Antimalarial Activity Of Compounds Research Articles

Ex vivo and In vitro antiplasmodial activities of approved drugs predicted to have antimalarial activities using chemogenomics and drug repositioning approach

High malaria mortality coupled with increased emergence of resistant multi-drug resistant strains of Plasmodium parasite, warrants the development of new and effective antimalarial drugs. However, drug design and discovery are costly and time-consuming with many active antimalarial compounds failing to get approved due to safety reasons. To address these challenges, the current study aimed at testing the antiplasmodial activities of approved drugs that were predicted using a target-similarity approach. This approach is based on the fact that if an approved drug used to treat another disease targets a protein similar to Plasmodium falciparum protein, then the drug will have a comparable effect on P. falciparum. In a previous study, in vitro antiplasmodial activities of 10 approved drugs was reported of the total 28 approved drugs. In this study, six out of 18 drugs that were previously not tested, namely epirubicin, irinotecan, venlafaxine, palbociclib, pelitinib, and PD153035 were tested for antiplasmodial activity. The drug susceptibility in vitro assays against five P. falciparum reference strains (D6, 3D7, W2, DD2, and F32 ART) and ex vivo assays against fresh clinical isolates were done using the malaria SYBR Green I assay. Standard antimalarial drugs were included as controls. Epirubicin and irinotecan showed excellent antiplasmodial ex vivo activity against field isolates with mean IC50 values of 0.044 ± 0.033 μM and 0.085 ± 0.055 μM, respectively. Similar activity was observed against W2 strain where epirubicin had an IC50 value of 0.004 ± 0.0009 μM, palbociclib 0.056 ± 0.006 μM, and pelinitib 0.057 ± 0.013 μM. For the DD2 strain, epirubicin, irinotecan and PD 153035 displayed potent antiplasmodial activity (IC50 < 1 μM). Epirubicin and irinotecan showed potent antiplasmodial activities (IC50 < 1 μM) against DD2, D6, 3D7, and F32 ART strains and field isolates. This shows the potential use of these drugs as antimalarials. All the tested drugs showed antiplasmodial activities with IC50 values below 20 μM, which suggests that our target similarity-based strategy is successful at predicting antiplasmodial activity of compounds thereby circumventing challenges in antimalarial drug discovery.

Steroids from Toona sureni-derived Endophytic Fungi Stemphylium sp. MAFF 241962 and Their Heme Polymerization Inhibition Activity

Abstract Antimalarial drug resistance is a major cause of the increasing incidence of malaria worldwide, necessitating an urgent demand for the development of new antimalarial drugs. However, the availability of bioactive natural compounds derived from plants is often limited. To address this issue, continuous exploration of bioactive secondary metabolites from endophytic fungi derived from medicinal plants has been recognized as a viable alternative. Therefore, this research aimed to isolate and characterize three ergosteroids, namely isocyathisterol (1), ergosterol-5,8-peroxide (3), cerevisterol (4), and a phytosterol, β-sitosterol (2), from the rice cultures of endophytic fungus Stemphylium sp. MAFF 241962, derived from Toona sureni. Endophytic fungi species were determined using molecular analysis of the internal transcribed region (ITS) of the ribosomal DNA. After comparing the sequence data to the NCBI database using BLAST, endophytic fungi were identified as Stemphylium sp. 241962 with 100% similarity. The chemical structures were elucidated using spectroscopic methods, including 1D and 2D NMR. Antimalarial activities of compounds 1-4 were evaluated using heme polymerization inhibition activity (HPIA) method. The results showed moderate inhibition activities with IC50 values of 7.70 ± 0.11, 9.48 ± 0.09, 7.88 ± 0.10, and 8.36 ± 0.56 mg/mL, respectively, compared to positive control chloroquine diphosphate with IC50 values of 1.59 ± 0.03 mg/mL. Keywords: Steroid, Stemphylium sp., Toona sureni, Antimalarial activity, Heme polymerization inhibition

Artocarpus sericicarpus stem bark contains antimalarial substances against Plasmodium falciparum.

The finding of alternative medicine for malarial treatment still has become a substantial demand. The plant is one of the potential sources of drugs, among other natural sources. Artocarpus species showed great potential as the antimalarial source. This study aims to obtain active antimalarial fractions from Artocarpus sericicarpus stem bark. Stem bark of A.sericicarpus was extracted by ultrasonic-assisted extraction method using n-hexane, dichloromethane, and methanol as solvents. Fractionation of dichloromethane extract was conducted by open column chromatography using octadecyl silica as a stationary phase and gradient acetonitrile-water as a mobile phase. The antimalarial activity was determined by lactate dehydrogenase (LDH) assay against Plasmodium falciparum 3D7 strain. A.sericicarpus n-hexane, dichloromethane, and methanol extracts were showed antimalarial activity with an IC50 value of >4, 2.11, and >4μg/mL, respectively. Fractionation of dichloromethane extract was obtained 13 fractions. Seven of the 13 fractions tested showed antimalarial activity. Fraction-6 performed the highest inhibition with an IC50 value of 1.53±0.04μg/mL. Phytochemistry screening revealed that Fraction-6 contains flavonoid, polyphenol, and terpenoid compounds that can take a role in its antimalarial activity. A.sericicarpus contains antimalarial substances mainly in Fraction-6, which strongly inhibited the growth of P.falciparum. The flavonoid, polyphenol, and terpenoid compounds were identified in Fraction-6, which need to be further isolated to obtain and elucidate the active antimalarial compounds.

Antiplasmodial activity of Ethanolic extract of Cassia spectabilis DC leaf and its inhibition effect in Heme detoxification

BackgroundIn previous studies, Cassia spectabilis DC leaf has shown a good antiplasmodial activity. Therefore, this study is a follow-up study of the extract of leaf of C. spectabilis DC on its in vitro and in vivo antiplasmodial activity and mechanism as an antimalarial.MethodsThe extract was fractionated, sub-fractionated and isolated to obtain the purified compound. In vitro antiplasmodial activity test against Plasmodium falciparum to find out the active compound. In vivo test against P. berghei ANKA-infected mice was conducted to determine prophylactic activity and antiplasmodial activity either alone or in combination with artesunate. The inhibition of heme detoxification test as one of the antimalarial mechanisms was carried out using the Basilico method.ResultsThe results showed that active antimalarial compound isolated from C. spectabilis DC leaf had a structural pattern that was identical to (−)-7-hydroxycassine. Prophylactic test of 90% ethanolic extract of C. spectabilis DC leaf alone against P. berghei ANKA-infected mice obtained the highest percentage inhibition was 68.61%, while positive control (doxycycline 13 mg/kg) was 73.54%. In combination with artesunate, 150 mg/kg three times a day of C. spectabilis DC (D0-D2) + artesunate (D2) was better than the standard combination of amodiaquine + artesunate where the inhibition percentages were 99.18 and 92.88%, respectively. The IC50 of the extract for the inhibitory activity of heme detoxification was 0.375 mg/ml which was better than chloroquine diphosphate (0.682 mg/ml).ConclusionC. spectabilis DC leaf possessed potent antiplasmodial activity and may offer a potential agent for effective and affordable antimalarial phytomedicine.

Antimalarial Activity, Phytochemical Composition and Acute Toxicity Tests of Ethanolic Stem Bark Extract of Alstonia boonei De Wild

Many modern medicines are derived from the chemicals available in plants. The utilization of plants against diseases by traditional medical practitioners is common in many parts of the world and several researches have been carried out to determine the scientific basis for the use of such plants. Alstonia boonei is one of the many medicinal plants found in Nigeria. The plant parts have been traditionally used to treat various ailments including malaria. This study was carried out to evaluate the antimalarial activity, phytochemical composition and toxicity of ethanolic stem bark extract of Alstonia boonei. The extract showed substantial dose dependent antimalarial activity as indicated by the recorded suppressive (45.67%, 58.53% and 74.68% for 100, 200 and 400 mgkg-1 body weights) prophylactic (33.57%, 45.64% and 61.23% for 100, 200 and 400 mgkg-1 body weights) and curative effects (62.35%, 68.57% and 79.63% for 100, 200 and 400 mgkg-1 body weights) on Plasmodium berghei infected white albino mice. The results of the antimalarial tests were significantly different compared to the negative control at P &lt; 0.05. The phytochemical evaluation showed that the plant contained important chemical compounds including tannins, flavonoids, steroids, phenols, alkaloids, saponins, glycosides and terpenoids. The acute toxicity test showed that the extract is safe as observed on the tested mice. It was concluded that the extract contains important active antimalarial compounds that are safe and should be further investigated for antimalarial drug development.

Melicope moluccana Antimalarial Activity of Furoquinoline Alkaloids from the Leaves of Melicope moluccana

Two furoquinoline alkaloids, leptanoine C (1) and haplopine-3,3´-dimethylallyl ether (2) were isolated from the leaves of Melicope moluccana. The chemical structure of both compounds was determined based on spectroscopic data, including UV, IR, HR-ESI-MS, 1D, and 2D NMR spectral data. The antimalarial activity of compounds 1-2 against Plasmodium falciparum 3D7 showing their IC50 values are 0.18 ppm and 2.28 µg/mL, respectively.

Determination of Cassiarin A Level of Cassia siamea Leaf Obtained from Various Regions in Indonesia Using the TLC-Densitometry Method.

Cassia siamea leaf has been proven in vitro and in vivo to have a strong antimalarial activity with Cassiarin A as its active compound. To obtain a source of C. siamea medicinal plant with high level of active antimalarial compound (Cassiarin A), a valid method for determining Cassiarin A level is needed. For this reason, this research conducts the validation of the Cassiarin A content with determination method using thin-layer chromatography (TLC) densitometry which includes the determination of selectivity (Rs), linearity (r), accuracy, precision, limit of detection (LOD), and limit of quantification (LOQ). Cassiarin A was chromatographed on silica gel 60 F254 TLC plate using chloroform : ethanol (85 : 15 v/v) as a mobile phase. Cassiarin A was quantified by densitometric analysis at 368 nm. The linear regression analysis data for the calibration plots showed good linear relationship with r = 0.9995. The method was validated for precision, recovery, repeatability. The minimum detectable amount was found to be 0.0027 μg/spot, whereas the limit of quantitation was found to be 0.008 μg/spot. The results of this validation are then used to determine the Cassiarin A level of C. siamea leaf from various regions in Indonesia. Based on the results of the study, it can be concluded that the TLC-densitometry method can be used to determine level of the Cassiarin A compound with the advantages of being fast, easy, accurate, and inexpensive. In addition, it showed that C. siamea leaves from Pacitan have the highest level of Cassiarin A compared to other areas studied.

Classification models for predicting the antimalarial activity against Plasmodium falciparum

ABSTRACTSupport vector machine (SVM) and general regression neural network (GRNN) were used to develop classification models for predicting the antimalarial activity against Plasmodium falciparum. Only 15 molecular descriptors were used to build the classification models for the antimalarial activities of 4750 compounds, which were divided into a training set (3887 compounds) and a test set (863 compounds). For the SVM model, its prediction accuracies are 89.5% for the training set and 87.3% for the test set. For the GRNN model, the prediction accuracies for the two sets are 99.7% and 88.9%, respectively. Both SVC and GRNN models have better prediction ability than the classification model based on binary logistic regression (BLR) analysis. Compared with previously published classification models both SVC and GRNN models are satisfactory in predicting antimalarial activities of compounds with in addition of fewer descriptors.

A multicomponent reaction to design antimalarial pyridyl-indole derivatives: Synthesis, biological activities and molecular docking

Using fragment-based design strategy, new pyridyl-indole hybrids 4a-y and indole intermediates 3a-e were synthesized using multicomponent one pot reaction. The synthesized compounds were subjected to screening for antimalarial activity against chloroquine sensitive (D6) and chloroquine resistant (W2) strains of Plasmodium falciparum. Several compounds exhibited antimalarial activity with IC50 values in the range of 1.47-9.23μM, and 1.16-7.66 μM, for D6 and W2 strains, respectively. Compounds 4a, 4k and 4u showed the highest selectivity index among all the tested compounds (S.I. ranged 3.8-10). Binding interactions between the active antimalarial compounds and the active site of quadruple mutant Plasmodium falciparum dihydrofolate reductase enzyme have been investigated using molecular docking analysis.

Antimalarial Activity of Lamiaceae Family Plants: Review

Malaria is a major infectious disease caused by Plasmodium sp., and it can infect human’s trough females’ mosquitos Anopheles sp. bite. Plasmodium resistance to malarial drugs used today occurs mostly in endemic areas, so it is necessary to look for alternative medicines for malaria, especially medicines derived from plants Objective: The objective of writing this literature review is to see the ability of the Lamiaceae family plant as a source of new malaria medicines. Methods: Scientific evidence of traditional use, antiplasmodial activity, and active antimalarial compounds from plants belong to Lamiaceae family used to support this article are carried out by searching online for articles related to the title of this article. Results: Lamiaceae family plants used for malaria treatment traditionally in many countries, and many of them have been examined for their antimalarial activity in vitro against P. falciparum or in vivo against P. berghei in mice, and they have antimalarial effect with various potency. There are forty active antimalarial compounds isolated from plants of Lamiaceae family, and these could be candidates for new antimalarial medicines. Conclusion: Lamiaceae family is proven to be a source of plants that have antimalarial activity, this can be seen from their traditional use as malarial drugs in various countries, the number of plant extracts with antimalarial activity and many active antimalarial substances isolated from Lamiaceae family plants, but they still need to be further examined to become antimalarial drugs.

Synthesis and Antiplasmodial Activity of 1,2,3-Triazole-Naphthoquinone Conjugates.

A series of 34 1,2,3-triazole-naphthoquinone conjugates were synthesized via copper-catalyzed cycloaddition (CuAAC). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and against three different tumor cell lines (SKBr-3, MCF-7, HEL). The most active antimalarial compounds showed a low antiproliferative activity. Simplified analogues were also obtained and some structure–activity relationships were outlined. The best activity was obtained by compounds 3s and 3j, having IC50 of 0.8 and 1.2 μM, respectively. Molecular dockings were also carried on Plasmodium falciparum enzyme dihydroorotate dehydrogenase (PfDHODH) in order to rationalize the results.

Designing novel inhibitors against falcipain-2 of Plasmodium falciparum

Coumarin containing pyrazoline derivatives have been synthesized and tested as inhibitors of in vitro development of a chloroquine-sensitive (MRC-02) and chloroquine-resistant (RKL-2) strain of Plasmodium falciparum and in vivo Plasmodium berghei malaria. Docking study was also done on cysteine protease falcipain-2 which showed that the binding pose of C-14 molecule and epoxysuccinate, inhibitor of falcipain-2, binds in the similar pattern. The most active antimalarial compound was 3-(1-benzoyl-5-(4-flurophenyl)-4,5-dihydro-1H-pyrazol-3yl)-7-(diethyamino)-2H-chromen-2-one C-14, with an IC50 of 4.21 µg/ml provided complete protection to the infected mice at 24 mg/kg X 4 days respectively.

Antimalarial activity of Malaria Box Compounds against Plasmodium falciparum clinical isolates

Malaria remains a major cause of childhood deaths in resource-limited settings. In the absence of an effective vaccine, drugs and other interventions have played very significant roles in combating the scourge of malaria. The recent reports of resistance to artemisinin necessitate the need for new antimalarial drugs with novel mechanisms of action. Towards the development of new, affordable and easily accessible antimalarial drugs for endemic regions, the Medicines for Malaria Venture (MMV) assembled a total of 400 active antimalarial compounds called the Malaria Box. The potency and the efficacy of the Malaria Box Compounds have been determined mainly using laboratory strains of P. falciparum.This study investigated the potency of twenty compounds from the Malaria Box against four clinical isolates from Ghana, using optimized in vitro growth inhibitory assays. Seven out of the 20 compounds screened had 50% inhibitory concentration (IC50) below 500 nM. The most active among the selected compounds was MMV006087 (average IC50 of 30.79 nM). Variations in the potency of the Malaria Box Compounds were observed between P. falciparum clinical isolates and Dd2 strain. We also investigated the sensitivity of the clinical isolates to chloroquine and artesunate. The N093 clinical isolate was found to be resistant to chloroquine but showed high sensitivity to artesunate.The results underscore the importance of including clinical isolates with different drug-resistant backgrounds, in addition to laboratory strains, in validating potential compounds during antimalarial compound screening programs.

Connexin-43 enhances tumor suppressing activity of artesunate via gap junction-dependent as well as independent pathways in human breast cancer cells

The gap junction (GJ) protein connexin-43 (Cx43) is considered as a tumour suppressor protein for its role in reversing the phenotype of the cancer cells. In this study, we exploited the antitumor property of Cx43 in conjunction with the artesunate (ART), a plant-based active anti-malarial compound. The reactive oxygen species (ROS) generated by ART resulted in DNA damage, which in turn led to DNA damage response by activation of DNA damage repair proteins. GJ deficient MCF-7 cells transfected with Cx43 gene showed an increased sensitivity towards dose-dependent ART treatment and required a significantly lower dose of ART to attain its IC50, as compared to parental cells. This would ultimately result in reduced dose-dependent side effects of ART. The Co-culture experiments involving GJ intercellular communication (GJIC) deficient and GJIC enabled cells, established the transfer of ROS to the neighbouring cancer cells not exposed to ART. The ROS accumulated in the ART-treated cells induced the oxidative damage in neighbouring cells, leading to bystander cell death and inhibition of bystander cell proliferation. Thus, our study revealed that expression of Cx43 helped in reducing the dose-dependent cytotoxicity of ART as well as enhanced the bystander apoptosis of the neighbouring cells.

Synthesis of Novel Hybrids of Quinazoline and Artemisinin with High Activities against Plasmodium falciparum, Human Cytomegalovirus, and Leukemia Cells.

Many quinazoline derivatives have been synthesized over the last few decades with great pharmacological potential, such as antimalarial, anti-inflammatory, antimicrobial, anticancer, and antiviral. But so far, no quinazoline–artemisinin hybrids have been reported in the literature. In the present study, five novel quinazoline–artemisinin hybrids were synthesized and evaluated for their in vitro biological activity against malarial parasites (Plasmodium falciparum 3D7), leukemia cells (CCRF-CEM and CEM/ADR5000), and human cytomegalovirus. Remarkably, hybrid 9 (EC50 = 1.4 nM), the most active antimalarial compound of this study, was not only more potent than artesunic acid (EC50 = 9.7 nM) but at the same time more active than the clinically used drugs dihydroartemisinin (EC50 = 2.4 nM) and chloroquine (EC50 = 9.8 nM). Furthermore, hybrids 9 and 10 were the most potent compounds with regard to anticytomegaloviral activity (EC50 = 0.15–0.21 μM). They were able to outperform ganciclovir (EC50 = 2.6 μM), which is the relevant standard drug of antiviral therapy, by a factor of 12–17. Moreover, we identified a new highly active quinazoline derivative, compound 14, that is most effective in suppressing cytomegalovirus replication with an EC50 value in the nanomolar range (EC50 = 50 nM). In addition, hybrid 9 exhibited an antileukemia effect similar to that of artesunic acid, with EC50 values in the low micromolar range, and was 45 times more active toward the multidrug-resistant CEM/ADR5000 cells (EC50 = 0.5 μM) than the standard drug doxorubicin.

(–)-Ampelopsin F, Dimerstilbene Compound from Dryobalanops oblongifolia and Antimalarial Activity Test

(–)-Ampelopsin F, Dimerstilbene Compound from Dryobalanops oblongifolia and Antimalarial Activity Test

In vivo antimalarial activity of extracts of Tanzanian medicinal plants used for the treatment of malaria.

Plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. The aim of this study was to evaluate in vivo antimalarial activity of four plants; Erythrina schliebenii Harms, Holarrhena pubescens Buch-Ham, Phyllanthus nummulariifolius Poir, and Caesalpinia bonducella (L.) Flem used for treatment of malaria in Tanzania. In vivo antimalarial activity was assessed using the 4-day suppressive antimalarial assay. Mice were infected by injection via tail vein with 2 × 107 erythrocytes infected with Plasmodium berghei ANKA. Extracts were administered orally, once daily, for a total of four daily doses from the day of infection. Chloroquine (10 mg/kg/day) and solvent (5 mL/kg/day) were used as positive and negative controls, respectively. The extracts of C. bonducella, E. schliebenii, H. pubescens, and P. nummulariifolius exhibited dose-dependent suppression of parasite growth in vivo in mice, with the highest suppression being by C. bonducella extract. While each of the plant extracts has potential to yield useful antimalarial compounds, the dichloromethane root extract of C. bonducella seems to be the most promising for isolation of active antimalarial compound(s). In vivo antimalarial activity presented in this study supports traditional uses of C. bonducella roots, E. schliebenii stem barks, H. pubescens roots, and P. nummulariifolius for treatment of malaria.

Effect of crude leaf extract of Osyris quadripartita on Plasmodium berghei in Swiss albino mice.

BackgroundContinuous emergence of multi-drug-resistant malaria parasites and their rapid spread across the globe warrant urgent search for new anti-malarial chemotherapeutics. Traditional medicinal plants have been the main sources for screening active phytochemicals against malaria. Accordingly, this study was aimed at evaluating the anti-malarial activity of Osyris quadripartita Salzm. Ex Decne., a plant which is used for traditional malaria treatment by local people in different parts of Ethiopia.MethodsAqueous, chloroform and methanol crude leaf extracts of the plant have been prepared and tested for acute toxicity and anti-malarial efficacy in Plasmodium berghei (ANKA strain)-infected Swiss albino mice.ResultsAt three oral doses of 200, 400 and 600 mg/kg the plant material was safe, chemosuppressive and thus prevented body weight loss, hematological abnormalities and increased mice mean survival time compared to the negative control. The most efficacious extract was that of chloroform which prolonged mean mouse survival past day 11 of infection with all the mice in this group having the highest parasitemia suppression rate (41.3 %, at 600 mg/kg) although parasite clearance was not achieved compared to the standard drug (chloroquine) against the parasite.ConclusionThe finding supports the traditional use of the plant for the treatment of malaria. However, further confirmatory studies followed by isolation and characterization of the active anti-malarial compound (s) of the plant that is/are responsible for the observed parasite suppression is needed before it is recommended for malaria drug search and discovery.

In vivo antiplasmodial and toxicological effect of crude ethanol extract of Echinops kebericho traditionally used in treatment of malaria in Ethiopia.

BackgroundMedicinal plants have contributed significantly to current malaria treatment. Emergence of resistance to currently available drugs has necessitated the search for new plant-based anti-malarial agents and several plant-based, pharmacologically active anti-malarial compounds have been isolated. This study was conducted to validate the traditional usage of Echinops kebericho for treating malaria in the traditional health care system of Ethiopia.MethodsThe roots of E. kebericho were collected from Masha Woreda, Sheka Zone. After collection, the plant materials were identified by a taxonomist, dried under shade and crushed to powder for extraction. The powdered roots were extracted by maceration using 70 % ethanol. Acute toxicity study of the crude extract was carried out in Swiss albino mice. The in vivo anti-malarial activity of plant extract (200, 350 and 500 mg/kg) of E. kebericho roots against a chloroquine (CQ) sensitive strain of Plasmodium berghei strain ANKA was assessed using the four-day suppressive test procedure. Parameters such as parasitaemia, packed cell volume, body weight and survival time were then determined using standard tests.ResultsOral administration of the ethanol extract showed significant (P <0.001) parasitaemia suppression at dose levels of 350 and 500 mg/kg in dose-related manner compared with the negative control. Five hundred mg/kg showed the highest (57.29 ± 1.76 %) parasitaemia suppression. The survival times of P. berghei-infected mice were also increased in a dose-dependent manner but the test material did not prevent weight loss associated with increased parasitaemia. The result also showed the plant material prevented the loss in packed cell volume associated with increased parasitaemia. Its oral LD50 was found to be greater than 5,000 mg/kg, indicating its wider safety margin in mice.ConclusionThe result revealed the ethanol extract of E. kebericho roots has anti-malarial activity against P. berghei in an animal model and lends support to the use of the plant to combat malaria in Ethiopian folk medicine. Further work is necessary to isolate, identify and characterize the active principles from the plant material.

Discovery of new potential antimalarial compounds using virtual screening of ZINC database.

Falcipain-3 (FP-3) is a cysteine protease of the malaria parasite Plasmodium falciparum which is a promising and attractive target enzyme for antiparasitic chemotherapy. In this study, a support vector machine (SVM) model based on fingerprint-based descriptors was developed on a dataset of 239 FP-3 inhibitors to identify the most active antimalarial compounds among the active compounds provided from similarity search. The satisfactory classification performance achieved by the SVM model shows its ability to use it as a further filter to distinguish the most active compounds. The accuracy in prediction for the training, test and external validation sets were 97.39%, 94.74% and 90.6%, respectively. Furthermore, the performance of the model was examined by plotting the receiver operating characteristic (ROC) curve, and the area under the ROC curve was 0.96 for the modeling set. The ability of a virtual screening scheme to scaffold hopping or lead hopping is known as a key ability of an effective method for virtual screening. Three diverse reference FP-3 structures were chosen as active antimalarial compounds to search the lead-like database of ZINC and retrieve the most similar compounds. Compounds having Tanimoto similarity coefficient above 0.8 were extracted for further analysis by classification model. The SVM model rendered five most active compounds and they were also analyzed by ADME/Tox and diversity measures. Maximum property-based distance between extracted compounds was found to be 0.70, which shows the importance of applying multiple diverse reference compounds in the similarity searching.