Potential Antimalarial Agents Research Articles

Integrating schiff base ligands with diorganotin(IV) metal: Crystallographic insights and biological potency against malaria and oxidative stress

Amidst the ongoing search for potent antimalarial agents, this research focuses on synthesizing and analyzing diorganotin(IV) complexes (3–10) with Schiff base ligands (1–2) derived from 2-amino-4‑tert-butylphenol and salicylaldehyde derivatives, revealing compelling medicinal applications. Comprehensive structural characterization of these compounds was conducted using a suite of analytical techniques, including FT-IR, NMR (1H, 13C and 119Sn), SEM-EDAX, TGA and mass spectrometry. These analyses unequivocally confirmed that the ligands coordinate to the diorganotin(IV) ion via oxygen and nitrogen donor sites in an iminol configuration, indicating a pentacoordinated stereochemistry. Furthermore, to confirm the complexes structural characteristics, SC-XRD was performed on the complex 7 [Me₂SnL2] which indicated that the compound crystallizes in a monoclinic system with distorted square pyramidal stereochemistry. Biological evaluations states that the complexes have superior biological activities compared to their respective ligands with the order of activity being: Ph2SnL1–2>Bu2SnL1−2>Et2SnL1−2>Me2SnL1−2. Complexes (6, 10) showed significant antimalarial and antioxidant efficacy, with IC50 values of 0.99 ± 0.18 - 1.69 ± 0.15 µM and 2.36 ± 0.05 - 3.16 ± 0.02 µM, respectively, comparable to standard therapeutic agents. ADMET lab 2.0 evaluation confirmed their adherence to Lipinski's Rule of Five and strong pharmacokinetic properties, including oral bioavailability, permeability and clearance, similar to standard drugs.

Total Syntheses of Strasseriolide A and Strasseriolide B, Potent Antimalarial Agents.

We describe the convergent total syntheses of strasseriolides A and B, which are potent antimalarial agents recently isolated from an unnamed plant found in a remote region of New Zealand. Both natural products exhibited potent activity against malaria parasite, Plasmodium falciparum. The synthesis involved asymmetric syn-aldol, asymmetric alkylation, and asymmetric Johnson-Claisen rearrangement to set six of the seven chiral centers of strasseriolide B. The synthesis also highlights the formation of an 18-membered macrolactone from a diacid by using a Yamaguchi macrolactonization protocol. Other key transformations involved Grubbs' cross-metathesis, selective 1,4-reduction, hydrostannylation reaction, and NHK coupling reaction. The convergent synthesis of strasseriolide A required 27 total synthetic steps and 16 longest linear steps from known readily available intermediates.

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.

Synthesis, Molecular Docking and Heme Detoxification of Pyrano[2,3-c]pyrazole-aminoquinoline Hybrids as Potential Antimalarial Agents

Synthesis, Molecular Docking and Heme Detoxification of Pyrano[2,3-c]pyrazole-aminoquinoline Hybrids as Potential Antimalarial Agents

The characteristic structural and functional dynamics of P. falciparum DHFR binding with pyrimidine chemotypes implicate malaria therapy design

Dihydrofolate reductase (DHFR) enzyme regulates de-novo folate synthesis in Plasmodium falciparum, hence a critical malaria drug target. Pyrimethamine inhibits DHFR, but resistance and lack of cross-species activity are key challenges. Therefore, this study is set to investigate more potent nitrogenous heterocyclic compounds against DHFR. Docking and MD simulations were employed to gain insight into the compounds’ binding free energies and conformational stabilities, while cross-species activity was determined using sequence alignment. Among the 500 screened compounds, PMD_01 (−12.2 kcal/mol), PMD_02 (−11.1 kcal/mol), PMD_03 (−10.7 kcal/mol), and PMD_04 (−10.7 kcal/mol) have the highest binding affinities against pfDHFR compared to pyrimethamine (−7.9 kcal/mol). Critical amino acids for binding interactions in the active site of pfDHFR include Leu45, Thr107, Ile164, and Thr170. PMD-bound systems showed higher binding free energy than pyrimethamine, except PMD_03. Hydrogen bonding interactions with Gly159, Ser101, Ser104, Ser160, Ile157, and Lys48 played significant roles in the binding interaction of these compounds as opposed to Asp53 in pyrimethamine. The four systems converged around 1.90 Å RMSD and showed more stability than pyrimethamine-bound and unbound pfDHFR. The pocket's residues across the four plasmodia were highly conserved, but Phe116 and Ile164 replaced Met in P. knowlesi and Tyr in the other species. PMD_01, PMD_02, PMD_03, and PMD_04 showed promising inhibition against pfDHFR and are, thus, potential antimalarial agents against plasmodia DHFR homologues.

Exploring novel camphor-derived heterocycles for antimalarial activity: Design, virtual screening, DFT, and molecular docking investigations

Nowadays, camphor-based heterocycles have attained the greater focus of the scientific community due to their specific and target-oriented medicinal properties. Based on the literature, it has been observed that the novel camphor-based heterocycles may act as prominent scaffolds to cure one of the potential diseases called malaria, which was caused by Plasmodium falciparum. In this regard, some novel camphor-based heterocycles have been designed to test their efficacy towards their antimalarial activity. First, using Spartan-14 software, Density Functional Theory investigations were conducted on the suggested heterocycles to ascertain their geometry and their associated chemical properties. All optimized camphor-based heterocycles have been docked against the proteins (PDB: 1LF3 & 3BPF) with Discovery Studio software and Autodock Vina and has been observed that the binding energies of the compounds CBH 1–15 with both the proteins have shown better results which are in the range of −6.0 to −8.6 kcal/mol. Based on docking examinations, the compounds with 1lF3 protein in CBH-10, CBH-11, and CBH-1/CBH-6 had the highest binding energies of −8.6, −8.3, and −8.2; for the compounds in CBH-11, CBH-10, and CBH-1/CBH-3 /CBH-6 CBH-13, the highest binding energies were −7.8, −7.7, and −7.6. In addition, the ADMET properties of all the compounds have been determined and observed that these compounds might be used as potential antimalarial agents.

Synthesis, In Silico Study and Antimalarial Activity of Triazolo[1,5‐a]pyrimidine Derivatives

AbstractThe present study mainly focused on synthesizing novel triazolo[1,5‐a]pyrimidine‐6‐carboxamide derivatives using multicomponent reaction. Synthesized derivatives were duly characterized using spectroscopic methods of analysis FT‐IR and mass spectroscopy, and 1H NMR and 13C NMR confirmed the structure of compounds. Further, the potential of the synthesized compounds against Plasmodium falciparum dihydrofolate reductase (Pf‐DHFR) inhibitors was evaluated by in vitro antimalarial activity, and the results of the study showed moderate to good antimalarial profile of synthesized entities. In silico study of all the synthesized compounds was carried out using Schrödinger LLC‐2020‐3 Software to explain the binding mode and interactions between molecules and pf DHFR enzyme. To study the drug likeliness of molecules, 3D QSAR and Pharmacokinetic studies have been carried out, and the results obtained showed a good pharmacokinetics profile of two compounds, namely AMP‐24 and AMP‐28, having good IC50 values concerning standard drugs. Further, the in vitro enzyme inhibition assay results suggested that the synthesized compound interacts nicely with the enzyme and might be used as a potent antimalarial agent.

Development of Phytoconstituents from Spathodea campanulata Flowers as Potential Antimalarial Agents

Background: Considering the majority of pharmaceutical firms focus on using herbal remedies as an alternative source of essential components, herbal remedies are extremely significant to pharmacological researchers. Spathodea campanulata is one of the members of the Bignoniaceae family. It is popular for its curative properties Aim: This research aimed to assess the possibility of bioactive elements and antioxidant impacts of the methanol fraction of Spathodea campanulata flowers. Objectives: The objective of this research was to assess the achievable bioactive elements and antioxidant impacts of the methanol fraction of Spathodea campanulata flowers. Methods: GC-MS was adopted to identify the phytoconstituents present in the extract. In the present study, we utilized computational modelling with the Schrödinger Maestro 11.2 edition to make benefit of interactions among 42 bio-active components and anti-malarial targets (1LDG and 2ANL). Results: In the methanol extract of the Spathodea campanulata flowers, phytochemical research revealed the presence of terpenoids, glycosides, carbohydrates, steroids, and flavonoids. Forty-two phytoconstituents, notably methyl-beta-d-galactopyranoside, 4-hydroxybenzoic acid, and 1,2- ethanediol monobenzoate, were determined through GC-MS analysis. Docking analysis of 42 bioactive compounds demonstrated that 1,2-ethanediol mono benzoate, 4-hydroxy benzoic acid, and methyl.beta.-d-galactopyranoside had higher G-Scores with 1LDG and 2ANL. Conclusion: In this work, multiple phytoconstituents discovered in a methanol extract of the S. campanulata flower were determined. As a result of this research, four phytoconstituents from the flower extracts may be created as an exciting new therapy for malaria.

Cu-catalyzed click reaction in synthesis of eugenol derivatives as potent antimalarial agents

Eugenol(1), a terpenoid found in Ocimum, has various biological activities. The present study aims at extraction, isolation of the plant secondary metabolite eugenol (1), it’s derivatisation and structure identification as bioactive molecules. Synthesis and antiplasmodial activity (in-vitro and in-vivo), of a series of fourteen novel eugenol-based 1,2,3-triazole derivatives was done in the present study. Derivatives 5a–5n showed good antimalarial activity against the strain Plasmodium falciparum NF54. Derivative 5 m, IC50 at 2.85 µM was found to be several times better than its precursor 1 (106.82 µM) whereas the derivative 5n showed three fold better activity than compound 1, in vitro. The structure-activity relationship of the synthesised compounds indicated that the presence of triazole ring in eugenol analogues is responsible for their good activity. Compound 5m, was further evaluated for in-vivo antimalarial activity which showed about 79% parasitemia suppression. It is the first report on antimalarial activity of triazole eugenol derivatives.

Synthetic account on indoles and their analogues as potential anti-plasmodial agents.

Malaria caused by P. falciparum, has been recognized as one of the major infectious diseases causing the death of several patients as per the reports from the World Health Organization. In search of effective therapeutic agents against malaria, several research groups have started working on the design and development of novel heterocycles as anti-malarial agents. Heterocycles have been recognized as the pharmacophoric features for the different types of medicinally important activities. Among all these heterocycles, nitrogen containing aza-heterocycles should not be underestimated owing to their wide therapeutic window. Amongst the aza-heterocycles, indoles and fused indoles such as marinoquinolines, isocryptolepines and their regioisomers, manzamines, neocryptolenines, and indolones have been recognized as anti-malarial agents active against P. falciparum. The present work unleashes the synthetic attempts of anti-malarial indoles and fused indoles through cyclocondensation, Fischer-indole synthesis, etc. along with the brief discussions on structure-activity relationships, in vitro or in vivo studies for the broader interest of these medicinal chemists, working on their design and development as potential anti-malarial agents.

Combined 3D-QSAR, molecular docking, ADMET, and drug-likeness scoring of novel diaminodihydrotriazines as potential antimalarial agents

Plasmodium falciparum dihydrofolate reductase (PfDHFR) is a promising therapeutic target for antimalarial interventions. Diaminodihydrotriazine derivatives have demonstrated their efficacy as antimalarial agents by targeting PfDHFR inhibition. In this study, we used a multifaceted approach including 3D-QSAR, in silico pharmacokinetic/ADMET evaluation, molecular docking techniques, and molecular dynamics simulation to explore a series of diaminodihydrotriazine compounds, to identify new antimalarial drug candidates featuring the diaminodihydrotriazine scaffold. Using comparative molecular similarity indices analysis (CoMSIA), we built a robust 3D-QSAR model exhibiting favorable statistical parameters, with Q2 and R2 values of 0.553 and 0.981, respectively. External validation using a test set yielded an R2pre value of 0.787, confirming the model's predictive ability. In addition, we performed comprehensive ADMET and drug similarity profile analyses for potent designed compounds, yielding promising results. Molecular docking studies further complemented our investigation facilitating the elucidation of optimal interaction modes between these inhibitors and their target receptor. Additionally, molecular dynamics simulation was conducted for the promising compound 8a. This study not only provides valuable insights into the design of new antimalarial agents but also highlights the importance of computational methods for accelerating drug discovery processes, particularly in the context of infectious disease control.

Unveiling potential repurposed drug candidates for Plasmodium falciparum through in silico evaluation: A synergy of structure-based approaches, structure prediction, and molecular dynamics simulations

The rise of drug resistance in Plasmodium falciparum, rendering current treatments ineffective, has hindered efforts to eliminate malaria. To address this issue, the study employed a combination of Systems Biology approach and a structure-based pharmacophore method to identify a target against P. falciparum. Through text mining, 448 genes were extracted, and it was discovered that plasmepsins, found in the Plasmodium genus, play a crucial role in the parasite's survival. The metabolic pathways of these proteins were determined using the PlasmoDB genomic database and recreated using CellDesigner 4.4.2. To identify a potent target, Plasmepsin V (PF13_0133) was selected and examined for protein-protein interactions (PPIs) using the STRING Database. Topological analysis and global-based methods identified PF13_0133 as having the highest centrality. Moreover, the static protein knockout PPIs demonstrated the essentiality of PF13_0133 in the modeled network. Due to the unavailability of the protein’s crystal structure, it was modeled and subjected to a molecular dynamics simulation study. The structure-based pharmacophore modeling utilized the modeled PF13_0133 (PfPMV), generating 10 pharmacophore hypotheses with a library of active and inactive compounds against PfPMV. Through virtual screening, two potential candidates, hesperidin and rutin, were identified as potential drugs which may be repurposed as potential anti-malarial agents.

Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis

BackgroundMalaria remains a global health burden, and the emergence and increasing spread of drug resistance to current antimalarials poses a major challenge to malaria control. There is an urgent need to find new drugs or strategies to alleviate this predicament. Celastrol (Cel) is an extensively studied natural bioactive compound that has shown potentially promising antimalarial activity, but its antimalarial mechanism remains largely elusive.MethodsWe first established the Plasmodium berghei ANKA-infected C57BL/6 mouse model and systematically evaluated the antimalarial effects of Cel in conjunction with in vitro culture of Plasmodium falciparum. The potential antimalarial targets of Cel were then identified using a Cel activity probe based on the activity-based protein profiling (ABPP) technology. Subsequently, the antimalarial mechanism was analyzed by integrating with proteomics and transcriptomics. The binding of Cel to the identified key target proteins was verified by a series of biochemical experiments and functional assays.ResultsThe results of the pharmacodynamic assay showed that Cel has favorable antimalarial activity both in vivo and in vitro. The ABPP-based target profiling showed that Cel can bind to a number of proteins in the parasite. Among the 31 identified potential target proteins of Cel, PfSpdsyn and PfEGF1-α were verified to be two critical target proteins, suggesting the role of Cel in interfering with the de novo synthesis of spermidine and proteins of the parasite, thus exerting its antimalarial effects.ConclusionsIn conclusion, this study reports for the first time the potential antimalarial targets and mechanism of action of Cel using the ABPP strategy. Our work not only support the expansion of Cel as a potential antimalarial agent or adjuvant, but also establishes the necessary theoretical basis for the development of potential antimalarial drugs with pentacyclic triterpenoid structures, as represented by Cel.5LH6oqsCtKBdVDis1L_PeKVideo

Indole clubbed 2,4-thiazolidinedione linked 1,2,3-triazole as a potent antimalarial and antibacterial agent against drug-resistant strain and molecular modeling studies.

In the face of escalating challenges of microbial resistance strains, this study describes the design and synthesis of 5-({1-[(1H-1,2,3-triazol-4-yl)methyl]-1H-indol-3-yl}methylene)thiazolidine-2,4-dione derivatives, which have demonstrated significant antimicrobial properties. Compared with the minimum inhibitory concentrations (MIC) values of ciprofloxacin on the respective strains, compounds 5a, 5d, 5g, 5l, and 5m exhibited potent antibacterial activity with MIC values ranging from 16 to 25 µM. Almost all the synthesized compounds showed lower MIC compared to standards against vancomycin-resistant enterococcus and methicillin-resistant Staphylococcus aureus strains. Additionally, the majority of the synthesized compounds demonstrated remarkable antifungal activity, against Candida albicans and Aspergillus niger, as compared to nystatin, griseofulvin, and fluconazole. Furthermore, the majority of compounds exhibited notable inhibitory effects against the Plasmodium falciparum strain, having IC50 values ranging from 1.31 to 2.79 μM as compared to standard quinine (2.71 μM). Cytotoxicity evaluation of compounds 5a-q on SHSY-5Y cells at up to 100 μg/mL showed no adverse effects. Comparison with control groups highlights their noncytotoxic characteristics. Molecular docking confirmed compound binding to target active sites, with stable protein-ligand complexes displaying drug-like molecules. Molecular dynamics simulations revealed dynamic stability and interactions. Rigorous tests and molecular modeling unveil the effectiveness of the compounds against drug-resistant microbes, providing hope for new antimicrobial compounds with potential safety.

Myco-synthesis of multi-twinned silver nanoparticles as potential antibacterial and antimalarial agents.

In recent days, biogenic and green approaches for synthesizing nanostructures have gained much attention in biological and biomedical applications. Endophytic fungi have been recognized to produce several important biomolecules for use in various fields. The present work describes the use of endophytic fungi isolated from Berberis aristata for the synthesis of multi-twinned silver nanoparticles (MT-AgNPs) and their successful applications in antimicrobial and antimalarial studies. TEM images reveal the formation of multi-twined structures in the synthesized silver nanoparticles. The synthesized MT-AgNPs have shown excellent antibacterial activities against five opportunistic bacteria, viz. Bacillus subtilis (MTCC 441), Pseudomonas aeruginosa (MTCC 424), Escherichia coli (MTCC 443), Klebsiella pneumonia (MTCC 3384), and Aeromonas salmonicida (MTCC 1522). The synthesized MT-AgNPs also exhibit interesting antimalarial activities against Plasmodium falciparum parasites (3D7 strain) by displaying 100% inhibition at a concentration of 1 μg mL-1 against the malaria parasite P. falciparum 3D7. Overall, the results describe a green method for the production of twinned-structured nanoparticles and their potential to be applied in the biomedical, pharmaceutical, food preservation, and packaging industries.

The design, synthesis and antiplasmodial evaluation of novel sulfoximine-isoxazole hybrids as potential antimalarial agents

A library of novel sulfoximine-isoxazole hybrids was synthesized and evaluated for antimalarial activity. The subsequential synthetic pathways, which included the alkylation of thiols and simultaneous sulfide oxidation and imination, yielded a library of sulfoximine derivatives 3a-s. These were coupled with brominated-isoxazoles 6a-c, to give sulfoximine-isoxazole hybrids 7a-v and further derivatized to compounds 8 and 9. The hybrid compounds were then investigated for their antiplasmodial activity against the wild-type drug-sensitive strain (NF54) and multidrug-resistant strain (K1). Only six (6) hybrids showed minor potency against the drug-sensitive and drug-resistant strains (IC50 values ranging between 4.1 and 5.8 μM). The selectivity studies indicated no significant toxicity of the hybrid compounds against mammalian cells.

Safety and antimalarial therapeutic index of alkaloid-rich extract of Phyllanthus amarus Schumach. & Thonn. in mice

BackgroundMalaria fever is known to cause around one million passings per annum. This life-threatening infection is predominant in most part of Africa. Malaria vaccinations are challenging in Nigeria, particularly in rural areas. Drugs derived from plants have been utilized customarily to treat malaria. In this manner, assurance of the harmfulness and antimalarial capacity of plant derived drugs can demonstrate to be the source of novel lead compound to control malaria. The aim of this study was to evaluate the safety and antimalarial therapeutic index of alkaloid-rich extract of Phyllanthus amarus in mice. MethodsThirty rats (n = 5/group) were used for the oral acute toxicity study and administered with varying doses (0, 100, 500, 1000, 2000 and 5000 mg/kg b.wt) of alkaloid-rich extract of P. amarus. The oral acute toxicity was carried out according to OECD guidelines.After 21 days of monitoring, serum liver function tests and liver histology were performed using documented methods. The antimalarial index was determined using median effective dose (ED50) of thirty five mice divided into 7 groups (n = 5). Resultsshowed that up to the highest dose (5000 mg/kg), there were no biochemical derangements in liver function. Physical signs of toxicity were also not observed. Antimalarial activity indices showed high potency with therapeutic index of 30.13. ConclusionAlkaloid-rich extract of Phyllanthus amarus is therefore, non-toxic with reputable antimalarial activity. The active alkaloid(s) deserve further study as source for possible development of new and more potent antimalarial agent.

Blood-stage antimalarial activity, favourable metabolic stability and in vivo toxicity of novel piperazine linked 7-chloroquinoline-triazole conjugates

The persistence of drug resistance poses a significant obstacle to the advancement of efficacious malaria treatments. The remarkable efficacy displayed by 1,2,3-triazole-based compounds against Plasmodium falciparum highlights the potential of triazole conjugates, with diverse pharmacologically active structures, as potential antimalarial agents. We aimed to synthesize 7-dichloroquinoline-triazole conjugates and their structure-activity relationship (SAR) derivatives to investigate their anti-plasmodial activity. Among them, QP11, featuring a m-NO2 substitution, demonstrated efficacy against both chloroquine-sensitive and -resistant parasite strains. QP11 selectively inhibited FP2, a cysteine protease involved in hemoglobin degradation, and showed synergistic effects when combined with chloroquine. Additionally, QP11 hindered hemoglobin degradation and hemozoin formation within the parasite. Metabolic stability studies indicated high stability of QP11, making it a promising antimalarial candidate. In vivo evaluation using a murine malaria model demonstrated QP11's efficacy in eradicating parasite growth without neurotoxicity, presenting it as a promising compound for novel antimalarial development.

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.

Drug repurposing approach for identifying Pfmrk inhibitors as potential antimalarial agents: An in silico analysis

Malaria represents a major global health concern, primarily due to the emergence of resistance against most currently available antimalarial drugs. This pressing issue necessitates the discovery of novel antimalarial agents to combat the escalating resistance. A cyclin-dependent kinase (CDK)-like protein, Pfmrk, found in Plasmodium falciparum, plays a crucial role in regulating cell proliferation and exhibits a 36.28% sequence homology with its human counterpart hCDK7. Pfmrk forms a complex with plasmodial cyclin (Pfcyc-1) and stimulates kinase activity. Pfcyc-1 from P. falciparum, with the highest sequence homology to human cyclin (cyclin H), binds and activates Pfmrk in a cyclin-dependent manner. This discovery provides the first indication that cyclin subunits may regulate both human and plasmodial CDKs in a similar fashion. In this study, we conducted molecular docking and simulation analysis to investigate the interaction between Pfmrk and a selection of the FDA-approved drugs retrieved from the ZINC15 database. The top five drugs – Lurasidone, Vorapaxar, Donovex, Alvesco, and Orap – were screened based on their binding energies, with the best-docked scores ranging between −8 kcal/mol and −12 kcal/mol. Further, evaluation through molecular dynamics simulations for 100 nanoseconds revealed that Lurasidone exhibited the highest binding affinity (−105.90 ± 57.72 kJ/mol) followed by Donovex (−92.877 ± 17.872 kJ/mol). They exhibited stable interactions with the amino acid residues located in the active site of Pfmrk. The results of the in silico investigation indicate that Lurasidone and Donovex exhibit antimalarial potential and could serve as promising Pfmrk inhibitors. Further, development of new drugs based on these findings warrants subsequent in vitro studies.