Antiplasmodial and Cytotoxic Flavonoids from Pappea capensis (Eckl. & Zeyh.) Leaves

Ethnobotanical surveys indicate that the Masai and Kikuyu in Kenya, the Venda in South Africa, and the Gumuz people of Ethiopia use Pappea capensis for the treatment of malaria. The present study aimed to investigate the phytochemical and antiplasmodial properties of the plant leaves. The bioactive compounds were isolated using chromatographic techniques. The structures were established using NMR, HRMS, and UV spectroscopy. Antiplasmodial activity of P. capensis leaf extract and isolated compounds against chloroquine-sensitive 3D7 P. falciparum was evaluated using the parasite lactate dehydrogenase assay. Cytotoxicity against HeLa (human cervix adenocarcinoma) cells was determined using the resazurin assay. The extract inhibited the viability of Plasmodium falciparum by more than 80% at 50 µg/mL, but it was also cytotoxic against HeLa cells at the same concentration. Chromatographic purification of the extract led to the isolation of four flavonoid glycosides and epicatechin. The compounds displayed a similar activity pattern with the extract against P. falciparum and HeLa cells. The results from this study suggest that the widespread use of P. capensis in traditional medicine for the treatment of malaria might have some merits. However, more selectivity studies are needed to determine whether the leaf extract is cytotoxic against noncancerous cells.     

In silico 3-D structure prediction and molecular docking studies of inosine monophosphate dehydrogenase from Plasmodium falciparum

Growing resistance in malarial parasites, particularly in Plasmodium falciparum needs a serious search for the discovery of novel drug targets. Inosine monophosphate dehydrogenase (IMPDH) is an important target for antimalarial drug discovery process in P. falciparum for the treatment of malaria. In the absence of x-ray crystal structure of this enzyme, homology modeling proved to be a reasonable alternate to study substrate binding mechanisms of this enzyme. In this study, a 3-D homology model for P. falciparum IMPDH was constructed taking human IMPDH (PDB code 1NF7) as template. Furthermore, an in-silico combinatorial library of ribavirin (RVP) derivatives (1347 molecules) was designed and virtually screened for ligands having selectively greater binding affinity with Plasmodium falciparum IMPDH relative to human IMPDH II. A total of five Ribavirin derivatives were identified as having greater binding affinity (−126 to −108 Kcal/mol and −9.4 to −8.6 Kcal/mol) with Plasmodium falciparum IMPDH. These five inhibitors should be used as selective and potent for Plasmodium falciparum IMPDH. Such type of study will provide information to synthetic medicinal chemist to enhance the potential of compounds (RVP derivatives) as chemotherapeutic agents to fight against the increasing burden of malarial infections.     

Easy-To-Access Quinolone Derivatives Exhibiting Antibacterial and Anti-Parasitic Activities

The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC₉₀ values in the range of 0.24–31 µM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4–20 µM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.     

Antiplasmodial and Leishmanicidal Activities of 2-Cyano-3-(4-phenylpiperazine-1-carboxamido) Quinoxaline 1,4-Dioxide Derivatives

Malaria and leishmaniasis are two of the World's most important tropical parasitic diseases. Thirteen new 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives (CPCQs) were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against erythrocytic forms of Plasmodium falciparum and axenic forms of Leishmania infantum. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. None of the tested compounds was efficient against Plasmodium, but two of them showed good activity against Leishmania. Toxicity on VERO was correlated with leishmanicidal properties.     

Microwave-assisted Friedländer synthesis of quinolines derivatives as potential antiparasitic agents

A series of substituted quinolines was developed via the Friedländer reaction employing microwave irradiation (MW), in the presence of a catalytic amount of hydrochloric acid. The products were obtained in good yields in 1.5-12 min and were tested in vitro against the parasites causative of malaria, leishmaniasis, sleeping sickness and Chagas’ disease (TDR, WHO). Some of these compounds exhibited activity against Plasmodium falciparum and others resulted moderately active against Trypanosoma cruzi.     

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.     

Nopol-Based Quinoline Derivatives as Antiplasmodial Agents

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (2–4) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf3D7 but inactive against chloroquine-resistant strains PfK1 and PfNF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC₅₀ in the PfK1 strain. However, 8 was more than two orders of magnitude less active against Pf3D7 and PfNF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax.     

Acyl derivatives of 5-amino-2-azabicyclo[3.2.2]nonanes

5-Amino-2-azabicyclo[3.2.2]nonanes possess activity against the causative organisms of Human African trypanosomiasis and Malaria tropica. Their newly prepared N-acyl derivatives were inactive against Trypanosoma b. rhodesiense, but some of them showed good antiplasmodial activity against a multiresistant strain of Plasmodium falciparum. The results are compared to the activities of the N-unsubstituted compounds and N-sulfonyl analogues. The diastereomeric character of the formed amides was elucidated by NMR spectroscopy.     

Kororamide A,a new tribrominated indole alkaloid from the Australian bryozoan Amathia tortuosa

A new tribrominated indole alkaloid, kororamide A together with the known alkaloid convolutamine F, were isolated through the application of mass directed purification from the bryozoan, Amathia tortuosa collected from northern New South Wales, Australia. The structure of kororamide A was deduced from the analysis of 1D/2D NMR and MS data. Kororamide A exists in solution as a mixture of interconverting cis–trans amide regioisomers in a ratio of 4:5. Bioactivity testing demonstrated that kororamide A was marginally active against chloroquine-sensitive and resistant strains of the malarial parasite Plasmodium falciparum, and was inactive against normal human cell lines.     

Assay Development and Identification of the First Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase Inhibitors

In the fight towards eradication of malaria, identifying compounds active against new drug targets constitutes a key approach. Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (PfHPPK) has been advanced as a promising target, as being part of the parasite essential folate biosynthesis pathway while having no orthologue in the human genome. However, no drug discovery efforts have been reported on this enzyme. In this study, we conducted a three-step screening of our in-house antifolate library against PfHPPK using a newly designed PfHPPK-GFP protein construct. Combining virtual screening, differential scanning fluorimetry and enzymatic assay, we identified 14 compounds active against PfHPPK. Compounds’ binding modes were investigated by molecular docking, suggesting competitive binding with the HMDP substrate. Cytotoxicity and in vitro ADME properties of hit compounds were also assessed, showing good metabolic stability and low toxicity. The most active compounds displayed low micromolar IC₅₀ against drug-resistant parasites. The reported hit compounds constitute a good starting point for inhibitor development against PfHPPK, as an alternative approach to tackle the malaria parasite.     

Easily synthesized antimalarial ferrocene triazacyclononane quinoline conjugates

Starting from triazacyclononane, easily accessible ferrocenic quinoline derivatives were synthesized. Their antiplasmodial properties were investigated against chloroquine sensitive (HB3) and chloroquine-resistant (Dd2) Plasmodium falciparum. One of them, 7-chloro-4-[4-(7-chloro-4-quinolyl)-7-ferrocenylmethyl-1,4,7- triazacyclononan-1-yl]quinoline (4) showed potent antimalarial activity in vitro against the chloroquine-resistant strain Dd2 and therefore revealed to be the most promising lead from the present work for new organometallic antimalarial agents.     

Single Tryptophan of Disordered Loop from Plasmodium falciparum Purine Nucleoside Phosphorylase: Involvement in Catalysis and Microenvironment

Among various tropical diseases, malaria is a major life-threatening disease caused by Plasmodium parasite. Plasmodium falciparum is responsible for the deadliest form of malaria, so-called cerebral malaria. Purine nucleoside phosphorylase from P. falciparum is a homohexamer containing single tryptophan residue per subunit that accepts inosine and guanosine but not adenosine for its activity. This enzyme has been exploited as drug target against malaria disease. It is important to draw together significant knowledge about inherent properties of this enzyme which will be helpful in better understanding of this drug target. The enzyme shows disorder to order transition during catalysis. The single tryptophan residue residing in conserved region of transition loop is present in purine nucleoside phosphorylases throughout the Plasmodium genus. This active site loop motif is conserved among nucleoside phosphorylases from apicomplexan parasites. Modification of tryptophan residue by N-bromosuccinamide resulted in complete loss of activity showing its importance in catalysis. Inosine was not able to protect enzyme against N-bromosuccinamide modification. Extrinsic fluorescence studies revealed that tryptophan might not be involved in substrate binding. The tryptophan residue localised in electronegative environment showed collisional and static quenching in the presence of quenchers of different polarities.     

Synthesis of novel β-lactams bearing an anthraquinone moiety,and evaluation of their antimalarial activities

A novel series of β-lactams bearing an anthraquinone moiety have been synthesized from imines derived from anthraquinone-2-carbaldehyde and ketenes by a [2+2] cycloaddition reaction. The cycloadducts were fully characterized and evaluated for their antimalarial activities against Plasmodium falciparum K14 resistant strain and showed moderate to excellent EC₅₀ values varying from 9 to 50 μM.     

Ziziphine N, O, P and Q, new antiplasmodial cyclopeptide alkaloids from Ziziphus oenoplia var. brunoniana

Bioassay-guided fractionation of the EtOAc extract of the roots of Thai Ziziphus oenoplia var. brunoniana resulted in the isolation of four new 13-membered cyclopeptide alkaloids of the 5(13) type, ziziphine N-Q. The structures of the new metabolites were elucidated on the basis of spectroscopic analyses and the stereochemical assignments were established by comparison with other related compounds of known stereochemistry. Ziziphine N and Q exhibited significant antiplasmodial activity against the parasite Plasmodium falciparum with the inhibitory concentration (IC₅₀) values of 3.92 and 3.5 μg/mL, respectively. Ziziphine N and Q also demonstrated weak antimycobacterial activity against Mycobacterium tuberculosis with the same MIC value of 200 μg/mL.     

Amidomethylation of amodiaquine: antimalarial N-Mannich base derivatives

Novel N-Mannich base-type derivatives of the antimalarial drug amodiaquine were synthesised by reaction with tertiary N-chloromethylamides. With the exception of the derivative of ethyl hippurate, all the so-formed (1-amidomethyl-1H-quinolin-4-ylidene)arylamines displayed high chemical and enzymatic stability. These compounds displayed antimalarial activity against the multi-drug resistant Plasmodium falciparum strain Dd2 (IC₅₀ values 15-31 nM) and demonstrated no significant loss in activity compared to amodiaquine (IC₅₀ 30 nM).     

Synthesis of febrifuginol analogues and evaluation of their biological activities

A new series of febrifuginol analogues was prepared from l-glutamic acid. An antimalarial activity evaluation against chloroquine-sensitive (T96) and chloroquine-resistant (K1) Plasmodium falciparum indicated that all the tested compounds had very strong inhibitory activity. Compounds 4 and 17b′ were inactive against KB, MCF7, HepG2 and LU1 cell lines even at a concentration of 100 μM, while they exhibited significant inhibition towards P. falciparum. Comparison of the antimalarial activity and the cytotoxic properties revealed that the 2′S isomers were more active than the corresponding 2′R isomers for this series of febrifuginol analogues, indicating that the C-2′ position is critical for the biological activity of this class of compounds.     

Synthesis and in vitro antimalarial and antitubercular activity of gold(III) complexes containing thiosemicarbazone ligands

Gold(III) thiosemicarbazone complexes derived from [Au(damp-C¹,N)Cl₂] (2), where damp = dimeth-ylaminoethylphenyl, have been synthesized. The compounds were characterised using various spectroscopic and analytical techniques, including NMR spectroscopy, mass spectrometry, infrared spectroscopy and elemental analysis. The gold complexes were screened for in vitro antimalarial and antitubercular activity. Although incorporation of the gold(III) centre into thiosemicarbazone scaffolds enhanced their efficacy against the malaria parasite Plasmodium falciparum, this trend was not observed for the antitubercular activity of selected thiosemicarbazones against the Mycobacterium tuberculosis virulent strain H₃₇Rv.     

Antiparasite and antimycobacterial activity of passifloricin analogues

Several structural analogues of the polyketide passifloricin lactone were synthesized using asymmetric stereoselective allylations and ring-closing methateses as key reactions. These compounds were active in vitro against intracellular amastigotes of Leishmania panamensis (strain UA140), trophozoites of Plasmodium falciparum (strain NF54), and Mycobacterium tuberculosis (strain H₃₇Rv). However, in spite of the significative antiparasitic activity of some synthetic analogues a high cytotoxicity was also observed. Based on these results a lactam derivative was also synthesized. This compound maintained a good level of activity with less toxicity.     

First total synthesis of versicotide D and analogs

The first total synthesis of cyclotetrapeptide versicotide D has been achieved in 21% overall yield using solid phase peptide synthesis and solution cyclization. In addition, in the search for candidates of antimalarial new drugs, one cyclic tetrapeptide analog which differs in the sequence, and four cyclic pentapeptide containing N-methyl amino acids, were prepared. The obtained compounds were evaluated against P. falciparum 3D7. Versicotide D showed low micromolar antiplasmodial activity.     

Microwave-assisted,rapid synthesis of 2-vinylquinolines and evaluation of their antimalarial activity

A rapid and efficient synthesis of 2-vinylquinolines via trifluoromethanesulfonamide-mediated olefination of 2-methylquinoline and aldehyde under microwave irradiation is reported. Biological evaluation of these scaffolds demonstrates that 2-vinylquinolines 3x-3z possess excellent antimalarial activities against chloroquine-resistant Dd2 strain of Plasmodium falciparum (IC₅₀ < 100 nM).