A Water-Soluble Polymer-Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria.

Uncomplicated malaria is effectively treated with oral artemisinin-based combination therapy (ACT). Yet, there is an unmet clinical need for the intravenous treatment of the more fatal severe malaria. There is no combination intravenous therapy for uncomplicated due to the nonavailability of a water-soluble partner drug for the artemisinin, artesunate. The currently available treatment is a two-part regimen split into an intravenous artesunate followed by the conventional oral ACT . In a novel application of polymer therapeutics, the aqueous insoluble antimalarial lumefantrine is conjugated to a carrier polymer to create a new water-soluble chemical entity suitable for intravenous administration in a clinically relevant formulation . The conjugate is characterized by spectroscopic and analytical techniques, and the aqueous solubility of lumefantrine is determined to have increased by three orders of magnitude. Pharmacokinetic studies in mice indicate that there is a significant plasma release of lumefantrine and production its metabolite desbutyl-lumefantrine (area under the curve of metabolite is ≈10% that of the parent). In a Plasmodium falciparum malaria mouse model, parasitemia clearance is 50% higher than that of reference unconjugated lumefantrine. The polymer-lumefantrine shows potential for entering the clinic to meet the need for a one-course combination treatment for severe malaria.

A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine.

Late-stage modification of drug molecules is a fast method to introduce diversity into the already biologically active scaffold. A notable number of analogs of mefloquine, chloroquine, and hydroxychloroquine have been synthesized, starting from the readily available active pharmaceutical ingredient (API). In the current review, all the modifications sites and reactivity types are summarized and provide insight into the chemistry of these molecules. The approaches include the introduction of simple groups and functionalities. Coupling to other drugs, polymers, or carriers afforded hybrid compounds or conjugates with either easily hydrolyzable or more chemically inert bonds. The utility of some of the compounds was tested in antiprotozoal, antibacterial, and antiproliferative assays, as well as in enantiodifferentiation experiments.

Novel hydrazone derivatives of N-amino-11-azaartemisinin with high order of antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via intramuscular route.

Novel hydrazone derivatives 10a-m were prepared from N-Amino-11-azaartemisinin (9) and screened for their antimalarial activity by oral and intramuscular (i.m.) routes against multidrug-resistant Plasmodium yoelii in Swiss mice model. Several of the hydrazone derivatives showed higher order of antimalarial activity. Compounds 10b, 10g, 10m provided 100% protection to the infected mice at the dose of 24 mg/kg × 4 days via oral route. Fluorenone based hydrazone 10m the most active compound of the series, provided 100% protection at the dose of 6 mg/kg × 4 days via intramuscular route and also provided 100% protection at the dose of 12 mg/kg × 4 days via oral route. While artemisinin gave 100% protection at 48 mg/kg × 4 days and only 60% protection at 24 mg/kg × 4 days via intramuscular (i.m.) route. Compound 10m found to be four-fold more active than artemisinin via intramuscular route.

Total Syntheses of Strasseriolide A and B, Antimalarial Macrolide Natural Products.

We report the first total syntheses of strasseriolide A and B. Strasseriolide B shows potent activity against the wild-type malaria parasite Plasmodium falciparum and good activity against a chloroquine-resistant strain. A convergent strategy was envisioned with an aldehyde-acid fragment and a vinyl iodide-alcohol fragment. Both fragments were prepared using chiral pool starting materials. They were combined with a Yamaguchi esterification and cyclized with a Nozaki-Hiyama-Kishi reaction. Strasseriolide B was assembled in a 16-step LLS.

Structure-activity and structure-property relationship studies of spirocyclic chromanes with antimalarial activity.

Malaria is a prevalent and lethal disease. The fast emergence and spread of resistance to current therapies is a major concern and the development of a novel line of therapy that could overcome, the problem of drug resistance, is imperative. Screening of a set of compounds with drug/natural product-based sub-structural motifs led to the identification of spirocyclic chroman-4-one 1 with promising antimalarial activity against the chloroquine-resistant Dd2 and chloroquine-sensitive 3D7 strains of the parasite. Extensive structure-activity and structure-property relationship studies were conducted to identify the essential features necessary for its activity and properties.

Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity.

Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100.17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties.

Adenine Modification at C7 as a Viable Strategy to Potentiate the Antimalarial Activity of Quinolones.

Although many quinolones have shown promise as potent antimalarials, their clinical development has been slow due to poor performance in vivo. Insights into structural modifications that can improve their therapeutic potential will be very valuable in this vibrant area of research. Our studies involving a library of quinolones which vary in substitution pattern at N1, C3, C6 and C7 positions have shown that the presence of adenine moiety at C7 can bring a noticeable improvement in activity compared to other heterocyclic groups at this location. The most potent compound emerged from this study showed IC50 values of 0.38 µM and 0.75 µM against chloroquine-sensitive and -resistant (W2) strains, respectively. Docking analysis in the Qo site of cytochrome bc1 complex revealed the contribution of a key H-bonding interaction from the adenine unit in target binding. This corroborates with compound-induced loss of mitochondrial functions. These findings not only open avenues for further exploration of antimalarial potential of adenine-modified quinolones, but also suggests broader opportunities during lead-optimization against other antimalarial targets.

Anti-plasmodial activity of aqueous neem leaf extract mediated green synthesis-based silver nitrate nanoparticles.

The objective of this study is to synthesize neem-silver nitrate nanoparticles (neem-AgNPs) using aqueous extracts of Azadirachta indica A. Juss for malaria therapy. Neem leaves collected from FRIM Malaysia were authenticated and extracted using Soxhlet extraction method. The extract was introduced to 1 mM of silver nitrate solution for neem-AgNPs synthesis. Synthesized AgNPs were further characterized by ultraviolet-visible spectroscopy and the electron-scanning microscopy. Meanwhile, for the anti-plasmodial activity of the neem-AgNPs, two lab-adapted Plasmodium falciparum strains, 3D7 (chloroquine-sensitive), and W2 (chloroquine-resistant) were tested. Red blood cells hemolysis was monitored to observe the effects of neem-AgNPs on normal and parasitized red blood cells. The synthesized neem-AgNPs were spherical in shape and showed a diameter range from 31-43 nm. When compared to aqueous neem leaves extract, the half inhibitory concentration (IC50) of the synthesized neem-AgNPs showed a four-fold IC50 decrease against both parasite strains with IC50 value of 40.920 µg/mL to 8.815 µg/mL for 3D7, and IC50 value of 98.770 µg/mL to 23.110 µg/mL on W2 strain. The hemolysis assay indicates that the synthesized neem-AgNPs and aqueous extract alone do not have hemolysis activity against normal and parasitized red blood cells. Therefore, this study shows the synthesized neem-AgNPs has a great potential to be used for malaria therapy.

Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria.

Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multi-drug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. The currently ongoing preclinical studies have demonstrated that combination therapy is a potent approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to exhibit potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria.

Synthesis, Molecular Docking and Antiplasmodial Activities of New Tetrahydro-ß-Carbolines.

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-ß-carbolines were designed, synthesized by the Pictet-Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.

Structure-activity relationship and molecular modelling studies of quinazolinedione derivatives MMV665916 as potential antimalarial agent.

A series of new quinazolinedione derivatives have been readily synthesized and evaluated for their in vitro antiplasmodial growth inhibition activity. Most of the compounds inhibited P. falciparum FcB1 strain in the low to medium micromolar concentration. The 2-ethoxy 8ag', 2-trifluoromethoxy 8ai' and 4-fluoro-2-methoxy 8ak' showed the best inhibitory activity with EC50 values around 5 µM and were non-toxic to the primary human fibroblast cell line AB943. However, these compounds were less potent than the original hit MMV665916, which showed remarkable growth inhibition with EC50 value of 0.4 µM and presented the highest selectivity index (SI > 250). In addition, a novel approach for determining the docking poses of these quinazolinedione derivatives with their potential protein target, the P. falciparum farnesyltransferase PfFT, was investigated.

1,2,3-Triazole derivatives: synthesis, docking, cytotoxicity analysis and in vivo antimalarial activity.

Malaria remains one of the most important parasitic diseases in the world. The multidrug-resistant Plasmodium strains make the treatment currently available for malaria less effective. Therefore, the development of new drugs is necessary to overcome therapy resistance. Triazole derivatives exhibit several biological activities and provide a moiety that is promising from the biological perspective. Due to the structural similarity to NADH, it is believed that triazoles can bind to the active site of the Plasmodium lactate dehydrogenase (pLDH) enzyme. The present work evaluates the antimalarial activity of 1,2,3-triazole derivatives by in silico, in vitro, and in vivo studies. Preliminary in silico ADMET studies of the compounds demonstrated good pharmacokinetic properties. In silico docking analysis against LDH of Plasmodium berghei (PbLDH) showed that all compounds presented interactions with the catalytic residue in the active site and affinity similar to that presented by chloroquine; the most common antimalarial drug. Cytotoxicity and hemolysis by these derivatives were evaluated in vitro. The compounds 1, 2, 5, 8, and 9 proved to be non-cytotoxic in the performed tests. In vivo antimalarial activity was evaluated using mice infected with Plasmodium berghei NK65. The five compounds tested exhibited antimalarial activity until nine days post-infection. The compound 5 showed promising activities, with about 70% parasitemia suppression. Considering the in vitro and in vivo studies, we believe the compound 5 to be the most promising molecule for further studies in antimalarial chemotherapy.

8-Amino-6-Methoxyquinoline-Tetrazole Hybrids: Impact of Linkers on Antiplasmodial Activity.

A new series of compounds was prepared from 6-methoxyquinolin-8-amine or its N-(2-aminoethyl) analogue via Ugi-azide reaction. Their linkers between the quinoline and the tert-butyltetrazole moieties differ in chain length, basicity and substitution. Compounds were tested for their antiplasmodial activity against Plasmodium falciparum NF54 as well as their cytotoxicity against L-6-cells. The activity and the cytotoxicity were strongly influenced by the linker and its substitution. The most active compounds showed good activity and promising selectivity.

A review of synthetic bioactive tetrahydro-ß-carbolines: A medicinal chemistry perspective.

1, 2, 3, 4-Tetrahydro-ß-carboline (THßC) scaffold is widespread in many natural products (NPs) and synthetic compounds which show a variety of pharmacological activities. In this article, we reviewed the design, structures and biological characteristics of reported synthetic THßC compounds, and structure and activity relationship (SAR) of them were also discussed. This work might provide a reference for subsequent drug development based on THßC.

Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials.

Twenty eight new N2,N4-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC50 of 0.66 µM at the 3D7 strain and a selectivity (SI) of ~ 40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low experimental logD7.4 (2.27), reasonable solubility (124 µg/ml), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compounds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homology modelling and molecular docking were used to evaluate whether compounds could indeed bind to these targets with valid binding modes. In vitro biological testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.

Novel naphthyl based 1,2,4-trioxanes: Synthesis and in vivo efficacy in the Plasmodium yoelii nigeriensis in Swiss mice.

A new series of 1,2,4-trioxanes 9a1-a4, 9b1-b4, 10-13 and 9c1-c4 were synthesized and evaluated against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via oral and intramuscular (i.m.) routes. Adamantane-based trioxane 9b4, the most active compound of the series, provided 100% protection to the infected mice at the dose 48 mg/kg × 4 days and 100% clearance of parasitemia at the dose 24 mg/kg × 4 days via oral route. Adamantane-based trioxane 9b4, is twice active than artemisinin. We have also studied the photooxygenation behaviour of allylic alcohols 6a-b (3-(4-alkoxynaphthyl)-but-2-ene-1-ols) and 6c (3-[4-(tert-butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-but-2-en-1-ol). Being behaving as dienes, they furnished corresponding endoperoxides, while behaving as allylic alcohols, they yielded ß-hydroxyhydroperoxides. All the endoperoxides (7a-c) and ß-hydroxyhydroperoxides (8a-c) have been separately elaborated to the corresponding 1,2,4-trioxanes, except from endoperoxide 7c. It is worthy to note that TBDMS protected naphthoyl endoperoxide 7c unable to deliver 1,2,4-trioxane, which demonstrated the strength of the O-Si bond is not easy to cleave under acidic condition.

Optimisation of 2-(N-phenyl carboxamide) triazolopyrimidine antimalarials with moderate to slow acting erythrocytic stage activity.

Malaria is a devastating parasitic disease caused by parasites from the genus Plasmodium. Therapeutic resistance has been reported against all clinically available antimalarials, threatening our ability to control the disease and therefore there is an ongoing need for the development of novel antimalarials. Towards this goal, we identified the 2-(N-phenyl carboxamide) triazolopyrimidine class from a high throughput screen of the Janssen Jumpstarter library against the asexual stages of the P. falciparum parasite. Here we describe the structure activity relationship of the identified class and the optimisation of asexual stage activity while maintaining selectivity against the human HepG2 cell line. The most potent analogues from this study were shown to exhibit equipotent activity against P. falciparum multidrug resistant strains and P. knowlesi asexual parasites. Asexual stage phenotyping studies determined the triazolopyrimidine class arrests parasites at the trophozoite stage, but it is likely these parasites are still metabolically active until the second asexual cycle, and thus have a moderate to slow onset of action. Non-NADPH dependent degradation of the central carboxamide and low aqueous solubility was observed in in vitro ADME profiling. A significant challenge remains to correct these liabilities for further advancement of the 2-(N-phenyl carboxamide) triazolopyrimidine scaffold as a potential moderate to slow acting partner in a curative or prophylactic antimalarial treatment.

Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones.

Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.

An overview of triazoloquinazolines: Pharmacological significance and recent developments.

Nitrogen heterocyclic rings have participated to constitute most of the drugs and several pharmacologically related compounds. The existence of such hetero atoms/groups in heterocyclic systems privileged specificities in their biological objectives. Particularly, quinazoline and triazole are biologically imperative platforms known to be linked with various pharmacological activities. Some of the prominent pharmacological responses ascribed to these systems are analgesic, antiinflammatory, anticonvulsant, hypnotic, antihistaminic, antihypertensive, anticancer, antimicrobial, antitubercular, antiviral and antimalarial activities. This diversity in the pharmacological outputs for both triazole and quinazoline systems has encouraged the medicinal chemistry researchers to create several chemical routes aiming at the incorporation of two rings in one molecule named triazoloquinazoline system. This system has shown multiple potential activities against numerous targets. Correlation the specific structural features of triazoloquinazoline system with its pharmacological purposes has successively been achieved by performing several pharmacological examinations and structure-activity relationship studies. The development of triazoloquinazoline derivatives and the understanding of their pharmacological targets offer opportunities for novel therapeutics. This review mainly emphases on the medicinal chemistry aspects of triazoloquinazolines including synthesis, reactivity, biological activity and structure activity relationship studies (SARs). Moreover, this review collates literature reported by researchers on triazoquinazolines and provides detailed attention on their analogs pharmacological activities in the perspective of drug development and discovery.

Synthesis of novel 1,2,4-trioxanes and antimalarial evaluation against multidrug-resistant Plasmodium yoelii nigeriensis.

Malaria epidemics represent one of the life-threatening diseases to low-income lying countries which subsequently affect the economic and social condition of mankind. In continuation in the development of a novel series of 1,2,4-trioxanes 13a1-c1, 13a2-c2, and 13a3-c3 have been prepared and further converted into their hemisuccinate derivatives 14a1-c1, 14a2-c2, and 14a3-c3 respectively. All these new compounds were evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in mice by both oral and intramuscular (im) routes. Hydroxy-functionalized trioxane 13a1 showed 80% protection and its hemisuccinate derivative 14a1 showed 100% protection at a dose of 48 mg/kg × 4 days by both routes, which is twice active than artemisinin by oral route.