Antiplasmodial Agents Research Articles

Design, synthesis and mechanistic exploration of anti-plasmodial Indolo[2,3-b]quinoxaline-7-chloroquinoline hybrids.

Aim: The aim of this study is to synthesize indolo[2,3-b]quinoxaline-4-aminoquinoline-based hybrids and evaluate their effectiveness against chloroquine-susceptible (3D7) and resistant (W2) Plasmodium falciparum strains, with expected inhibition of P. falciparum chloroquine resistance transporter (PfCRT) and heme.Methods: The hybrids were synthesized and in vitro evaluated against both susceptible and resistant strains. Molecular docking and studies were conducted to assess the binding affinities for the PfCRT protein. Additionally, heme-inhibition studies using hemin chloride provided valuable insights into the interaction between the ligand and heme. The binding constant (logK) was calculated, providing quantitative details about the strength of this interaction.Conclusion: The synthesized hybrids showed reasonable potency against both P. falciparum strains. The most potent hybrid 10d, with fluorine-substitution exhibited good activity. Molecular docking studies indicated strong binding affinities for the PfCRT protein. Heme inhibition studies further supported the potential of 10d as an effective anti-plasmodial agent.

Structure Activity Relationship of Diarylidenecyclopentanone Derivatives as Potent Antiplasmodial Agents

AbstractIn our efforts to design mono‐carbonyl analogues of curcumin with potential antiplasmodial activity, diarylidenecyclopentanone (DACP) derivatives, Ia–Iu and II–V, have been synthesized and characterized using 1H NMR, 13C NMR, IR, UV–Vis, and mass spectrometry. Structure of one of these DACPs has been verified by single crystal XRD. At the outset, all 25 DACPs were first screened at 12.5 µM for their in vitro antiplasmodial activity against the chloroquine (CQ)‐sensitive Pf3D7. The three most potent compounds (In, It, and Ik) were further tested at <10 µM concentrations against Pf3D7, PfINDO (CQ resistant), and PfMRA‐1240 (Artemisinin resistant) strains for determination of their IC50s and resistance indices. The drug profile of the DACPs was found to be very promising, with the most active compound It (IC50 1.39 µM against PfINDO) showing a selectivity index of ∼17 tested using HUH‐7 and HEK‐293T mammalian cell lines. Molecular docking studies with Pf pyridoxal synthase showed a good correlation between docking scores of DACPs and in vitro antiplasmodial activity. Further, high conformity with Lipinski's parameters indicates that these DACPs are promising antiplasmodial lead compounds.

DIVERSE SYNTHETIC APPROACHES TO CRAFT IMIDAZOLES - A REVIEW

Imidazoles are five membered heterocyclic ring compounds containing two nitrogen atoms as a part of a five membered ring. Imidazole is a pharmacologically important molecule mainly used as antihypertensive, antiplasmodial, antifungal and anticancer agents etc. It can be synthesized by using a variety of starting materials by different synthesis such as – Debus Radziszewski, Van Leusen, Wallach synthesis to name a few. By altering the starting materials different derivatives of imidazole can be synthesized and show a wide range of pharmacological activites. Hence organic chemists are continuously striving to synthesize novel imidazole derivatives that could show better pharmacological effects. This review article focuses on different types of synthesis available to chemists for this versatile molecule.

Optimization of B-Ring-Functionalized Antimalarial Tambjamines and Prodiginines.

Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half a million deaths. Resistance to current therapies is of great concern, and there is a dire need for novel and well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported that both tambjamines and prodiginines are highly potent novel antiplasmodial agents, but they required rigor optimizations to enhance the oral efficacy, safety, and physicochemical properties. Here, we launched a comprehensive structure-activity relationship study for B-ring-functionalized tambjamines and prodiginines with 54 novel analogues systematically designed and synthesized. A number of compounds exhibited remarkable antiplasmodial activities against asexual erythrocytic Plasmodium parasites, with improved safety and metabolic profiles. Notably, several prodiginines cured erythrocytic Plasmodium yoelii infections after oral 25 mg/kg × 4 days in a murine model and provided partial protection against liver stage Plasmodium berghei sporozoite-induced infection in mice.

Natural and Bioinspired Lipidic Alkynylcarbinols as Leishmanicidal, Antiplasmodial, Trypanocidal, Fungicidal, Antibacterial, and Antimycobacterial Agents.

The present review article recapitulates for the first time the antipathogenic biological data of a series of lipidic natural products and synthetic analogues thereof characterized by the presence in their structure of an alkynylcarbinol unit. The cytotoxic properties of such natural and bioinspired compounds have been covered by several literature overviews, but to date, no review article detailing their activity against pathogens has been proposed. This article thus aims at providing a comprehensive overview of the field including early studies from the 1970s and 1980s with a specific focus on results published from the late 1990s until nowadays. Publications presenting the data of almost 50 different natural products are reported. Detailed activities encompass the fields of leishmanicidal, antiplasmodial, trypanocidal, fungicidal, and mainly antibacterial and antimycobacterial compounds. The few published studies aimed at exploring the structure-activity relationship in these series are also described. Around 15 different synthetic analogues of natural products, selected among the most active reported, are also presented. The rare data available regarding the antipathogenic mode of action of these products are recalled, and finally, a comparative analysis of the available biological data is proposed with the aim of identifying the key structural determinants for the bioactivity against pathogens of these unusual compounds.

Chloroformate-mediated ring cleavage of indole alkaloids leads to re-engineered antiplasmodial agents.

Natural product ring distortion strategies have enabled rapid access to unique libraries of stereochemically complex compounds to explore new chemical space and increase our understanding of biological processes related to human disease. Herein is described the development of a ring-cleavage strategy using the indole alkaloids yohimbine, apovincamine, vinburnine, and reserpine that were reacted with a diversity of chloroformates paired with various alcohol/thiol nucleophiles to enable the rapid synthesis of 47 novel small molecules. Ring cleavage reactions of yohimbine and reserpine produced two diastereomeric products in moderate to excellent yields, whereas apovincamine and vinburnine produced a single diastereomeric product in significantly lower yields. Free energy calculations indicated that diastereoselectivity regarding select ring cleavage reactions from yohimbine and apovincamine is dictated by the geometry and three-dimensional structure of reactive cationic intermediates. These compounds were screened for antiplasmodial activity due to the need for novel antimalarial agents. Reserpine derivative 41 was found to exhibit interesting antiplasmodial activities against Plasmodium falciparum parasites (EC50 = 0.50 μM against Dd2 cultures), while its diastereomer 40 was found to be three-fold less active (EC50 = 1.78 μM). Overall, these studies demonstrate that the ring distortion of available indole alkaloids can lead to unique compound collections with re-engineered biological activities for exploring and potentially treating human disease.

Antiplasmodial action of 4-nitrobenzenesulfonamide chalcones: Design, synthesis, characterisation, in vitro and in silico evaluation against blood stages of Plasmodium falciparum 3D7.

Malaria is an intracellular protozoan parasitic disease caused by Plasmodium species with significant morbidity and mortality in endemic regions. The complex lifecycle of the parasite and the emergence of drug-resistant Plasmodium falciparum have hampered the efficacy of current anti-malarial agents. To circumvent this situation, the present study attempts to demonstrate the blood-stage anti-plasmodial action of 26 hybrid compounds containing the three privileged bioactive scaffolds (sulfonamide, chalcone, and nitro group) with synergistic and multitarget action. These three parent scaffolds exhibit divergent activities, such as antibacterial, anti-malarial, anti-fungal, anti-inflammatory, and anticancer. All the synthesised compounds were characterised using various spectroscopic techniques. The in vitro blood-stage inhibitory activity of 26 hybrid compounds was evaluated against mixed-stage culture (asynchronize) of human malarial parasite P. falciparum, Pf 3D7 at different concentrations ranging from 25.0 µg/mL to 0.78 µg/mL using SYBR 1 green assay, with IC50 values determined after 48 h of treatment based on the drug-response curves. Two potent compounds (11 and 10), with 2-Br and 2,6-diCl substitutions, showed pronounced activity with IC50 values of 5.4 µg/mL and 5.6 µg/mL, whereas others displayed varied activity with IC50 values ranging from 7.0 µg/mL to 22.0 µg/mL. Both 11 and 10 showed greater susceptibility towards mature-stage trophozoites than ring-stage parasites. The hemolytic and in vitro cytotoxicity assays revealed that compounds 11 and 10 did not cause any toxic effects on host red blood cells (uninfected), human-derived Mo7e cells, and murine-derived BA/F3 cells. The in vitro observations are consistent with the in silico studies using P. falciparum-dihydrofolate reductase, where 11 and 10 showed a binding affinity of -10.4 Kcal/mol. This is the first report of the hybrid scaffold, 4-nitrobenzenesulfonamide chalcones, demonstrating its potential as an anti-plasmodial agent.

Diversified Synthesis of N-Benzoyl Piperidine Tetraoxane Analogues Using Molybdenum Trioxide as a Newer Catalyst and Its Antiplasmodial Activity.

Molybdenum trioxide has been proven to be an efficient catalyst in synthesizing mixed N-benzoyl piperidine dispiro-1,2,4,5-tetraoxane analogues using a one-pot reaction. This catalyst facilitated the synthesis of 21 tetraoxanes using cyclic, acyclic, and aromatic ketones. The structure and methodology of this reaction have been validated by single-crystal X-ray analysis of compound ″3g″. The nature of dispiro-1,2,4,5-tetraoxane being synthesized has an impact on the overall yield of tetraoxanes such as symmetric dispiro-1,2,4,5-tetraoxanes ranging from 53 to 82%, while yields of N-benzoyl piperidine dispiro-1,2,4,5-tetraoxanes ranged from 26 to 51%. Additionally, the in vitro antiplasmodial activity of the newly developed tetraoxanes against Plasmodium falciparum was assessed, which exhibited significantly higher activity in the nanomolar range, with values ranging from 6.35 to 44.65 nM. Molecular docking studies revealed that newer tetraoxane derivatives bind to the active site of the falcipain-2 enzyme through H-bonding and hydrophobic contacts, which are the primary indicators of the effectiveness of the synthesized compounds. Findings suggest that these peculiar compounds may act as antiplasmodial agents, which spur further study and advancement in the battle against malaria.

Neuroprotective potentials of the essential oil of Curcuma aeruginosa Roxburg rhizomes in mice with cerebral malaria

BackgroundOne of the three principles that govern the pathogenesis of cerebral malaria (CM) is the activation of immunological and systemic inflammatory responses. Available reports have revealed the anti-inflammatory and antioxidant activity of the essential oils of Curcuma aeruginosa Roxb. rhizomes (CAEO). Therefore, CAEO may improve treatment outcome in CM induced mice. PurposeTo investigate the neuroprotective potentials of CAEO in mice induced with CM, when administered alone or in combination with quinine. MethodsThe CAEO was obtained by subjecting macerated rhizomes of Curcuma aeruginosa to hydro-distillation for 4 h using Clevenger-type apparatus. Swiss mice of either sex induced with CM were divided into 14 groups, namely: parasitized and quinine controls, CAEO (6.25, 12.5, 25, 50, 100 and 200 mg/kg) and their corresponding combinations with quinine. The CAEO was administered once daily while quinine was administered at a dose of 20 mg/kg stat, then 10 mg/kg bid. Non parasitized (n = 6) and parasitized controls were treated with vehicle (5 % tween 80 in distilled water). The progression of CM was daily monitored via parasitemia, weight, and SHIRPA functional and behavioural indices. Brains were harvested from surviving mice for histomorphological examination. Phytochemical profiling of CAEO was performed using GC–MS, and the detected phytochemicals were subjected to ADMET screening. ResultThe CAEO was mildly toxic, restored weight loss in mice with CM, showed potential to prolong the survival rate of mice with CM, acted synergistically with quinine in a dose-dependent manner as antiplasmodial agent, and showed neuroprotective potential in mice with CM, when used alone or in combination at lower doses. GC–MS analysis detected twelve phytochemicals, with good ADMET profiles, having potentials to have contributed to the observed biological effects. ConclusionAntiplasmodial and central nervous system protective activity of CAEO increased synergistically when used in combination with quinine. However, to prevent associated toxic effects, low dose combination is recommended.

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.

Three Decades of Targeting Falcipains to Develop Antiplasmodial Agents: What have we Learned and What can be Done Next?

Malaria is a devastating infectious disease that affects large swathes of human populations across the planet's tropical regions. It is caused by parasites of the genus Plasmodium, with Plasmodium falciparum being responsible for the most lethal form of the disease. During the intraerythrocytic stage in the human hosts, malaria parasites multiply and degrade hemoglobin (Hb) using a battery of proteases, which include two cysteine proteases, falcipains 2 and 3 (FP-2 and FP-3). Due to their role as major hemoglobinases, FP-2 and FP-3 have been targeted in studies aiming to discover new antimalarials and numerous inhibitors with activity against these enzymes, and parasites in culture have been identified. Nonetheless, cross-inhibition of human cysteine cathepsins remains a serious hurdle to overcome for these compounds to be used clinically. In this article, we have reviewed key functional and structural properties of FP-2/3 and described different compound series reported as inhibitors of these proteases during decades of active research in the field. Special attention is also paid to the wide range of computer-aided drug design (CADD) techniques successfully applied to discover new active compounds. Finally, we provide guidelines that, in our understanding, will help advance the rational discovery of new FP-2/3 inhibitors.

Antimicrobial and Antiplasmodial Activities of Endophytic Fungi Associated with Psidium guajava

Infections due to antimicrobial-resistant microorganisms have become widespread in recent years. Thus, searching for novel antimicrobial agents to combat such pathogens has become crucial. The current study aimed to evaluate the antimicrobial, antiplasmodial, and immunomodulatory activities of the extracts of endophytic fungi isolated from Psidium guajava. Isolation, identification, fermentation, and extraction of the secondary metabolites of the fungal endophytes were carried out following standard procedures. The extracts were subjected to High-Performance Liquid Chromatography-Diode Array Detector (HPLC-DAD) analysis to detect their bioactive components. The Antimicrobial activity and Minimum Inhibitory Concentration of the fungal extracts were evaluated against pure cultures of Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Salmonella typhi, and Klebsiella pneumonia using Agar well diffusion and Agar dilution method respectively. The acute toxicity study (LD50) was carried out using Lorke’s method. The extracts were tested in vivo in mice for antiplasmodial activity against Plasmodium berghei and in vitro against Plasmodium falciparum using Peter and Reyley's curative test method and WHO standardized micro-test system with modification respectively. The immunomodulatory activity of the extracts was evaluated by cyclophosphamide-induced myelosuppression (hematological parameters). Active extracts were further subjected to Delayed-Type Hypersensitivity Response (DTHR) and Haemagglutination Inhibition Assay using Sheep Red Blood Cells as antigens. The result showed Alternaria sp. (PGL1, PGL2, PGL3), from P. guajava. The HPLC-DAD analysis revealed the presence of bioactive compounds previously reported to have antimicrobial, antiplasmodial, and immunomodulatory properties. The fungal extracts exhibited varying degrees of antimicrobial activity. The LD50 of the fungi extracts was>5000 mg/kg in mice. The extracts at 100 and 200 mg/kg body weight in mice showed varying degrees of antiplasmodial activity. Growth of P. berghei was significantly (p<0.001) inhibited, curative effect ranges from 59.09 – 100%. Schizont maturation of P. falciparum isolates was inhibited and the highest level of inhibition was observed at 1 mg/ml (p<0.05). The fungal extracts reversed the effect of cyclophosphamide-induced reduction in total white blood cell counts and % neutrophil. This study showed that the tested plant harbors species of endophytic fungi that contain numerous secondary metabolites. The endophytic fungi showed prophylactic, immunostimulatory, and antiplasmodial activities, which can be exploited to develop antimicrobial, antiplasmodial, and immunomodulatory agents.

Development of Novel Peptidyl Nitriles Targeting Rhodesain and Falcipain-2 for the Treatment of Sleeping Sickness and Malaria.

In recent decades, neglected tropical diseases and poverty-related diseases have become a serious health problem worldwide. Among these pathologies, human African trypanosomiasis, and malaria present therapeutic problems due to the onset of resistance, toxicity problems and the limited spectrum of action. In this drug discovery process, rhodesain and falcipain-2, of Trypanosoma brucei rhodesiense and Plasmodium falciparum, are currently considered the most promising targets for the development of novel antitrypanosomal and antiplasmodial agents, respectively. Therefore, in our study we identified a novel lead-like compound, i.e., inhibitor 2b, which we proved to be active against both targets, with a Ki = 5.06 µM towards rhodesain and an IC50 = 40.43 µM against falcipain-2.

Antiplasmodial potential of phytochemicals from Citrus aurantifolia peels: a comprehensive in vitro and in silico study

Phytochemical investigation of Key lime (Citrus aurantifolia L., F. Rutaceae) peels afforded six metabolites, known as methyl isolimonate acetate (1), limonin (2), luteolin (3), 3ˋ-hydroxygenkwanin (4), myricetin (5), and europetin (6). The structures of the isolated compounds were assigned by 1D NMR. In the case of limonin (2), further 1- and 2D NMR experiments were done to further confirm the structure of this most active metabolite. The antiplasmodial properties of the obtained compounds against the pathogenic NF54 strain of Plasmodium falciparum were assessed in vitro. According to antiplasmodial screening, only limonin (2), luteolin (3), and myricetin (5) were effective (IC50 values of 0.2, 3.4, and 5.9 µM, respectively). We explored the antiplasmodial potential of phytochemicals from C. aurantifolia peels using a stepwise in silico-based analysis. We first identified the unique proteins of P. falciparum that have no homolog in the human proteome, and then performed inverse docking, ΔGBinding calculation, and molecular dynamics simulation to predict the binding affinity and stability of the isolated compounds with these proteins. We found that limonin (2), luteolin (3), and myricetin (5) could interact with 20S a proteasome, choline kinase, and phosphocholine cytidylyltransferase, respectively, which are important enzymes for the survival and growth of the parasite. According to our findings, phytochemicals from C. aurantifolia peels can be considered as potential leads for the development of new safe and effective antiplasmodial agents.

Synthesis and biological evaluation of hydantoin derivatives as potent antiplasmodial agents

Malaria, a devastating disease, has claimed numerous lives and caused considerable suffering, with young children and pregnant women being the most severely affected group. However, the emergence of multidrug-resistant strains of Plasmodium and the adverse side effects associated with existing antimalarial drugs underscore the urgent need for the development of novel, well-tolerated, and more efficient drugs to combat this global health threat. To address these challenges, six new hydantoins derivatives were synthesized and evaluated for their in vitro antiplasmodial activity. Notably, compound 2c exhibited excellent inhibitory activity against the tested Pf3D7 strain, with an IC50 value of 3.97 ± 0.01 nM, three-fold better than chloroquine. Following closely, compound 3b demonstrated an IC50 value of 27.52 ± 3.37 µM against the Pf3D7 strain in vitro. Additionally, all the hydantoins derivatives tested showed inactive against human MCR-5 cells, with an IC50 value exceeding 100 μM. In summary, the hydantoin derivative 2c emerges as a promising candidate for further exploration as an antiplasmodial compound.

Synthesis of 2,3-diaminopyridine-derived 4-azabenzimidazoles and (benzylimino)pyridine analogues as potential anti-plasmodial agents

Synthesis of 2,3-diaminopyridine-derived 4-azabenzimidazoles and (benzylimino)pyridine analogues as potential anti-plasmodial agents

Design, synthesis and mechanistic insights into triclosan derived dimers as potential anti-plasmodials.

In pursuit of novel anti-plasmodial agents, a library of triclosan-based dimers both with and without a 1H-1,2,3 triazole core were designed and synthesized in order to achieve a multitargeted approach. In vitro assessment against chloroquine-susceptible (3D7) and resistant (W2) P. falciparum strains identified that two of the synthesized dimers containing triazole were the most potent in the series. The most potent of the synthesized compounds exhibited IC50 values of 9.27 and 12.09 μM against the CQ-resistant (W2) and CQ-susceptible (3D7) strains of P. falciparum, with an RI of 0.77, suggesting little or no cross-resistance with CQ. Heme binding and molecular modelling studies revealed the most promising scaffold as a dual inhibitor for hemozoin formation and a P. falciparum chloroquine resistance transporter (PfCRT), respectively. In silico studies of the most potent compound revealed that it shows better binding affinity with PfACP and PfCRT compared to TCS. To the best of our knowledge, this is the first report of triclosan-based compounds demonstrating promising heme-inhibition behaviour, with binding values comparable to those of chloroquine (CQ).

SYNTHESIS, ANTIPLASMODIAL, ANTIOXIDANT, AND MOLECULAR DOCKING INVESTIGATION OF NOVEL 4-AMINOQUINOLINE-ISOINDOLIN-1-ONES HYBRIDS

Four novel 4-aminoquinoline-isoindolin-1-one hybrids 5a-d have been designed as antiplasmodial and antioxidant agents by combining the 4-aminoquinoline unit and isoindolin-1-one moiety using the flexible alkyl linker. The hybrids were synthesized in two steps via aromatic nucleophilic substitution and nucleophilic addition reactions and were obtained with yields up to 83%. The evaluation of their anti-plasmodial activity was conducted against Plasmodium falciparum 3D7, whereas the antioxidant activity was assessed using the DPPH method. Among the four hybrids, the hybrid of 3-benzyl-2-(6-((7-chloroquinolin-4-yl)amino)hexyl)-3-hydroxyisoindolin-1-one 5c demonstrated excellent antiplasmodial (IC50 of 0.01 µg/mL) and antioxidant (IC50 of 46.58 µg/mL) activities. The molecular docking study was conducted using PfOAT as the protein target. The docking results were in line with the in vitro antiplasmodial assay, where hybrid 5c displayed the lowest binding energy of -8.43 kcal/mol

S-MGBs bearing amidine tail groups are potent, selective antiplasmodial agents.

There were an estimated 249 million cases of malaria globally in 2022, causing approximately 608 000 deaths. Most of these are attributed to infection by P. falciparum. Strathclyde minor groove binders (S-MGBs) are a promising new class of anti-infective agent that have been shown to be effective against many infectious organisms, including P. falciparum. A panel of 25 S-MGBs was synthesised, including those bearing an amidine tail group, and their antiplasmodial activity against 3D7 and Dd2 strains was determined in vitro using an asexual P. falciparum imaging assay. Determination of activity against HEK293 cells allowed for selective cytotoxicity to be measured. DNA binding studies were carried out using native mass spectrometry and DNA thermal shift assays. A comparison of 3D7 (chloroquine sensitive) and Dd2 (chloroquine resistant) potency showed no evidence of cross-resistance across the S-MGB set. S-MGB-356, S-MGB-368 and S-MGB-359, amidine tail containing S-MGBs, were identified as the most promising hit compounds based on their selectivity indices (HEK293/3D7) of >612.6, >335.8 and >264.8, respectively. S-MGB-356, S-MGB-368 and S-MGB-359 were confirmed to bind to DNA as dimers, with gDNA thermal shifts (ΔT m) of 12 °C, 3 °C and 16 °C, respectively. Together, these data demonstrate that amidine tail bearing S-MGBs are promising hit compounds against P. falciparum, and can be further optimised into lead compounds.

2,4-disubstituted 6-fluoroquinolines as potent antiplasmodial agents: QSAR, homology modeling, molecular docking and ADMET studies

ObjectiveThis work was designed to study 2,4-disubstituted 6-fluoroquinolines as antiplasmodial agents by using in silico techniques, to aid in the design of novel analogs with high potency against malaria and high inhibition of Plasmodium falciparum translation elongation factor 2 (PfeEF2), a novel drug target. MethodsQuantitative structure-activity relationships (QSAR) of 2,4-disubstituted 6-fluoroquinolines were studied with the genetic function approximation technique in Material Studio software. The 3D structure of PfeEF2 was modeled in the SWISS-MODEL workspace through homology modeling. A molecular docking study of the modeled PfeEF2 and 2,4-disubstituted 6-fluoroquinolines was conducted with Autodock Vina in Pyrx software. Furthermore, the in silico pharmacokinetic properties of selected compounds were investigated. ResultsA robust, reliable and predictive QSAR model was developed that related the chemical structures of 2,4-disubstituted 6-fluoroquinolines to their antiplasmodium activities. The model had an internal squared correlation coefficient R2 of 0.921, adjusted squared correlation coefficient R2adj of 0.878, leave-one-out cross-validation coefficient Q2cv of 0.801 and predictive squared correlation coefficient R2pred of 0.901. The antiplasmodium activity of 6-fluoroquinolines was found to depend on the n5Ring, GGI9, TDB7u, TDB8u and RDF75i physicochemical properties: n5Ring, TDB8u and RDF75i were positively associated, whereas GGI9 and TDB7u were negatively associated, with the antiplasmodium activity of the compounds. Stable complexes formed between the compounds and modeled PfeEF2, with binding affinity ranging from −8.200 to −10.700 kcal/mol. Compounds 5, 11, 16, 22 and 24 had better binding affinities than quinoline-4-carboxamide (DDD107498), as well as good pharmacokinetic properties, and therefore may be better inhibitors of this novel target. ConclusionQSAR and docking studies provided insight into designing novel 2,4-disubstituted 6-fluoroquinolines with high antiplasmodial activity and good structural properties for inhibiting a novel antimalarial drug target.