Potent Antimalarial Activity Research Articles

The antimalarial activity of 1,2,4-trioxolane/trioxane hybrids and dimers: A review.

Malaria, a mosquito-borne parasitic infection caused by protozoan parasites belonging to the genus Plasmodium, is a dangerous disease that contributes to millions of hospital visits and hundreds and thousands of deaths across the world, especially in Sub-Saharan Africa. Antimalarial agents are vital for treating malaria and controlling transmission, and 1,2,4-trioxolane/trioxane-containing agents, especially artemisinin and its derivatives, own antimalarial efficacy and low toxicity with unique mechanisms of action. Moreover, artemisinin-based combination therapies were recommended by the World Health Organization as the first-line treatment for uncomplicated malaria infection and have remained as the mainstay of the treatment of malaria, demonstrating that 1,2,4-trioxolane/trioxane derivatives are useful prototypes for the control and eradication of malaria. However, malaria parasites have already developed resistance to almost all of the currently available antimalarial agents, creating an urgent need for the search of novel pharmaceutical interventions for malaria. The purpose of this review article is to provide an emphasis on the current scenario (January 2012 to January 2022) of 1,2,4-trioxolane/trioxane hybrids and dimers with potential antimalarial activity and the structure-activity relationships are also discussed to facilitate further rational design of more effective candidates.

Integrated Computational Analysis on Some Indolo-quinoline Derivatives for the Development of Novel Antiplasmodium Agents: CoMFA, Pharmacophore Mapping, Molecular Docking and ADMET Studies

Background: The development of multi-resistant strains of the Plasmodium parasite has become a global problem. Therefore, designing of new antimalarial agents is an exclusive solution. Objective: To improve the activity and identify potentially efficacious new antimalarial agents, integrated computational perspectives such as pharmacophore mapping, 3D-QSAR and docking study have been applied to a series of indolo-quinoline derivatives. Methods: The pharmacophore mapping generated various hypotheses based on key functional features and the best hypothesis ADRRR_1 revealed that indolo-quinoline scaffold is essential for antimalarial activity. 3D-QSAR model was established based on CoMFA and CoMSIA models by using 30 indolo-quinoline analogues as training set and the rest of 19 as test set. Results: The molecular field analysis (MFA) with PLS (partial least-squares) method was used to develop significant CoMFA (q2=0.756, r2=0.996) and CoMSIA (q2=0.703, r2=0.812) models. The CoMFA and CoMSIA models showed good predictive ability with r2 pred values of 0.9623 and 0.9214 respectively. Docking studies were performed by using pfLDH to identify structural insight into the active site and results signify that the quinoline nitrogen acts as a hydrogen bond acceptor region to facilitate interaction with Glu122. Finally, designed molecules were screened through the ADMET tool to evaluate the pharmacokinetic and drug-likeness parameters. Conclusion: Thus, these studies suggested that established models have good predictability and would help in the optimization of newly designed molecules that may produce potent antimalarial activity.

Bioactivities and Mode of Actions of Dibutyl Phthalates and Nocardamine from Streptomyces sp. H11809.

Dibutyl phthalate (DBP) produced by Streptomyces sp. H11809 exerted inhibitory activity against human GSK-3β (Hs GSK-3β) and Plasmodium falciparum 3D7 (Pf 3D7) malaria parasites. The current study aimed to determine DBP’s plausible mode of action against Hs GSK-3β and Pf 3D7. Molecular docking analysis indicated that DBP has a higher binding affinity to the substrate-binding site (pocket 2; −6.9 kcal/mol) than the ATP-binding site (pocket 1; −6.1 kcal/mol) of Hs GSK-3β. It was suggested that the esters of DBP play a pivotal role in the inhibition of Hs GSK-3β through the formation of hydrogen bonds with Arg96/Glu97 amino acid residues in pocket 2. Subsequently, an in vitro Hs GSK-3β enzymatic assay revealed that DBP inhibits the activity of Hs GSK-3β via mixed inhibition inhibitory mechanisms, with a moderate IC50 of 2.0 µM. Furthermore, the decrease in Km value with an increasing DBP concentration suggested that DBP favors binding on free Hs GSK-3β over its substrate-bound state. However, the antimalarial mode of action of DBP remains unknown since the generation of a Pf 3D7 DBP-resistant clone was not successful. Thus, the molecular target of DBP might be indispensable for Pf survival. We also identified nocardamine as another active compound from Streptomyces sp. H11809 chloroform extract. It showed potent antimalarial activity with an IC50 of 1.5 μM, which is ~10-fold more potent than DBP, but with no effect on Hs GSK-3β. The addition of ≥12.5 µM ferric ions into the Pf culture reduced nocardamine antimalarial activity by 90% under in vitro settings. Hence, the iron-chelating ability of nocardamine was shown to starve the parasites from their iron source, eventually inhibiting their growth.

An innovative study design with intermittent dosing to generate a GLP-regulatory package in preclinical species for long lasting molecule M5717, inhibitor of Plasmodium eukaryotic translation elongation factor 2

M5717 is a novel drug inhibiting synthesis of elongation factor 2 (PeEF2) in Plasmodium species, showing potent anti-malarial activity in preclinical studies. Traditional daily-dosing animal experiments estimating maximum safe starting dose for a first-in-human study (‘no observed adverse effect level’; NOAEL) were unsuccessful due to the long pharmacokinetic half-life of M5717, causing significant drug accumulation and high exposure. This study describes an innovative strategy to produce a GLP-certified toxicology package and estimate NOAEL for long-lasting molecules like M5717. Simulated pharmacokinetic/toxicokinetic profiles were used to design the dosing schedule for preclinical safety studies and to determine the 14-day total exposure. Animals (rats/dogs) were administered various doses of M5717 using an intermittent dosing schedule allowing partial drug elimination and alleviation of toxicity during off-treatment days to maintain a minimal parasitical concentration (MPC) of 10 ng/mL; subsequently animals were monitored for toxicity and mortality. Results showed good correlation to the modelled data used to design the dosing regimen and required MPC was reached for M5717 in study animals and could be used to calculate NOAEL. This fit-for-purpose study design allowed for maintaining clinically relevant exposure to M5717, whilst minimizing toxicity-causing compound accumulation, an aspect unaddressed by traditional NOAEL-estimating experiments. This is the first time that a compound-specific, species-specific, kinetic model-based approach to preclinical study design for regulatory toxicology studies has been described and applied to an antimalarial drug candidate with long pharmacokinetic half-life. It has potential for application to other drugs with long half-lives, supporting their clinical development.

Synthesis and antimalarial activity of amide and ester conjugates of siderophores and ozonides.

Despite advances in chemotherapeutic interventions for the treatment of malaria, there is a continuing need for the development of new antimalarial agents. Previous studies indicated that co-administration of chloroquine with antioxidants such as the iron chelator deferoxamine (DFO) prevented the development of persistent cognitive damage in surrogate models of cerebral malaria. The work described herein reports the syntheses and antimalarial activities of covalent conjugates of both natural (siderophores) and artificial iron chelators, namely DFO, ferricrocin and ICL-670, with antimalarial 1,2,4-trioxolanes (ozonides). All of the synthesized conjugates had potent antimalarial activities against the in vitro cultures of drug resistant and drug sensitive strains of Plasmodium falciparum. The work described herein provides the basis for future development of covalent combination of iron chelators and antimalarial chemotherapeutic agents for the treatment of cerebral malaria.

Evaluation of the antimalarial activity and toxicity of Mahanil-Tang-Thong formulation and its plant ingredients

BackgroundNovel potent antimalarial agents are urgently needed to overcome the problem of drug-resistant malaria. Herbal treatments are of interest because plants are the source of many pharmaceutical compounds. The Mahanil-Tang-Thong formulation is a Thai herbal formulation in the national list of essential medicines and is used for the treatment of fever. Therefore, this study aimed to evaluate the antimalarial activity of medicinal plants in the Mahanil-Tang-Thong formulation.MethodsNine medicinal plant ingredients of the Mahanil-Tang-Thong formulation were used in this study. Aqueous and ethanolic extracts of all the plants were analyzed for their phytochemical constituents. All the extracts were used to investigate the in vitro antimalarial activity against Plasmodium falciparum K1 (chloroquine-resistant strain) by using the lactate dehydrogenase (pLDH) method and cytotoxicity in Vero cells by using the 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Additionally, an extract with potent in vitro antimalarial activity and no toxicity was selected to determine the in vivo antimalarial activity with Peters’ 4-day suppressive test against the Plasmodium berghei ANKA strain. Acute toxicity was evaluated in mice for 14 days after the administration of a single oral dose of 2000 mg/kg.ResultsThis study revealed that ethanolic extracts of Sapindus rarak DC., Tectona grandis L.f., Myristica fragrans Houtt. and Dracaena loureiri Gagnep. exhibited potent antimalarial activity, with half-maximal inhibitory concentration (IC50) values of 2.46, 3.21, 8.87 and 10.47 μg/ml, respectively, while the ethanolic of the formulation exhibited moderate activity with an IC50 value of 37.63 μg/ml and its aqueous extract had no activity (IC50 = 100.49 μg/ml). According to the in vitro study, the ethanolic wood extract of M. fragrans was selected for further investigation in an in vivo mouse model. M. fragrans extract at doses of 200, 400, and 600 mg/kg body weight produced a dose-dependent reduction in parasitemia by 8.59, 31.00, and 52.58%, respectively. No toxic effects were observed at a single oral dose of 2000 mg/kg body weight.ConclusionThis study demonstrates that M. fragrans is a potential candidate for the development of antimalarial agents.

In Vitro Antimalarial Activity and Phytochemical Analysis of Aerial Parts of Artemisia fragrans Willd.

Background: Malaria is one of the most momentous transmittable diseases globally. Medicinal herbs like Artemisia species might be possible sources of new, effective, and cheap antiplasmodial products, making up the leading molecules to investigate new antimalarial drugs. The Artemisia genus, which belongs to the Asteraceae family, is a widely distributed medicinal plant in Iran. Methods: In this study, the antimalarial activities of essential oil, different extracts, and vacuum liquid chromatography (VLC) fractions of A. fragrans Willd. were examined by a cell-free β-hematin formation assay. The aerial parts of A. fragrans were extracted by a Soxhlet extractor, and essential oil was obtained by a Clevenger apparatus. Then, GC-MS analysis was used to identify volatile compounds of essential oil and the 100% VLC fraction of chloroform. Results: Among the extracts, chloroform extract illustrated considerable antimalarial activity compared to the control (P < 0.001), with the IC50 value of 1.22 ± 0.05 mg/mL. Among the fractions, 100% VLC fraction of chloroform extract illustrated potent antimalarial effects compared to the control (P < 0.001). The volatile oil demonstrated moderate antimalarial effects (P < 0.001) compared with the control. Besides, GC-MS determined that sesquiterpenes in the 100% ethyl acetate fraction of the chloroform extract and oxygenated monoterpenes in the essential oil might be responsible for the potent antimalarial activity of this plant. Conclusions: The 100% ethyl acetate fraction of chloroform extract along with the essential oil of A. fragrans indicated potent and moderate activity, possibly due to sesquiterpenes and oxygenated monoterpenes, respectively.

Biologically active mixed ligand complexes of Co(II), Ni(II), Cu(II) and Zn(II) as potential antimalarial, antidibetic and anticancer agents

Mixed ligand complexes of transition metal ions Co(II), Ni(II), Cu(II) and Zn(II) were synthesized using bidentate Schiff’s base (E)-2-((benzo[d]thiazol-2-yliminomethyl)-6-methoxyphenol (L1), derived from condensation reaction of 2-aminobenzothiazole and 2-hydroxy-3-methoxybenzaldehyde, and 5-Chloro-8-hydroxyquinoline (5CHQ) (L2) as ligands. All the synthesized compounds were characterized using elemental analysis, IR, electronic, 1H and 13C NMR spectra, TGA-DTA and Powder XRD analysis, molar conductivity and magnetic susceptibility measurements. Based on the results obtained all the synthesized complexes are proposed to have tetrahedral geometry. All the synthesized compounds were screened for their antioxidant, antimicrobial, antimalarial, antidibetic, anticancer activities and cytotoxicity study using MTT assay. The complexes are proposed to have potential antimalarial, antidibetic and anticancer activities.

Synthesis, biological evaluation, Structure − Activity relationship studies of quinoline-imidazole derivatives as potent antimalarial agents

In our efforts to identify novel chemical scaffolds for the development of antimalarial agents, a series of quinoline − imidazole hybrid compounds were synthesized and their blood-stage antimalarial activity was evaluated in both drug-sensitive and –multi drug-resistant (MDR) P. falciparum strains. The new analogs possess sub-micromolar activities against Plasmodium falciparum. Among all synthesized derivatives, 11(xxxii) exhibited significant antimalarial efficacy in-vitro against both CQ-sensitive (IC50-0.14 μM) and MDR strain (IC50- 0.41 μM) with minimal cytotoxicity and high selectivity. Structure-activity relationships revealed that Br and OMe substitutions on quinoline ring improved the antimalarial activity and selectivity index. The role of stereochemistry in the inhibitory activity was assessed by enantiomeric separation of a racemic mixture of 11(xxxii). The enantiomer (−)-11(xxxii) had potent antimalarial activity over the other isomer, with IC50 of 0.10 µM.

Effect of Cymbopogon citratus and Piliostigma reticulatum Aqueous Leaf Extracts on Rat Liver Function and In vitro Schizont Maturation Inhibition

The most severe form of malaria is caused by the parasite Plasmodium falciparum, which undergoes antigenic variation. However, plant products continue to make an immense contribution to malaria chemotherapy. In this research, the inhibitory effect of C. citratus and P. reticulatum on schizont maturation was investigated using in vitro assay. Also, effect of the extract on some enzymatic and non-enzyme liver function parameters was determined after sub-chronic oral administration of the extracts to albino rats. From the result it was observed that C. citratus and P. reticulatum extract inhibited schizont growth with an IC50 of 7.25 mg/L and 3.25 mg/L, respectively. The dosage (250, 750 and 1500 mg/kg) of both plants administered to experimental rats significantly (p<0.05) increased the enzymatic parameters (AST, ALT and ALP) and non-enzymatic parameters (serum total proteins, albumin, total bilirubin and conjugated bilirubin) of liver function indices particularly at the high doses of 750 and 1500 mg/kg when compared with the control value. The finding of this research demonstrates that although C. citratus and P. reticulatum extract may have potential antimalarial activity but may have the potential to be hepatotoxic.

Assessment of the activities of Chasmanthera dependens Hochst. combined with other plants on chloroquine-sensitive and chloroquine-resistant Plasmodium berghei

The prevalence of Plasmodium strains resistant to conventional monotherapy drugs has necessitated the need for more effective and affordable antimalarial agents. This study aimed at evaluating the antimalarial activities of some indigenous plants alone and in combination with chloroquine with a view to proffering herbal combination therapy as an alternative to the currently used antimalarial combination therapy. Extracts obtained separately from the decoctions of the roots of Chasmanthera dependens Hochst. (Menispermaceae), Vernonia amygdalina Delile (Asteraceae) and methanol extract of Sphenocentrum jollyanum Pierre (Menispermaceae) leaf were analysed by high resolution liquid chromatography-mass spectrometry and evaluated for repeated-dose oral toxicity in mice using standard protocols. Assessments of C. dependens and V. amygdalina with their combination were carried out on chloroquine-sensitive Plasmodium-infected mice with the 4-day chemosuppressive antimalarial test. Sphenocentrum jollyanum, C. dependens and their combinations with chloroquine (10 mg/kg) were assessed on chloroquine-resistant Plasmodium using the curative test model. The combination of C. dependens and V. amygdalina exhibited chemosuppression (71.1±3.7%) that was not significantly (p>0.05) different from chloroquine (80.1±1.9%). In the curative model, a significant parasite clearance (98.2%) was observed with the combination of C. dependens and chloroquine. The study concluded that the aqueous root extracts possessed potent antimalarial activity in chloroquine-sensitive malaria infection. It also revealed an additive interaction between C. dependens and chloroquine that could be further investigated as a herbal combination for chloroquine-resistant malaria.

The Changing Global Landscape in the Development of Artemisinin-Based Treatments: A Clinical Trial Perspective.

Artemisinin and its derivatives (ARTs), due to their potent antimalarial activities, are widely used as frontline antimalarials across the world. Although the large-scale deployment of ARTs has significantly contributed to a substantial decline in malaria deaths, the global malaria burden is still high. New antimalarial treatments need to be developed to manage the growing artemisinin resistance. Understanding the status of ART development is crucial for developing strategies for new alternatives and identifying opportunities to develop ART-based treatments. This study sampled ART clinical trials from the past two decades to gain an overview of the global ART-development landscape. A total of 768 trials were collected to analyze the disease focuses, activity trends, development status, geographic distribution, and combination treatment profiles of ART trials. The findings highlighted the constant focus of ARTs on malaria, the evolving combination research focus, the distinctions between ART development preferences across global regions, the urgent demands for treatments for artemisinin-resistant malaria, and the unavoidable need to consider ART combinations in the development of new antimalarials.

Evaluation of the Potency and Safety of Model Clinic Polyherbal Anti-Malaria Tea

Background: The Model Clinic Antimalaria Tea (AMT) is a product of the Herbal Clinic unit, Department of Pharmacognosy, University of Lagos. Its ingredients are the dried and powdered leaves of Mangifera indica, Psidium guajava, Carica papaya and Cymbopogon citratus. Objective: The objective of this study is to evaluate the potency and safety of AMT. Materials and methods: AMT was assessed for antimalarial activity against chloroquine- sensitive Plasmodium bergheii NK65 – infected mice using the suppressive and the curative test procedures at its half, full and double the prescribed dose (3.45, 6.90, and 13.80 mg kg-1 respectively). Chloroquine 5 mg kg-1 (CQ) was used as positive control while water was the normal control. The test parameters were parasitaemia, weight, PCV and temperature. AMT safety was assessed by acute toxicity test and microbial limit (using the pour plate method) and heavy metals limit test (using spectrophotometry). Results: All the treated groups, except water, showed curative and suppressive antimalarial activity in the following order: CQ > AMT 13.80 mg kg-1 > AMT 6.90 mg kg-1 > 3.45 mg kg-1 which is dose-dependent. Oral administration of AMT at a dose of 4,000 mg kg-1 produced no noticeable deleterious effect. The microbial load and heavy metals content were within passable official limits. Arsenic and Mercury were not detected while Copper, Lead and Zinc occurred in 0.576 ppm, 0.108 ppm and 0.673 ppm respectively. Conclusion: AMT has been shown to exhibit potent and dose-dependent anti-malarial activity against P. bergheii and it is also safe for consumption.

Synthesis of novel aminoquinolines with potential leishmanicidal and antimalarial biological activity / Síntese de novas aminoquinolinas com potencial actividade biológica leishmanicida e antimalárica

Leishmaniasis is a disease transmitted by different parasite species of the genus Leishmania, while malaria, by protozoa of the genus Plasmodium sp. These diseases affect tropical and subtropical regions, where about half of the world's population live. However, leishmaniasis and malaria are considered neglected diseases because these regions are poor, and consequently have precarious essential sanitation networks. In response to the lack of vaccines and effective medical measures, some natural and synthetic medicines are used as forms of treatment, such as quinoline derivatives necessary to treat malaria. Even so, the parasites have shown resistance to forms of treatment, which makes needed the constant development of new drugs with potential against them. Quinoline derivatives, chloroquine analogues, have potential activity for the diseases of interest, while anilines are molecules used in nucleophilic reactions on different substrates. Therefore, the work consisted of exploring the synthesis between these two compounds through subsequent reactions involving the formation of intermediates that resulted in the products of interest. Twelve novel derivatives with potential leishmanicidal and antimalarial biological activity were synthesized. The molecules produced were purified and rightly characterized by several methods, such as mass spectrometry, infrared spectroscopy, and Nuclear Magnetic Resonance of Carbon (13C) and Hydrogen (1H). Also, were obtained the melting points of the synthesized molecules. Finally, all products were sent for biological tests against the parasites, getting highly effective results for the protozoa responsible for leishmaniasis.

Dihydrolucilactaene, a Potent Antimalarial Compound from Fusarium sp. RK97-94.

A recently discovered secondary metabolism regulator, NPD938, was used to alter the secondary metabolite profile in Fusarium sp. RK97-94. Three lucilactaene analogues were detected via UPLC-ESI-MS analysis in NPD938-treated culture. The three metabolites were successfully purified and identified as dihydroNG391 (1), dihydrolucilactaene (2), and 13α-hydroxylucilactaene (3) via extensive spectroscopic analyses. DihydroNG391 (1) exhibited weak in vitro antimalarial activity (IC50 = 62 μM). In contrast, dihydrolucilactaene (2) and 13α-hydroxylucilactaene (3) showed very potent antimalarial activity (IC50 = 0.0015 and 0.68 μM, respectively). These findings provide insight into the structure-activity relationship of lucilactaene and its analogues as antimalarial lead compounds.

Appraisal of Bioactive Compounds of Betel Fruit as Antimalarial Agents by Targeting Plasmepsin 1 and 2: A Computational Approach.

In many countries, the fruit of betel (Piper betle Linn) is traditionally used as medicine for treating malaria. It is a fatal disease, and existing medications are rapidly losing potency, necessitating the development of innovative pharmaceutics. The current study attempted to determine the compounds in the n-hexane fraction of betel fruit extract and investigate the potential inhibition of bioactive compounds against aspartic protease plasmepsin 1 (PDB ID: 3QS1) and plasmepsin 2 (PDB ID: 1LEE) of Plasmodium falciparum using a computational approach. The ethanol extract was fractionated into n-hexane and further analyzed using gas chromatography-mass spectrometry (GC-MS) to obtain information regarding the compounds contained in betel fruit. Each compound’s potential antimalarial activity was evaluated using AutoDock Vina and compared to artemisinin, an antimalarial drug. Molecular dynamics simulations (MDSs) were performed to evaluate the stability of the interaction between the ligand and receptors. Results detected 20 probable compounds in the n-hexane extract of betel fruit based on GC-MS analysis. The docking study revealed that androstan-17-one,3-ethyl-3-hydroxy-, (5 alpha)- has the highest binding affinity for plasmepsin 1 and plasmepsin 2. The compound exhibits a similar interaction with artemisinin at the active site of the receptors. The compound does not violate Lipinski’s rules of five. It belongs to class 5 toxicity with an LD50 of 3000 mg/kg. MDS results showed stable interactions between the compound and the receptors. Our study concluded that androstan-17-one,3-ethyl-3-hydroxy-, (5 alpha)- from betel fruit has the potential to be further investigated as a potential inhibitor of the aspartic protease plasmepsin 1 and plasmepsin 2 of Plasmodium falciparum.

Rational drug design, synthesis, and biological evaluation of novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamides as potential antimalarial, antifungal, and antibacterial agents

ObjectiveSulfanilamide, sulfadiazine, and dapsone were the first sulfonamides to be used to treat malaria by disrupting the folate biosynthesis process, which is essential for parasite survival. Therefore, we aimed to synthesize novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives through a rational drug design approach. MethodsAll compounds were synthesized by the conventional method, and the products were characterized by spectral analysis (1H NMR and mass spectrometry). The progression of the reaction was monitored using thin-layer chromatography (TLC). All the derivatives were analyzed for their effective binding mode in the allosteric site of the plasmodium cysteine protease falcipain-2. Antibacterial and antifungal activities were determined using the broth dilution method. ResultsS6 (N-(2-thiazol-4yl)-acetyl-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S9 (N-(1H-benzo[d]imidazol-2-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed five hydrogen bonds; S8 (N-(2-1H-imidazol-2yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S10 (N-(1H-benzo[d]imidazol-5-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed four hydrogen bonds with the allosteric site of the enzyme. Considering the docking scores and formation of hydrogen bonds with the target enzyme, the novel derivatives were processed for wet lab synthesis. All the newly synthesized derivatives were subjected to in vitro antimalarial, antifungal, and antibacterial activities. All the derivatives exhibited sufficient sensitivity to the Plasmodium falciparum strain compared to the standards. Moreover, compounds S9 and S10 showed the most potent dual antimicrobial and antimalarial activities. They also exhibited powerful molecular interactions in molecular docking studies. ConclusionBased on the above results, it was concluded that N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives have excellent biological potential to act as antimalarial, antifungal, and antibacterial agents.

Synthesis and in silico ADME/Tox profiling studies of heterocyclic hybrids based on chloroquine scaffolds with potential antimalarial activity.

A series of heterocyclic chloroquine hybrids containing either a β-phenethylamine fragment or a 2-aminoindane moiety were synthesized and screened in vitro as inhibitors of β-hematin formation and in vivo for their antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA. Although these new compounds were not found to be more active than chloroquine in vivo, all new compounds significantly reduced heme crystallization with IC50 values < 1 μM. Compounds 12 and 13 were able to inhibit heme crystallization with IC50 values of 0.39 ± 0.09 and 0.48 ± 0.02 μM, respectively, and these values were comparable to that of chloroquine with an IC50 value of 0.18 ± 0.03. It was also determined that the physicochemical and pharmacokinetic properties were moderately favorable after in silico evaluation, derivatives 8 and 10 did not present hepatotoxicity, and the in vitro hemolytic activity against red blood cells was found to be low. Spectral (infrared, nuclear magnetic resonance, and elemental analysis) data for all final compounds were consistent with the proposed structures.

Novel Dual Acting Antimalarial Antileishmanial Agents Derived from Pyrazole Moiety

Malaria and leishmaniasis are two highly detrimental parasitic diseases with a global impact. Attempts to eradicate malaria and control leishmaniasis are generally unsuccessful due to the rapidly developing resistance to currently used drug therapy. The pyrazole ring is a key moiety reported to have a variety of biological activities. The current study aimed to design, synthesize and evaluate an array of pyrazole derivatives for potential antimalarial antileishmanial activity. The scheme for the synthesis of the pyrazole derivatives is presented. The antimalarial activity was assessed in-vivo on P. berghei ANKA infected mice to determine % parasitemia and mean survival time. The antileishmanial activity was assessed in-vitro, and IC50 for each compound was calculated. In-vivo acute toxicity and molecular docking on putative antimalarial and antileishmanial drug targets were performed using the most active compounds. All the derivatives exhibited significant antimalarial activity, the highest being 95% suppression of parasitemia with compounds 9a and 9b. The mean survival time of mice treated with these two compounds was also the highest (16-17 days) but was lower than chloroquine, the standard agent. Compounds 9a and 9b exhibited superior antileishmanial activity as compared to miltefosine. However, they were less potent than amphotericin. The compounds were safe and well-tolerated at toxic, oral and intraperitoneal, doses of 150mg/kg and 75mg/kg, respectively. Molecular docking of compound 9a revealed a good fitting pose with plasmodial Pf-DHFR enzyme and Lm-PTR1 enzyme, which explains the biological activity noted with this compound. Pyrazole derivatives 9a and 9b exhibited substantial dual antimalarial antileishmanial activity and may be a valuable scaffold for the design of further derivatives with antiprotozoal potential.

A non-reactive natural product precursor of the duocarmycin family has potent and selective antimalarial activity

We identify a selective nanomolar inhibitor of blood-stage malarial proliferation from a screen of microbial natural product extracts. The responsible compound, PDE-I2, is a precursor of the anticancer duocarmycin family that preserves the class's sequence-specific DNA binding but lacks its signature DNA alkylating cyclopropyl warhead. While less active than duocarmycin, PDE-I2 retains comparable antimalarial potency to chloroquine. Importantly, PDE-I2 is >1,000-fold less toxic to human cell lines than duocarmycin, with mitigated impacts on eukaryotic chromosome stability. PDE-I2 treatment induces severe defects in parasite nuclear segregation leading to impaired daughter cell formation during schizogony. Time-of-addition studies implicate parasite DNA metabolism as the target of PDE-I2, with defects observed in DNA replication and chromosome integrity. We find the effect of duocarmycin and PDE-I2 on parasites is phenotypically indistinguishable, indicating that the DNA binding specificity of duocarmycins is sufficient and the genotoxic cyclopropyl warhead is dispensable for the parasite-specific selectivity of this compound class.