Potent Antimalarial Activity Research Articles

Potensi Aktivitas Antimalaria Residu Hidrodestilasi Kulit Kayu Manis (Cinnamomum Burmanii) Melalui Penghambatan Polimerisasi Heme

Cinnamon (Cinnamomum burmanii) is a herbal plant from Indonesia which is widely used in cooking, cosmetics and medicine. Cinnamon bark isolate is thought to contain compounds with the structure of isoquinoline which are known to be used as antimalarials. The aim of this study was to examine the potential antimalarial activity of extracts and fractions of cinnamon bark hydrodistillation residue based on the % inhibition and IC50 value. These results will also be compared with extracts and fractions of cinnamon bark without hydrodistillation as controls. The test method is carried out in vitro by heme polymerization inhibitor. The test results showed that the n-hexane fraction, DCM fraction did not have inhibitory activity, while the ethyl acetate fraction had better potential than other extracts and fractions, where the ethyl acetate fraction after hydrodistillation (residue) had an IC50 value of 71.84 µg/mL, while the ethyl acetate fraction without hydrodistillation (control) had an IC50 value of 120.05 µg/mL. This result is better than hydroxychloroquine as positive control which has an IC50 value of 184.98 µg/mL. These results indicate that the ethyl acetate fraction from the hydrodistillation residue of cinnamon bark can be utilized and has potential as an antimalarial.

Design and synthesis of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids as effective antimalarial compounds

In this work, a series of nineteen novel pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids were synthesized as potent antimalarial agents by covalently linking the scaffolds of 4-aminoquinoline and pyrano[2,3-c]pyrazoles via an ethyl linker and characterized using Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR). Molecular docking was used to test each hybrid's and standard chloroquine's ability to bind to Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH), an important enzyme in the parasite's glycolytic pathway. The hybrid compounds had a stronger binding affinity than the standard chloroquine (CQ). The schizontical antimalarial test of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrid compound shows that all nineteen hybrid compounds were potent with the IC50 values ranging from 0.0151 to 0.301 μM against the CQ-sensitive 3D7 P. falciparum strain, and were active against the CQ-resistant K1 P. falciparum strain with the IC50 values ranging from 0.01895 to 2.746 μM. All the tested hybrid compounds were less potent than the standard drug chloroquine dipaspate (CQDP) against the CQ-sensitive 3D7 strain. In contrast, nine of the nineteen hybrids (16d, 16g, 16h, 16i, 16l, 16n, 16o, 16r, and 16s) displayed superior antimalarial activity than the CQDP against the CQ-resistant K1 P. falciparum strain. Among all the tested hybrids, 16c against the 3D7 strain and 16h against the K1 strain were the most promising antimalarial agents with 0.0151 and 0.01895 μM of IC50 values, respectively. In addition, the compounds were selective, showing moderate to low cytotoxic activity against a human normal liver WRL68 cell line. The synthesis of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids introduces new chemical entities that have the potential to exhibit potent antimalarial activity. It could address the ongoing challenge of drug resistance in malaria treatment.

Inhibition of falcilysin from Plasmodium falciparum by interference with its closed-to-open dynamic transition

In the absence of an efficacious vaccine, chemotherapy remains crucial to prevent and treat malaria. Given its key role in haemoglobin degradation, falcilysin constitutes an attractive target. Here, we reveal the mechanism of enzymatic inhibition of falcilysin by MK-4815, an investigational new drug with potent antimalarial activity. Using X-ray crystallography, we determine two binary complexes of falcilysin in a closed state, bound with peptide substrates from the haemoglobin α and β chains respectively. An antiparallel β-sheet is formed between the substrate and enzyme, accounting for sequence-independent recognition at positions P2 and P1. In contrast, numerous contacts favor tyrosine and phenylalanine at the P1’ position of the substrate. Cryo-EM studies reveal a majority of unbound falcilysin molecules adopting an open conformation. Addition of MK-4815 shifts about two-thirds of falcilysin molecules to a closed state. These structures give atomic level pictures of the proteolytic cycle, in which falcilysin interconverts between a closed state conducive to proteolysis, and an open conformation amenable to substrate diffusion and products release. MK-4815 and quinolines bind to an allosteric pocket next to a hinge region of falcilysin and hinders this dynamic transition. These data should inform the design of potent inhibitors of falcilysin to combat malaria.

Optimization of pyrazolopyridine 4-carboxamides with potent antimalarial activity for which resistance is associated with the P. falciparum transporter ABCI3

Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual parasite identified the pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of this chemotype defined that the N1-tert-butyl group and aliphatic foliage in the 3- and 6-positions were necessary for activity, while the inclusion of a 7′-aza-benzomorpholine on the 4-carboxamide motif resulted in potent anti-parasitic activity and increased aqueous solubility. A previous report that resistance to the pyrazolopyridine class is associated with the ABCI3 transporter was confirmed, with pyrazolopyridine 4-carboxamides showing an increase in potency against parasites when the ABCI3 transporter was knocked down. The low metabolic stability intrinsic to the pyrazolopyridine scaffold and the slow rate by which the compounds kill asexual parasites resulted in poor performance in a P. berghei asexual blood stage mouse model. Lowering the risk of resistance and mitigating the metabolic stability and cytochrome P450 inhibition will be challenges in the future development of the pyrazolopyrimidine antimalarial class.

Discovery of antimalarial drugs from secondary metabolites in actinomycetes culture library

BackgroundNatural products play a key role as potential sources of biologically active substances for the discovery of new drugs. This study aimed to identify secondary metabolites from actinomycete library extracts that are potent against the asexual stages of Plasmodiumfalciparum (P.falciparum).MethodsSecondary metabolites from actinomycete library extracts were isolated from culture supernatants by ethyl acetate extraction. Comprehensive screening was performed to identify novel antimalarial compounds from the actinomycete library extracts (n = 28). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) lines of P.falciparum. The cytotoxicity was then evaluated in primary adult mouse brain (AMB) cells.ResultsOut of the 28 actinomycete extracts, 17 showed parasite growth inhibition > 50% at a concentration of 50 µg/mL, nine were identified with an IC50 value < 10 µg/mL, and seven suppressed the parasite significantly with an IC50 value < 5 µg/mL. The extracts from Streptomycesaureus strains HUT6003 (Extract ID number: 2), S.antibioticus HUT6035 (8), and Streptomyces sp. strains GK3 (26) and GK7 (27), were found to have the most potent antimalarial activity with IC50 values of 0.39, 0.09, 0.97, and 0.36 µg/mL (against 3D7), and 0.26, 0.22, 0.72, and 0.21 µg/mL (against Dd2), respectively. Among them, Streptomycesantibioticus strain HUT6035 (8) showed the highest antimalarial activity with an IC50 value of 0.09 µg/mL against 3D7 and 0.22 µg/mL against Dd2, and a selective index (SI) of 188 and 73.7, respectively.ConclusionSecondary metabolites obtained from the actinomycete extracts showed promising antimalarial activity in vitro against 3D7 and Dd2 cell lines of P.falciparum with minimal toxicity. Therefore, secondary metabolites obtained from actinomycete extracts represent an excellent starting point for the development of antimalarial drug leads.

Mitochondria mediated inhibitory effect of Nyctanthes arbor-tristis (L.) flower extract against breast adenocarcinoma and T-cell lymphoma: An in vitro and in vivo study

Ethnopharmacological relevanceThe flowers of Nyctanthes arbor-tristis (L.) heals mouth ulcers. Its tinctures promote gastric secretions, and improve lung expectoration when taken orally. It has traditionally been used to treats scabies and other skin problems. The leaves of NAT(L.) plant are used in Ayurvedic medicine to treat sciatica, chronic fever, rheumatism, internal worm infections, and as a laxative, diaphoretic, and diuretic. The bark used in treatment of snakebite and bronchitis. In addition to traditional uses, pharmacologically this plant has potent antimalarial, antiarthritic, anticancer and antidiabetic activity. However, the mechanistic antiproliferative potentials of NAT(L.) flower as anticancer therapeutics has not yet been explored. Aim of the studyThe current study is based on a broad range of scientific literature that highlights the nutritional and therapeutic benefits of NAT (L.). Present investigation was carried out to determine the therapeutic efficacy of NAT (L.) against breast adenocarcinoma cells and T-cell lymphoma. Materials and methodsThe ethyl-acetate extract of NAT(L.) was tested against breast cancer cells to assess the anticancer potential. To evaluate apoptosis, intracellular ROS levels and mitochondrial dynamics, fluorescence microscopy and flow cytometry were employed. Additionally, cell cycle analysis and western blotting were also performed. Furthermore, in vivo antitumor efficacy of flower extracts was investigated in T-cell lymphoma-bearing BALB/c mice model. ResultsOur present study revealed that NAT (L.) exert anticancer activity against breast cancer cells effectively at IC50 320 μg/ml while having less impact on normal cells with IC50 more than 480 μg/ml. Fluorescence imaging showed that NAT (L.) treatment elicits a concentration-dependent rise in the occurrence of apoptotic cell deaths with altered mitochondrial dynamics and was subsequently confirmed by flow cytometry. Further, flow cytometric analysis delineates ethyl acetate flower extract exposure promotes arrest of cells in S phase of the cell cycle. The differential expression of apoptotic proteins such as Bax, Bcl-2, cleaved PARP-1, cleaved caspase 3, Cytochrome-c, p53 and VEGF A were influenced by NAT (L.) treatment. The in vivo antitumor activity study delineates that NAT(L.) therapy significantly increased the life span of T-cell lymphoma bearing mice while reducing tumor load and belly size growth pattern without causing significant other distinct side effects as evident by histopathological studies. ConclusionOur current findings unveil that NAT(L.) ethyl acetate flower extract potentially induces mitochondrial pathway of apoptosis, promote cell cycle arrest, reduces tumor load of mice, enhances survivability and could be a promising agent against the triple negative breast cancer and lymphoma.

Antimalarial activity of cecropin antimicrobial peptides derived from Anopheles mosquitoes.

The emergence of clinically drug-resistant malaria parasites requires the urgent development of new drugs. Mosquitoes are vectors of multiple pathogens and have developed resistance mechanisms against them, which often involve antimicrobial peptides (AMPs). An-cecB is an AMP of the malaria-transmitting mosquito genus Anopheles, and we herein report its antimalarial activity against Plasmodium falciparum 3D7, the artemisinin-resistant strain 803, and the chloroquine-resistant strain Dd2 in vitro. We also demonstrate its anti-parasite activity in vivo, using the rodent malaria parasite Plasmodium berghei (ANKA). We show that An-cecB displays potent antimalarial activity and that its mechanism of action may occur through direct killing of the parasite or through interaction with infected red blood cell membranes. Unfortunately, An-cecB was found to be cytotoxic to mammalian cells and had poor antimalarial activity in vivo. However, its truncated peptide An-cecB-1 retained most of its antimalarial activity and avoided its cytotoxicity in vitro. An-cecB-1 also showed better antimalarial activity in vivo. Mosquito-derived AMPs may provide new ideas for the development of antimalarial drugs against drug-resistant parasites, and An-cecB has potential use as a template for antimalarial peptides.

Indoloquinoline Alkaloids as Antimalarials: Advances, Challenges, and Opportunities.

Malaria infections affect almost half of the world's population, with over 200 million cases reported annually. Cryptolepis sanguinolenta, a plant native to West Africa, has long been used across various regions of Africa for malaria treatment. Chemical analysis has revealed that the plant is abundant in indoloquinolines, which have been shown to possess antimalarial properties. Cryptolepine, neocryptolepine, and isocryptolepine are well-studied indoloquinoline alkaloids known for their potent antimalarial activity. However, their structural rigidity and associated cellular toxicity are major drawbacks for preclinical development. This review focuses on the potential of indoloquinoline alkaloids (cryptolepine, neocryptolepine, and isocryptolepine) as scaffolds in drug discovery. The article delves into their antimalarial effects in vitro and in vivo, as well as their proposed mechanisms of action and structure-activity relationship studies. Several studies aim to improve these leads by reducing cytotoxicity while preserving or enhancing antimalarial activity and gaining insights into their mechanisms of action. These investigations highlight the potential of indoloquinolines as a scaffold for developing new antimalarial drugs.

Optimization of diastereomeric dihydropyridines as antimalarials

The increase in research funding for the development of antimalarials since 2000 has led to a surge of new chemotypes with potent antimalarial activity. High-throughput screens have delivered several thousand new active compounds in several hundred series, including the 4,7-diphenyl-1,4,5,6,7,8-hexahydroquinolines, hereafter termed dihydropyridines (DHPs). We optimized the DHPs for antimalarial activity. Structure-activity relationship studies focusing on the 2-, 3-, 4-, 6-, and 7-positions of the DHP core led to the identification of compounds potent (EC50 < 10 nM) against all strains of P. falciparum tested, including the drug-resistant parasite strains K1, W2, and TM90-C2B. Evaluation of efficacy of several compounds in vivo identified two compounds that reduced parasitemia by >75 % in mice 6 days post-exposure following a single 50 mg/kg oral dose. Resistance acquisition experiments with a selected dihydropyridine led to the identification of a single mutation conveying resistance in the gene encoding for Plasmodium falciparum multi-drug resistance protein 1 (PfMDR1). The same dihydropyridine possessed transmission blocking activity. The DHPs have the potential for the development of novel antimalarial drug candidates.

Synthesis of 4-(3-(1-substituted/unsubstituted-phenyl-1H-1,2,3-triazole-4-yl)propoxy)benzaldehydes: In vitro antimicrobial, antimalarial activities and In silico docking study

In this work, we have developed new derivatives of 4-(3-(1-substituted/unsubstituted phenyl-1H-1,2,3-triazol-4-yl)propoxy)benzaldehydes 3(a-o) in good to excellent yield through the click reaction catalyzed by Copper(II) sulfate pentahydrate. 5-chloropent-1‑yne was used as an alkynylation reagent for 4-hydroxybenzaldehyde, whereas the aromatic azides were prepared from the corresponding diazonium salt by diazotization. All the newly synthesized derivatives were well characterized by FT-IR, 1H/ 13C NMR, high-resolution mass spectrometry and elemental analyses. These compounds were evaluated for their in vitro anti-microbial against six pathogenic strains as well as two pathogenic strains as anti-fungal activities using the broth dilution method. The activity results show that most of the compounds exhibit moderate to very good antibacterial and antifungal activities compared to the reference drugs. Furthermore, the in vitro antimalarial assay of synthesized compounds was screened against P. falciparum strain and then compared to Quinine and Chloroquine as the reference drugs. The results from the activity evaluation revealed that three out of fifteen compounds presented moderate efficacy when compared to Quinine. The structure-activity relationship (SAR) study indicated that substituted compounds with deactivating groups have potent antibacterial, antifungal, and antimalarial activities. Moreover, in silico molecular docking assay shows that 3 m is the most potent amongst 3(a-o) with a binding energy of -8.1 kcal/mol and -8.9 kcal/mol in the binding pocket of the receptor for bacterial and fungal infections, respectively compared to the standard drugs. The molecule 3 m has been studied in details for its ADMET properties and showed the most promise as a drug candidate.

Exploring the unexplored chemical space: Rational identification of new Tafenoquine analogs with antimalarial properties

Patents tend to define a huge chemical space described by the combinatorial nature of Markush structures. However, the optimization of new principal active ingredient is frequently driven by a simple Free Wilson approach. This procedure leads to a highly focused study on the chemical space near a hit compound leaving many unexplored regions that may present highly biological active reservoirs. This study aims to demonstrate that this unveiled chemical space can hide compounds with interesting potential biological activity that would be worth pursuing. This underlines the value and necessity of broadening an approach beyond conventional strategies. Hence, we advocate for an alternative methodology that may be more efficient in the early drug discovery stages. We have selected the case of Tafenoquine, a single-dose treatment for the radical cure of P. vivax malaria approved by the FDA in 2018, as an example to illustrate the process. Through the deep exploration of the Tafenoquine chemical space, seven compounds with potential antimalarial activity have been rationally identified and synthesized. This small set is representative of the chemical diversity unexplored by the 58 analogs reported to date. After biological assessment, results evidence that our approach for rational design has proven to be a very efficient exploratory methodology suitable for the early drug discovery stages.

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

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

In Silico Approach Triterpene Glycoside of H. atra Targeting Orotidine 5-Monophosphate Decarboxylase Protein (PfOMPDC) in P. falciparum Infection Mechanism.

This study accessed the potential antimalarial activity of triterpene glycoside of H. atra through targeting orotidine 5-monophosphate decarboxylase protein (PfOMPDC) in P. falciparum by molecular docking. Nine triterpene glycosides from H. atra extract modeled the structure by the Corina web server and interacted with PfOMPDC protein by using Hex 8.0.0. The docking results were visualized and analyzed by Discovery Studio version 21.1.1. 17-Hydroxyfuscocineroside B showed the lowest binding energy in PfOMPDC interaction, which was -1,098.13 kJ/mol. Holothurin A3, echinoside A, and fuscocineroside C showed low binding energy. Nine triterpene glycosides of H. atra performed interaction with PfOMPDC protein at the same region. Holothurin A1 posed interaction with PfOMPDC protein by 8 hydrogen bonds, 3 hydrophobic interactions, and 8 unfavorable bonds. Several residues were detected in the same active sites of other triterpene glycosides. Residue TYR111 was identified in all triterpene glycoside complexes, except holothurin A3 and calcigeroside B. In summary, the triterpene glycoside of H. atra is potentially a drug candidate for malaria therapeutic agents. In vitro and in vivo studies were required for further investigation.

In Vitro Analysis of Antimalarial Activity of Achillea fragrantissima (Forssk.) Sch.Bip Extracts Based on Beta-Hematin Formation

Introduction: The use of medicinal plants from traditional knowledge systems has increased in recent years. Achillea fragrantissima-infused water has a historical use in relieving gastrointestinal complaints and treating skin inflammations. With the rising resistance to antimalarial drugs, finding safe and affordable new drugs is crucial. Exploring medicinal plants shows promise for drug development in the fight against malaria. Methods: The objective of this research is to examine the in vitro antimalarial activity of A. fragrantissima-infused water, as well as water-ethanol extracts of its leaves, flowers, and stems based on β-hematin formation. Colorimetric semiquantitative assessments based on β-hematin inhibition and evaluation of optical density at 405 nm were employed. Results: The results demonstrated promising antimalarial activity of the different plant parts. The aqueous flower extract exhibited strong activity, comparable to that of the positive control. The leaves extract also showed strong antimalarial activity. The stem's aqueous and ethanolic extracts exhibited lower inhibitory activity compared to flowers and leaves. Synergistic antimalarial activity was observed when mixing the stem and leaves water extracts, as well as when mixing each of the stem and leaves extracts with the flower extract. The highest synergistic effect was observed when all three parts of the plant were mixed, resulting in activity comparable to the positive control. The high-performance liquid chromatography photodiode array (HPLC-PDA) chromatographic method confirmed the presence of rutin in the leaves extract. Conclusion: The findings of this study highlight the potential antimalarial activity of A. fragrantissima. The aqueous flower extract and leaves extract exhibited strong antimalarial activity, while the stem extracts showed relatively lower activity. Furthermore, synergistic effects were observed when combining different parts of the plant. These results suggest that A. fragrantissima holds promise as a potential source for the development of new antimalarial drugs. The confirmation of rutin presence in the leaves extract through HPLC-PDA analysis provides additional insights into the plant's chemical composition.

Comprehensive Investigation of Juniperus virginiana Essential Oil: GC/MS Analysis, Thermoanalytical Characterization, and Evaluation of Bioactive Potential

Due to the ever-increasing unregulated antibiotic use, there have been increased risks of antibiotic-resistant bacterial infections. Natural agents, their products, and derivatives have been used for centuries to cure a variety of ailments. In the present study, an attempt was made to explore the physiochemical properties of the CEO. GC-MS analysis was used to identify the volatile components present in the oil. Additionally, TGA and DSC analysis were carried out to understand the thermal properties of the oil. The oil was characterized by higher amounts of terpenoids. The essential oil has potent anticancer, cytotoxic, antimalarial, and anti-inflammatory activity. This study concludes that the Juniperus virginiana essential oil could be used as a therapeutic agent.&#x0D; Keywords: Anticancer, Antioxidant, Cedarwood, Cytotoxicity, Essential oil

Potential role of CI-679 against artemisinin-resistant &lt;i&gt;Plasmodium falciparum&lt;/i&gt;

Purpose: To investigate the role of nitroquine (CI-679) against artemisinin-resistant Plasmodium falciparum (P. falciparum) C580Y strain.&#x0D; Methods: Antimalarial activity of CI-679 against blood stages in Plasmodium yoelii (P. yoelii) - infected BALB/c mice model was first identified. Thereafter, in vitro assays were performed to investigate the inhibitory activity against blood stages of artemisinin-sensitive P. falciparum 3D7 strain. Finally, the potential effect of CI-679 was also investigated on artemisinin-resistant P. falciparum, which was constructed by introducing C580Y mutation in K13 of the 3D7 using the CRISPR-CAS9 technology.&#x0D; Results: CI-679 significantly suppressed the growth of rodent malaria parasite, P. yoelii BY265, in a dose-dependent manner, and also inhibited the development of the parasites in mice (p &lt; 0.05). Furthermore, CI-679 efficiently inhibited the growth of artemisinin-sensitive P. falciparum 3D7 in vitro, with more sensitivity against late phase of blood stages (p &lt; 0.05). Also, CI-679 suppressed the development of artemisinin-resistant P. falciparum C580Y strain, and the inhibitory effect was comparable to that of artemisinin-sensitive 3D7 strain.&#x0D; Conclusion: CI-679 exhibits potent antimalarial activity against blood stages of P. yoelii BY265 in vivo, and both artemisinin-sensitive P. falciparum 3D7 and artemisinin-resistant P. falciparum C580Y in vitro. Further pharmacokinetic properties, tolerability and safety of the compound need to be investigated to support this claim.

Synthesis, antileishmanial, antimalarial evaluation and molecular docking study of some hydrazine-coupled pyrazole derivatives

Pyrazole-bearing compounds are known for their diverse pharmacological effects including potent antileishmanial and antimalarial activities. Herein, some hydrazine-coupled pyrazoles were successfully synthesized and their structures were verified by employing elemental microanalysis, FTIR, and 1H NMR techniques. The in vitro antileishmanial and in vivo antimalarial activities of the synthesized pyrazole derivatives (9–15) were evaluated against Leishmania aethiopica clinical isolate and Plasmodium berghei infected mice, respectively. The result revealed that compound 13 displayed superior antipromastigote activity (IC50 = 0.018) that was 174- and 2.6-fold more active than the standard drugs miltefosine (IC50 = 3.130) and amphotericin B deoxycholate (IC50 = 0.047). The molecular docking study conducted on Lm-PTR1, complexed with Trimethoprim was acquired from the Protein Data Bank (PDB ID:2bfm), justified the better antileishmanial activity of compound 13. Furthermore, the target compounds 14 and 15 elicited better inhibition effects against Plasmodium berghei with 70.2% and 90.4% suppression, respectively. In conclusion, the hydrazine-coupled pyrazole derivatives may be considered potential pharmacophores for the preparation of safe and effective antileishmanial and antimalarial agents.

Evaluation of the antimalarial properties of Solanum incanum L. leaf extract fractions and its ability to downregulate delta aminolevulinate dehydratase to prevent the establishment of malaria infection

Ethnopharmacological relevanceSolanum incanum L. is commonly used in traditional herbal medicine (THM) in Kenya for treating various ailments. Recent developments in disease treatment have introduced the concept of host-directed therapy (HDT). This approach involves targeting factors within the host cell that can impede the growth or replication of a pathogen. One such host factor is delta aminolevulinate dehydratase (δ-ALAD), the second enzyme in the heme biosynthesis pathway utilized by Plasmodium for growth. Studies using mice models have shown an increase in δ-ALAD expression during Plasmodium berghei infection. Another plant in the Solanum genus, S. guaranticum, has been found to inhibit δ-ALAD in red blood cells in vitro and in the brain in vivo. Is it possible that the bioactive compounds in S. incanum extracts could also be effective in HDT for malaria treatment? Aim of studyTo better assess the effectiveness of S. incanum leaf extracts as a curative and prophylaxis in malaria parasite infection, and to test the plant’s ability to decrease δ-ALAD expression. Materials and methodsThe leaves of S. incanum were collected, dried, and pulverized before being subjected to a successive extraction protocol to obtain crude, hexane, ethyl acetate, and aqueous extract fractions. Phytochemical analysis was conducted on all extract fractions, followed by GC-MS analysis of the fraction with the most potent antimalarial activity. An acute toxicity study was also performed on the extracted fractions. The potency of the extract fractions as curative and prophylactic antimalarial was then evaluated in THM using Plasmodium berghei-infected mice at a dose of 100 mg/kg. The extract fraction with the highest activity was further evaluated at varying doses and its effect on δ-ALAD was measured using RT-qPCR. The percentage of parasitemia and chemosuppression, and mean survival time were used as indices of activity. ResultsPhytochemical analysis revealed that the ethyl acetate and aqueous extract fractions contained high terpenoids, flavonoids, and phenols levels. However, alkaloids were only present in moderate quantities in the aqueous extract, and quinones were found in high levels only in the crude extract. Additionally, all extract fractions contained saponins in high levels but lacked tannins. While the plant extracts were found to be non-toxic, they did not exhibit curative antimalarial activity. However, all extract fractions showed prophylactic antimalarial activity, with the ethyl acetate extract having the highest percentage of chemosuppression even at doses of 250 and 1000 mg/kg. In the negative control, the expression of δ-ALAD was 5.4-fold, but this was significantly reduced to 2.3-fold when mice were treated with 250 mg/kg of the ethyl acetate fraction. GC-MS analysis of the ethyl acetate fraction revealed high percentages of 2-methyloctacosane, tetracosane, and decane. ConclusionThe fractions extracted from S. incanum leaves have been found to possess only antimalarial prophylactic properties, with the ethyl acetate extract fraction showing the most effective results. The activity of this fraction may be attributed to its ability to decrease the expression of δ-ALAD, as it contains an alkane compound implicated with enzyme-inhibitory activity.

Synthesis of chalcone derivatives with methoxybenzene and pyridine moieties as potential antimalarial agents

Malaria remains an endemic disease in tropical regions, urgently needed the search for effective antimalarial agents due to resistance against existing drugs. This study investigated the potential antimalarial activity of pyridine-based chalcone derivatives against P. falciparum 3D7 and FCR3 strains. The chalcones were synthesized through a one-pot method using various pyridine carbaldehyde, resulting in yields ranging from 53.74 to 86.37%, and all products were characterized using FTIR, GC-MS, and NMR spectroscopies. Among the six chalcones tested, chalcone A [1-(2-methoxyphenyl)-3-(pyridin-2-yl)prop-2-en-1-one] displayed the highest antimalarial activity with IC50 values of 0.48 and 0.31 μg/mL against P. falciparum 3D7 and FCR3 strains, respectively, and a resistance index of 0.65. Molecular docking studies highlighted the interaction of the carbonyl group of all chalcones with Asn108 amino acid residue in the PfDHFR-TS active site via hydrogen bonding, demonstrating their potential as the antimalarial agent. Notably, the positioning of methoxy and pyridine substituents significantly influenced the antimalarial activity of the chalcones.

Antimalarial Activity of Anacardium occidentale Leaf Extracts Against Plasmodium falciparum Transketolase (PfTK).

As per estimates by WHO in 2021 almost half of the world's population was at risk of malaria and > 0.6 million deaths were attributed to malaria. Therefore, the present study was aimed to explore the antimalarial activity of extracts derived from the leaves of the plant Anacardium occidentale L., which has been used traditionally for the treatment of malaria. Different extracts of A. occidentale leaves were prepared and tested for their inhibitory activity against recombinant P. falciparum transketolase (rPfTK) enzyme, in vitro. Further, growth inhibitory activity against cultivated blood stage P. falciparum parasites (3D7 strain), was studied using SYBR Green fluorescence-based in vitro assays. Acute toxicity of the hydro alcoholic extracts of leaves of A. occidentale (HELA) at different concentrations was evaluated on mice and Zebra fish embryos. HELA showed 75.45 ± 0.35% inhibitory activity against the recombinant PfTk and 99.31 ± 0.08% growth inhibition against intra-erythrocytic stages of P. falciparum at the maximum concentration (50µg/ml) with IC50 of 4.17 ± 0.22µg/ml. The toxicity testresults showed that the heartbeat, somite formation, tail detachment and hatching of embryos were not affected when Zebra fish embryos were treated with 0.1 to 10µg/ml of the extract. However, at higher concentrations of the extract, at 48h (1000µg/ml) and 96h (100µg/ml and 1000µg/ml, respectively) there was no heartbeat in the fish embryos. In the acute oral toxicity tests performed on mice, the extract showed no toxicity up to 300mg/kg body weight in mice. The hydro-alcoholic extract of leaves of A. occidentale L. showed potent antimalarial activity against blood stage P. falciparum. Based on the observed inhibitory activity on the transketolase enzyme of P. falciparum it is likely that this enzyme is the target for the development of bioactive molecules present in the plant extracts. The promising anti-malarial activity of purified compounds from leaves of A. occidentale needs to be further explored for development of new anti-malarial therapy.