Chloroquine-resistant Strains Research Articles

Biological activity of 1,2,3-triazole-2-amino-1,4-naphthoquinone derivatives and their evaluation as therapeutic strategy for malaria control

Malaria can be caused by several Plasmodium species and the development of an effective vaccine is challenging. Currently, the most effective tool to control the disease is the administration of specific chemotherapy; however, resistance to the frontline antimalarials is one of the major problems in malaria control and thus the development of new drugs becomes urgent. The study presented here sought to evaluate the antimalarial activities of compounds derived from 2-amino-1,4-naphthoquinones containing 1,2,3-triazole using in vivo and in vitro models. 1H-1,2,3-Triazole 2-amino-1,4-naphthoquinone derivatives were synthesized and evaluated for antimalarial activity in vitro, using P. falciparum W2 chloroquine (CQ) resistant strain and in vivo using the murine-P. berghei ANKA strain. Acute toxicity was determined as established by the OECD (2001). Cytotoxicity was evaluated against HepG2 and Vero mammalian cell lines. Transmission electron microscopy of the Plasmodium falciparum trophozoite (early and late stages) was used to evaluate the action of compounds derived at ultra-structural level. The compounds displayed low cytotoxicity CC50 > 100 μM, neither did they cause hemolysis at the tested doses and nor the signs of toxicity in the in vivo acute toxicity test. Among the five compounds tested, one showed IC50 values in submicromolar range of 0.8 μM. Compounds 7, 8 and 11 showed IC50 values < 5 μM, and selectivity index (SI) ranging from 6.8 to 343 for HepG2, and from 13.7 to 494.8 for Vero cells. Compounds 8 and 11 were partially active against P. berghei induced parasitemia in vivo. Analysis of the ultrastructural changes associated with the treatment of these two compounds, showed trophozoites with completely degraded cytoplasm, loss of membrane integrity, organelles in the decomposition stage and possible food vacuole deterioration. Our results indicated that compounds 8 and 11 may be considered hit molecules for antimalarial drug discovery platform and deserve further optimization studies.

Incorporation of Trifluoromethyltriazoline in the Side Chain of 4-Aminoquinolines: Synthesis and Evaluation as Antiplasmodial Agents.

Reported herein is the identification of a novel class of 4-aminoquinoline-trifluormethyltriazoline compounds as possible antiplasmodial agents. The compounds were accessed through a silver-catalyzed three-component reaction of trifluorodiazoethane with in situ generated Schiff base from corresponding quinolinylamine and aldehydes. While attempting to incorporate a sulfonyl moiety, the triazoline formed underwent spontaneous oxidative aromatization to afford triazole derivatives. All synthesized compounds were tested for their antimalarial potential in vitro and in vivo. Out of 32 compounds, four showed the most promising antimalarial activity with IC50 values ranging from 4 to 20 nM against Pf3D7 (chloroquine-sensitive) and from 120 to 450 nM against PfK1 (chloroquine-resistant) strains. One of these compounds was also found to be effective in animal studies; it showed a 99.9 % decrease in parasitic load on day 7 post-infection along with a 40 % cure rate and longest host life span.

New antimalarial fusarochromanone analogs produced by the fungal strain Fusarium sp. FKI-9521.

Two new antimalarial compounds, named deacetyl fusarochromene (1) and 4'-O-acetyl fusarochromanone (2), were discovered from the static fungal cultured material of Fusarium sp. FKI-9521 isolated from feces of a stick insect (Ramulus mikado) together with three known compounds fusarochromanone (3), 3'-N-acetyl fusarochromanone (4), and 5 (fusarochromene or banchromene). The structures of 1 and 2 were elucidated as new analogs of 3 by MS and NMR analyses. The absolute configurations of 1, 2, and 4 were determined by chemical derivatization. All five compounds showed moderate in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with IC50 values ranging from 0.08 to 6.35 µM.

Design, synthesis and evaluation of novel pyrrole-hydroxybutenolide hybrids as promising antiplasmodial and anti-inflammatory agents

In the pursuance of novel scaffolds with promising antiplasmodial and anti-inflammatory activity, a series of twenty-one compounds embraced with most promising penta-substituted pyrrole and biodynamic hydroxybutenolide in single skeleton was designed and synthesized. These pyrrole-hydroxybutenolide hybrids were evaluated against Plasmodium falciparum parasite. Four hybrids 5b, 5d, 5t and 5u exhibited good activity with IC50 of 0.60, 0.88, 0.97 and 0.96 μM for chloroquine sensitive (Pf3D7) strain and 3.92, 4.31, 4.21 and 1.67 μM for chloroquine resistant (PfK1) strain, respectively. In vivo efficacy of 5b, 5d, 5t and 5u was studied against the P. yoelii nigeriensis N67 (a chloroquine-resistant) parasite in Swiss mice at a dose of 100 mg/kg/day for 4 days via oral route. 5u was found to show maximum 100% parasite inhibition with considerably increased mean survival time. Simultaneously, the series of compounds was screened for anti-inflammatory potential. In preliminary assays, nine compounds showed more than 85% inhibition in hu-TNFα cytokine levels in LPS stimulated THP-1 monocytes and seven compounds showed more than 40% decrease in fold induction in reporter gene activity analyzed via Luciferase assay. 5p and 5t were found to be most promising amongst the series, thus were taken up for further in vivo studies. Wherein, mice pre-treated with them showed a dose dependent inhibition in carrageenan induced paw swelling. Moreover, the results of in vitro and in vivo pharmacokinetic parameters indicated that the synthesized pyrrole-hydroxybutenolide conjugates abide by the required criteria for the development of orally active drug and thus this scaffold can be used as pharmacologically active framework that should be considered for the development of potential antiplasmodial and anti-inflammatory agents.

Antiplasmodial, Antioxidant and Cytotoxicity Activity of Ethanol and Aqueous Extracts of Khaya grandifoliola Stem Bark.

Malaria is a serious public health problem, especially in sub-Saharan Africa. The aim of this study was to scientifically provide baseline information on the use of Khaya grandifoliola stem bark as an antimalaria drug by traditional healers. The stem barks of K.grandifoliola were harvested and dried to obtain powder, and fifty grams of the powder were soaked in ethanol and hot distilled water respectively, for the preparation of ethanol and aqueous extracts, then dried in an oven at 40°C for the ethanol extract and 50°C for the aqueous extract. Plasmodium falciparum strains 3D7 sensitive and Dd2 resistant to chloroquine, were used to evaluate in vitro antiplasmodial activity using SYBR Green. The ability of the extracts to prevent oxidative stress was assessed by trapping 2, 2'-diphenyl-1-picrylhydrazyl (DPPH); nitric oxide, hydrogen peroxide and ferric reducing power. The cytotoxicity test of the extracts was carried out on RAW 264.7 cell lines and on erythrocytes. The data obtained were entered in the Excel software, then in Graph pad where the IC50 was calculated and the curves plotted. The fifty percent inhibition (IC50) of the antiplasmodial activity of the chloroquine-resistant strain PfDd2 were 54.27 ± 2.41 μg/mL and 31.19 ± 4.06 μg/mL respectively, for the aqueous and ethanol extracts. As for the Chloroquino-sensitive Pf3D7, IC50 of 53.06 μg/mL was obtained for the aqueous extract and 28.03 ± 1.90 μg/mL for ethanol. The DPPH radical scavenging activity presented IC50 of 104 μg/mL for the aqueous and 2.617 μg/mL for the ethanol extract; for the Nitric oxide (NO) presented an IC50 of 301 ± 21 μg/mL for the aqueous extract 140.7 ± 21 μg/mL for the ethanol; for hydrogen peroxide the ethanol and aqueous presented IC50 of 845.1 ± 21 μg/mL and 509.4 ± 21 μg/mL respectively. The cytotoxicity on RAW 264.7 cells presented High CC50 in particular >1000 μg/mL and 467.4 μg/mL respectively for the aqueous and ethanol extract. Extracts of Khaya grandifoliola exhibited antiplasmodial activity. The ability to inhibit oxidative stress as well as lower cell toxicity on RAW 264.7 and erythrocytes, is a good indicator. However, in vivo tests remain important in order to confirm the use of this plant for the treatment of malaria.

Bioguided Fractionation and Isolation of an Antiplasmodial Saponin from the Roots of Nauclea xanthoxylon (A.Chev.) Aubrév. (Rubiaceae).

The root extract of Nauclea xanthoxylon (A.Chev.) Aubrév. displayed significant 50 % inhibition concentration (IC50 s) of 0.57 and 1.26 μg/mL against chloroquine resistant and sensitive Plasmodium falciparum (Pf) Dd2 and 3D7 strains, respectively. Bio-guided fractionation led to an ethyl acetate fraction with IC50 s of 2.68 and 1.85 μg/mL and subsequently, to the new quinovic acid saponin named xanthoxyloside (1) with IC50 s of 0.33 and 1.30 μM, respectively against the tested strains. Further compounds obtained from ethyl acetate and hexane fractions were the known clethric acid (2), ursolic acid (3), quafrinoic acid (4), quinovic acid (5), quinovic acid 3-O-β-D-fucopyranoside (6), oleanolic acid (7), oleanolic acid 3-acetate (8), friedelin (9), β-sitosterol (10a), stigmasterol (10b) and stigmasterol 3-O-β-D-glucopyranoside (11). Their structures were characterised with the aid of comprehensive spectroscopic methods (1 and 2D NMR, Mass). Bio-assays were performed using nucleic acid gel stain (SYBR green I)-based fluorescence assay with chloroquine as reference. Extracts and compounds exhibited good selectivity indices (SIs) of >10. Significant antiplasmodial activities measured for the crude extract, the ethyl acetate fraction and xanthoxyloside (1) from that fraction can justify the use of the root of N. xanthoxylon in ethnomedicine to treat malaria.

Rubia cordifolia L. Crude Aerial Part Extracts Show a High Potential as Antimalarials against Chloroquine Resistant Plasmodium falciparum Strains in vitro

Pharmacognosy Research,2023,15,2,288-296.DOI:10.5530/pres.15.2.031Published:February 2023Type:Original Article Authors:Magara Jeremiah, Lucy Kamau, Grace Nyambati, and Hastings Ozwara Author(s) affiliations:Magara Jeremiah1, Lucy Kamau1, 2,*, Grace Nyambati3, Hastings Ozwara4 1Department of Zoological Sciences, Kenyatta University, Nairobi, KENYA. 2Department of Animal Sciences, Kenyatta University, Nairobi, KENYA. 3Department of Biomedical Sciences and Technology, The Technical University of Kenya, Nairobi, KENYA. 4Department of Tropical and Infectious Diseases, Institute of Primate Research, Nairobi, KENYA. Abstract:Introduction: Plasmodium falciparum human malaria parasite is resistant to most available medicines in Africa, necessitating research for new drugs. Rubia cordifolia L. is used in traditional malaria treatment in Kenya despite no supporting scientific data. Objectives: To evaluate anti-plasmodial efficacy of extracts from the aerial part of Rubia cordifolia against chloroquine sensitive (3D7) and resistant (W2) Plasmodium falciparum strains. Methods: Hexane, methanol and water were separately used in crude extractions from open shade dried aerial plant parts. Phytochemical composition was determined qualitatively. Anti-plasmodial efficacy of serial dilutions (range; 0.4 to 50 μg/ml) of each extract were evaluated in vitro and compared using ANOVA and Tukey’s HSD test, at p<0.05). Results: All the extracts significantly inhibited parasites growth, in a dose dependent manner. At 50 μg/ml, inhibition was (84.07%, 77.94% and 66.08%) for hexane, methanol and water extracts respectively against W2 and (80.06%, 78.36% and 60.92%) against 3D7 strain. Hexane extract showed IC50 0.551 μg/ml and 2.747 micrograms/ml against W2 and 3D7 respectively. Methanol extract, IC50 1.231 and 3.528 μ g/ml respectively, aqueous extract showed moderate activity, IC50 5.348 μg/ml and 17.341 μg/ml against the strains respectively. Chloroquine resistant (W2 strain) was more responsive to the extracts than 3D7 strain. Conclusion: Anti-plasmodial activities were in the order, Hexane>methanol>aqueous and were attributed to the phytochemicals present in the extracts. This presents evidence of R. cordifolia as anti-malarial drugs’ source. Further work is required to identify, purify, and characterize active molecules for development of anti-malaria drugs. Keywords:Antimalarial activity, Crude extracts, in vitro, Plasmodium falciparum, Rubia cordifolia.View:PDF (236.96 KB)

Antimalarial and Cytotoxic Activity of Native Plants Used in Cabo Verde Traditional Medicine.

Medicinal plants have historically been a source of drugs in multiple applications, including the treatment of malaria infections. The Cabo Verde archipelago harbors a rich diversity of native plants, most of which are used for medicinal purposes. The present study investigated the in vitro antiplasmodial activities of four native plants from Cabo Verde (i.e., Artemisia gorgonum, Lavandula rotundifolia, Sideroxylon marginatum, and Tamarix senegalensis). Traditional preparations of these medicinal plants, namely aqueous extracts (infusions) and ethanolic extracts, were tested against both chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains using the SYBR Green detection method. The in vitro cytotoxicity was evaluated in Caco-2 and PLP2 cells using a sulforhodamine B colorimetric assay. An ethanolic extract of A. gorgonum and infusions of T. senegalensis exhibited high antiplasmodial activities (EC50 < 5 μg/mL) without cytotoxicity (GI50 > 400 μg/mL). Extracts of L. rotundifolia and S. marginatum exhibited moderate activities, with EC50 values ranging from 10-30 μg/mL. The A. gorgonum ethanolic extract showed activity toward early ring stages, and parasites treated with the T. senegalensis infusions progressed to the early trophozoite stage, although did not develop further to the late trophozoite or schizont stages. Antimalarial activities and the lack of cytotoxicity of the extracts are reported in the present study and support previous claims by traditional practitioners for the use of these plants against malaria while suggesting their ethnopharmacological usefulness as future antimalarials.

Antimalarial Activity of Tri- and Tetra-Substituted Anilino Pyrazoles

Pyrazole core represents a privilege scaffold in medicinal chemistry; a number of pyrazole compounds are endowed with various pharmacological activities in different therapeutic areas including antimalarial treatment. Supported by this evidence, a series of 5-anilino-3-(hetero)arylpyrazoles were evaluated for their antiplasmodial activity in in vitro assays. The compounds were synthesized according to regioselective and versatile protocols that combine active methylene reagents, aryl isothiocyanates and (substituted)hydrazines. The considered derivatives 2 allowed the definition of consistent structure-activity relationships and compounds 2b,e,k,l were identified as the most interesting derivatives of the series showing micromolar IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium strains. Additionally, the most active anilino-pyrazoles did not show any cytotoxicity against tumor and normal cells and were predicted to have favorable drug-like and pharmacokinetic properties.

Challenges Based on Antiplasmodial and Antiviral Activities of 7-Chloro-4-aminoquinoline Derivatives.

We report the structural functionalization of the terminal amino group of N1 -(7-chloroquinolin-4-yl) butane-1,4-diamine, leading to a series of 7-chloro-4-aminoquinoline derivatives, and their evaluation as potent anti-malarial and anti-viral agents. Some compounds exhibited promising anti-malarial effects against the Plasmodium falciparum 3D7 (chloroquine-sensitive) and Dd2 (chloroquine-resistant) strains. In addition, these compounds were assayed in vitro against influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compound 5 h, bearing an N-mesityl thiourea group, displayed pronounced anti-infectious effects against malaria, IAV, and SARS-CoV-2. These results provide new insights into drug discovery for the prevention or treatment of malaria and virus co-infection.

Investigation of bioorganometallic artemisinins as antiplasmodials

The aim of this study was to improve the activity of artemisinin-based compounds for the treatment of malaria, primarily caused by Plasmodium falciparum. The artemisinin scaffold was functionalized with an appropriate N,N’– coordinated ruthenium p-cymene complex or ferrocene complex. For the preparation of the ruthenium complexes, two novel ligands were prepared: artemisinyl-triazole pyridine (compound 1) and pyridyl amido-artesunate (compound 4). The organometallic moieties were linked by a triazole or an amide-alkyl-ester to the artemisinin scaffold. Six new organometallic artemisinin-based complexes were synthesised and characterised (compounds 2a, 2b, 3, 5a, 5b and 6). Of the six organometallic artemisinin compounds, the ferrocenyl amido-artesunate, compound 6, was the most active against the chloroquine-resistant strain (Dd2) with IC50 = 3.0 nM ± 1.6 nM followed by the triazole derivative, compound 3, with IC50 = 4.8 nM ± 0.6 nM. The most active compound overall was the ligand precursor, compound 4 with IC50 = 0.6 nM ± 0.1 nM. All compounds showed almost no cytotoxicity towards the HEK293 cell line. The “most” cytotoxic agent was compound 1, with IC50 = 5975.0 nM ± 912 nM, which is 1810-fold higher compared to its activity against the Dd2 strain.

Antiplasmodial activity of coumarins isolated from Polygala boliviensis: in vitro and in silico studies

Polygala boliviensis is found in the Brazilian semiarid region. This specie is little chemically and biologically studied. Polygala spp. have different metabolites, especially coumarins. Studies indicate that coumarins have antimalarial potential, denoting the importance of researching new active compounds from plants, since the resistance of Plasmodium strains to conventional therapy has increased. The present study aimed to evaluate the antiplasmodial activity of auraptene and poligalen against a chloroquine-resistant strain of Plasmodium falciparum. Coumarins were isolated from P. boliviensis by open column chromatography and identified by Nuclear Magnetic Resonance Spectroscopy. A cytotoxicity assay was carried out using MTT test, and the in vitro antiplasmodial activity was evaluated using the W2 strain. The antiplasmodial activity results found were IC50=0.171 ± 0.016 for auraptene and 0.164 ± 0.012 for poligalen; the selectivity indexes were 78.71 and 609.76, respectively. Inverse virtual screening in the BRAMMT database by OCTOPUS 1.2 was applied to coumarins to find potential P. falciparum targets and showed higher affinity energy of auraptene for purine nucleoside phosphorylase (PfPNP) and of poligalen for dihydroorotate dehydrogenase (PfDHODH). Molecular Dynamics studies (MD and MM-GBSA) approach were applied to calculate binding energies against selected P. falciparum targets and showed that all coumarins were stable at the binding site during simulations. Furthermore, energies were favorable for complexation. This is the first report of auraptene in P. boliviensis species and of in vitro antiplasmodial activity of auraptene and poligalen. In silico studies indicated that the mechanism of action of coumarins is the inhibition of PfPNP and PfDHODH. Communicated by Ramaswamy H. Sarma

In vitro evaluation of alkaline lignins as antiparasitic agents and their use as an excipient in the release of benznidazole

The Amazon rainforest is considered the largest tropical timber reserve in the world. The management of native forests in the Amazon is one of the most sensitive geopolitical issues today, given its national and international dimension. In this work, we obtained and characterized physicochemical lignins extracted from branches and leaves of Protium puncticulatum and Scleronema micranthum. In addition, we evaluated in vitro its potential as an antioxidant, cytotoxic agent against animal cells and antiparasitic against promastigotes of Leishmania amazonensis, trypomastigotes of T. cruzi and against Plasmodium falciparum parasites sensitive and resistant to chloroquine. The results showed that the lignins obtained are of the GSH type and have higher levels of guaiacyl units. However, they show structural differences as shown by spectroscopic analysis and radar charts. As for biological activities, they showed antioxidant potential and low cytotoxicity against animal cells. Antileishmanial/trypanocidal assays have shown that lignins can inhibit the growth of promastigotes and trypomastigotes in vitro. The lignins in this study showed low anti-Plasmodium falciparum activity against susceptible strains of Plasmodium falciparum and were able to inhibit the growth of the chloroquine-resistant strain. And were not able to inhibit the growth of Schistosoma mansoni parasites. Finally, lignins proved to be promising excipients in the release of benznidazole. These findings show the potential of these lignins not yet studied to promote different biological activities.

Antiplasmodial activity, structure–activity relationship and studies on the action of novel benzimidazole derivatives

Malaria cases and deaths keep being excessively high every year. Some inroads gained in the last two decades have been eroded especially due to the surge of resistance to most antimalarials. The search for new molecules that can replace the ones currently in use cannot stop. In this report, the synthesis of benzimidazole derivatives guided by structure–activity parameters is presented. Thirty-six molecules obtained are analyzed according to their activity against P. falciparum HB3 strain based on the type of substituent on rings A and B, their electron donor/withdrawing, as well as their dimension/spatial properties. There is a preference for electron donating groups on ring A, such as Me in position 5, or better, 5, 6-diMe. Ring B must be of the pyridine type such as picolinamide, other modifications are generally not favorable. Two molecules, 1 and 33 displayed antiplasmodial activity in the high nanomolar range against the chloroquine sensitive strain, with selectivity indexes above 10. Activity results of 1, 12 and 16 on a chloroquine resistance strain indicated an activity close to chloroquine for compound 1. Analysis of some of their effect on the parasites seem to suggest that 1 and 33 affect only the parasite and use a route other than interference with hemozoin biocrystallization, the route used by chloroquine and most antimalarials.

Ultrasound-assisted-one-pot synthesis and antiplasmodium evaluation of 3-substituted-isoindolin-1-ones.

As the attempts to control malaria through chemotherapy strategies are restricted, we have prepared a small library of 3-substituted-isoindolinones from (Z)-3-benzylideneisobenzofuran-1(3H)-ones in one-pot fashion under ultrasound irradiation. The one-pot reaction was scalable and efficiently produced the desired products (1a-m) in high yields in a short reaction time. Evaluation of their in vitro antiplasmodium assay against the 3D7 (chloroquine-sensitive) and FCR3 (chloroquine-resistant) strains of Plasmodium falciparum demonstrated that they displayed moderate to strong antiplasmodium activities (the IC50 values ranging from 4.21-34.80 μM) and low resistance indices. The in silico prediction of ADME and physicochemical properties showed that the synthesized compounds met the drug-likeliness requirements and featured low toxicity effects. Based on the evaluation of the antiplasmodium profiles, 3-substituted-isoindolinone derivatives of 1a, 1d, 1h, and 1l may become potential antiplasmodium candidates.

Development of Mitochondria Targeting AIE-Active Cyclometalated Iridium Complexes as Potent Antimalarial Agents.

The emergence of resistance to conventional antimalarial treatments remains a major cause for concern. New drugs that target the distinct development stages of Plasmodium parasites are required to address this risk. Herein, water-soluble aggregation-induced emission active cyclometalated iridium(III) polypyridyl complexes (Ir1-Ir12) are developed for the elimination of malaria parasites. Remarkably, these complexes show potent antimalarial activity in low nanomolar range against 3D7 (chloroquine and artemisinin sensitive strain), RKL9 (chloroquine resistant strain), and R539T (artemisinin resistant strains) strains of Plasmodium falciparum with faster killing rate of malaria parasites. Concomitantly, these complexes exhibit efficient in vivo antimalarial activity against both the asexual and gametocyte stages of Plasmodium berghei malaria parasite, suggesting promising transmission-blocking potential. The complexes tend to localize into mitochondria of P. falciparum determined by image and cell-based assay. The mechanistic studies reveal that these complexes exert their antimalarial activity by increasing reactive oxygen species levels and disrupting its mitochondrial membrane potential. Furthermore, the mitochondrial-dependent antimalarial activity of these complexes is confirmed in yeast model. Thus, this study for the first time highlights the potential role of targeting P. falciparum mitochondria by iridium complexes in discovering and developing the next-generation antimalarial agents for treating multidrug resistant malaria parasites.

Design and development of novel N-(4-aminobenzoyl)- l-glutamic acid conjugated 1,3,5-triazine derivatives as Pf-DHFR inhibitor: An in-silico and in-vitro study.

In the present work, a library of 120 compounds was prepared using various aliphatic and aromatic amines. Finally, 10 compounds were selected through in silico screening carrying 4-aminobenzoyl-l-glutamic acid and 1,3,5-triazine moiety. The docking results of compounds 4d16 and 4d38 revealed higher binding interaction with amino acids Asp54 (-537.96 kcal/mol) and Asp54, Phe116 (-618.22 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR inhibitors and were comparable to standard WR99210. These compounds were developed by facile and microwave-assisted synthesis via nucleophilic substitution reaction and characterized by different spectroscopic methods. In vitro antimalarial assay results also suggested that these two compounds were having higher antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strain out of the ten synthesized compounds with IC50 13.25 μM and 14.72 μM, respectively. These hybrid scaffolds might be useful in the lead discovery of a new class of Pf-DHFR inhibitors.

Evaluation of Chiral Organosulfur Compounds on Their Activity against the Malaria Parasite Plasmodium falciparum.

Malaria is one of the deadliest tropical diseases, especially causing havoc in children under the age of five in Africa. Although the disease is treatable, the rapid development of drug resistant parasites against frontline drugs requires the search for novel antimalarials. In this study, we tested a series of organosulfur compounds from our internal library for their antiplasmodial effect against Plasmodium falciparum asexual and sexual blood stages. Some active compounds were also obtained in enantiomerically pure form and tested individually against asexual blood stages of the parasite to compare their activity. Out of the 23 tested compounds, 7 compounds (1, 2, 5, 9, 15, 16, and 17) exhibited high antimalarial activity, with IC50 values in the range from 2.2 ± 0.64 to 5.2 ± 1.95 µM, while the other compounds showed moderate to very low activity. The most active compounds also exhibited high activity against the chloroquine-resistant strain, reduced gametocyte development and were not toxic to non-infected red blood cells and Hela cells, as well as the hematopoietic HEL cell line at concentrations below 50 µM. To determine if the enantiomers of the active compounds display different antimalarial activity, enantiomers of two of the active compounds were separated and their antimalarial activity compared. The results show a higher activity of the (-) enantiomers as compared to their (+) counterparts. Our combined data indicate that organosulfur compounds could be exploited as antimalarial drugs and enantiomers of the active compounds may represent a good starting point for the design of novel drugs to target malaria.

Anti-malarial investigation of Acorus calamus, Dichapetalum gelonioides, and Leucas aspera on Plasmodium falciparum strains.

Malaria is a significant global health concern and adversely affects people in developing countries including Bangladesh. The causative agent Plasmodium falciparum is resistant to several currently available anti-malarial drugs, such as mefloquine, chloroquine, and artemisinin-based combination therapy (ACT), and this has been a major global challenge towards the control of the disease. There is urgent need for novel anti-malarial chemotherapeutic agents. The present study aimed to evaluate antimalarial activity of methanolic extracts of three Bangladeshi medicinal plants- Acorus calamus, Dichapetalum gelonioides and Leucas aspera - against both chloroquine sensitive (3D7) and resistant (Dd2) strains of P. falciparum. Histidine-rich protein 2 (HRP2) based ELISA was used to evaluate the in vitro inhibitory activity of the extracts. D. gelonioides extract showed moderate (IC50 = 19.15 µg/mL) and promising activity (IC50 = 10.43 µg/mL) against 3D7 and Dd2 strains respectively. A. calamus remained inactive against both 3D7 (IC50 = 72.29 µg/mL) and Dd2 strain (IC50 = 67.81 µg/mL). L. aspera initially remained inactive against 3D7 strain (IC50 = 60.51 µg/mL), but displayed promising activity (IC50 = 7.693) against Dd2 strain. This is the first time these plant materials have been assessed for their in vitro antimalarial properties. It is pivotal to conduct further phytochemical analysis of D. gelonioides and L. aspera to evaluate the presence of potential novel antimalarial drug compounds.

Phytoconstituents Assisted Biofabrication of Copper Oxide Nanoparticles and Their Antiplasmodial, and Antilarval Efficacy: A Novel Approach for the Control of Parasites

The present work aimed to biofabricate copper oxide nanoparticles (CuO NPs) using Tinospora cordifolia leaf extract. The biofabricated CuO NPs were treated against the malarial parasite of chloroquine-resistant Plasmodium falciparum (INDO) and the antilarval efficacy was evaluated against the malaria vector Anopheles stephensi and dengue vector Aedes aegypti. The prominence at 285 nm in the UV-visible spectrum helped to identify the produced CuO NPs. Based on the XRD patterns, the concentric rings correspond to reflections at 38.26° (111), 44.11° (200), 64.58° (220), and 77.34° (311). These separations are indicative of CuO's face-centered cubic (fcc) structure. The synthesized CuO NPs have FTIR spectra with band intensities of 3427, 2925, 1629, 1387, 1096, and 600 cm-1. The absorbance band at 3427 cm-1 is known to be associated with the stretching O-H due to the alcoholic group. FTIR proved that the presence of the -OH group is responsible for reducing and capping agents in the synthesis of nanoparticles (NPs). The synthesized CuO NPs were found to be polymorphic (oval, elongated, and roughly spherical) in form with a size range of 11-47 nm and an average size of 16 nm when the morphology was examined using FESEM and HRTEM. The highest antiplasmodial efficacy against the chloroquine-resistant strain of P. falciparum (INDO) was found in the synthesized CuO NPs, with LC50 values of 19.82 µg/mL, whilst HEK293 cells are the least toxic, with a CC50 value of 265.85 µg/mL, leading to a selectivity index of 13.41. However, the antiplasmodial activity of T. cordifolia leaf extract (TCLE) and copper sulfate (CS) solution showed moderate activity, with LC50 values of 52.24 and 63.88 µg/mL, respectively. The green synthesized NPs demonstrated extremely high antilarval efficacy against the larvae of An. stephensi and Ae. aegypti, with LC50 values of 4.06 and 3.69 mg/L, respectively.