molecular architecture. Thus, Im2 and Im22 have phenyl rings at positions 4 and 5 of imidazole ring along with n‐hexyl at N3 position, and differ in the C2 substituent (3‐cyclopentyloxy‐4‐methoxy phenyl for Im2) versus naphthyl for Im22. In contrast, positions 4 and 5 in Im5 have pyridyl rings, with unsubstituted N3. Further, curative antimalarial studies with Im2 and Im5 in a Plasmodium berghei (ANKA) infected mouse model of malaria, revealed an increase in average survival time to 28.6±4.2 and 27.4±4 days respectively, as compared to 20.2±2.3 days for untreated control mice. Results of in vitro combination (Im22+Artemisinin) with ΣFIC50: 0.34–0.79, indicated promising synergy and prospects for the use of Im22 as a new constituent in Artemisinin combination therapy (ACT).