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1.
BMC Res Notes ; 14(1): 264, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238361

RESUMO

OBJECTIVE: Malaria is a major global health concern with the urgent need for new treatment alternatives due to the alarming increase of drug-resistant Plasmodium strains. Chalcones and its derivatives are important pharmacophores showing antimalarial activity. Determination of the pharmacokinetic variables at the preliminary step of drug development for any drug candidates is an essential component of in vivo antimalarial efficacy tests. Substandard pharmacokinetic variables are often responsible for insufficient therapeutic effect. Therefore, three chalcone derivatives, 1, 2, and 3, having antimalarial potency were studied further for potential therapeutic efficacy. RESULTS: In vivo pharmacokinetic studies of these three derivatives were performed on New Zealand White rabbits. The three derivatives were administered intra-peritoneally or orally at effective dose concentration and blood samples at different time points were collected. The determination of drug concentration was done through reverse phase-high performance liquid chromatography. The peak plasma concentration of derivative 1, 2, and 3 were 1.96 ± 0.46 µg/mL (intraperitoneal route), 69.89 ± 5.49 µg/mL (oral route), and 3.74 ± 1.64 µg/mL (oral route). The results indicate a very low bioavailability of these derivatives. The present study gives a benchmark to advance the investigation of more derivatives in order to revamp the pharmacokinetic variables while maintaining both potency and metabolic constancy.


Assuntos
Antimaláricos , Chalcona , Chalconas , Malária , Plasmodium , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Chalcona/farmacologia , Chalcona/uso terapêutico , Chalconas/uso terapêutico , Malária/tratamento farmacológico , Plasmodium falciparum , Coelhos
2.
Front Cell Infect Microbiol ; 11: 672691, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34222045

RESUMO

Elucidation of the mechanisms of drug resistance in malaria parasites is crucial for combatting the emergence and spread of resistant parasites, which can be achieved by tracing resistance-associated mutations and providing useful information for drug development. Previously, we produced a novel genetic tool, a Plasmodium berghei mutator (PbMut), whose base substitution rate is 36.5 times higher than that of wild-type parasites. Here, we report the isolation of a mutant with reduced susceptibility to piperaquine (PPQ) from PbMut under PPQ pressure by sequential nine-cycle screening and named it PbMut-PPQ-R-P9. The ED50 of PbMut-PPQ-R-P9 was 1.79 times higher than that of wild-type parasites, suggesting that its PPQ resistance is weak. In the 1st screen, recrudescence occurred in the mice infected with PbMut but not in those infected with wild-type parasites, suggesting earlier emergence of PPQ-resistant parasites from PbMut. Whole-genome sequence analysis of PbMut-PPQ-R-P9 clones revealed that eight nonsynonymous mutations were conserved in all clones, including N331I in PbCRT, the gene encoding chloroquine resistance transporter (CRT). The PbCRT(N331I) mutation already existed in the parasite population after the 2nd screen and was predominant in the population after the 8th screen. An artificially inserted PbCRT(N331I) mutation gave rise to reduced PPQ susceptibility in genome-edited parasites (PbCRT-N331I). The PPQ susceptibility and growth rates of PbCRT-N331I parasites were significantly lower than those of PbMut-PPQ-R-P9, implying that additional mutations in the PbMut-PPQ-R9 parasites could compensate for the fitness cost of the PbCRT(N331I) mutation and contribute to reduced PPQ susceptibility. In summary, PbMut could serve as a novel genetic tool for predicting gene mutations responsible for drug resistance. Further study on PbMut-PPQ-R-P9 could identify genetic changes that compensate for fitness costs owing to drug resistance acquisition.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Parasitos , Animais , Antimaláricos/farmacologia , Malária/tratamento farmacológico , Camundongos , Plasmodium berghei/genética , Plasmodium falciparum , Proteínas de Protozoários/genética , Quinolinas , Roedores
3.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073419

RESUMO

Specific adhesion of P. falciparum parasite-infected erythrocytes (IE) in deep vascular beds can result in severe complications, such as cerebral malaria, placental malaria, respiratory distress, and severe anemia. Cerebral malaria and severe malaria syndromes were associated previously with sequestration of IE to a microvasculature receptor ICAM-1. The screening of Torrey Pines Scaffold Ranking library, which consists of more than 30 million compounds designed around 75 molecular scaffolds, identified small molecules that inhibit cytoadhesion of ICAM-1-binding IE to surface-immobilized receptor at IC50 range down to ~350 nM. With their low cytotoxicity toward erythrocytes and human endothelial cells, these molecules might be suitable for development into potentially effective adjunct anti-adhesion drugs to treat cerebral and/or severe malaria syndromes. Our two-step high-throughput screening approach is specifically designed to work with compound mixtures to make screening and deconvolution to single active compounds fast and efficient.


Assuntos
Antimaláricos , Eritrócitos , Molécula 1 de Adesão Intercelular/metabolismo , Malária Falciparum , Plasmodium falciparum/metabolismo , Bibliotecas de Moléculas Pequenas , Antimaláricos/química , Antimaláricos/farmacologia , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Eritrócitos/patologia , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/metabolismo , Malária Falciparum/patologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
4.
Molecules ; 26(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066964

RESUMO

The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.


Assuntos
Antimaláricos/farmacologia , Simulação por Computador , Desenho de Fármacos , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico , Antimaláricos/química , Sítios de Ligação , Domínio Catalítico , Avaliação Pré-Clínica de Medicamentos , Evolução Molecular , Simulação de Acoplamento Molecular , Peptídeos/química , Peptídeos/farmacologia , Domínios Proteicos , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Eletricidade Estática , Termodinâmica , Água/química
5.
Molecules ; 26(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068519

RESUMO

Malaria remains one of the leading causes of death in sub-Saharan Africa, ranked in the top three infectious diseases in the world. Plants of the Eriosema genus have been reported to be used for the treatment of this disease, but scientific evidence is still missing for some of them. In the present study, the in vitro antiplasmodial activity of the crude extract and compounds from Eriosema montanum Baker f. roots were tested against the 3D7 strain of Plasmodium falciparum and revealed using the SYBR Green, a DNA intercalating compound. The cytotoxicity effect of the compounds on a human cancer cell line (THP-1) was assessed to determine their selectivity index. It was found that the crude extract of the plant displayed a significant antiplasmodial activity with an IC50 (µg/mL) = 17.68 ± 4.030 and a cytotoxic activity with a CC50 (µg/mL) = 101.5 ± 12.6, corresponding to a selective antiplasmodial activity of 5.7. Bioactivity-guided isolation of the major compounds of the roots' crude extract afforded seven compounds, including genistein, genistin and eucomic acid. Under our experimental conditions, using Artemisinin as a positive control, eucomic acid showed the best inhibitory activity against the P. falciparum 3D7, a well-known chloroquine-sensitive strain. The present results provide a referential basis to support the traditional use of Eriosema species in the treatment of malaria.


Assuntos
Antimaláricos/farmacologia , Fabaceae/química , Raízes de Plantas/química , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/química , Antimaláricos/isolamento & purificação , Morte Celular/efeitos dos fármacos , Cloroquina/farmacologia , Misturas Complexas , Humanos , Células THP-1
6.
Molecules ; 26(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070798

RESUMO

A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).


Assuntos
Alcaloides Indólicos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Anti-Infecciosos/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Alcaloides Indólicos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/metabolismo , Relação Estrutura-Atividade
7.
Acta Crystallogr C Struct Chem ; 77(Pt 6): 262-270, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089249

RESUMO

The X-ray structures of three new 1:1 pharmaceutical cocrystals of 11-azaartemisinin (11-Aza; systematic name: 1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.04,13.08,13]hexadecan-10-one, C15H23NO4) with bromo-substituted salicylic acids [namely, 5-bromo- (5-BrSalA, C7H5BrO3), 4-bromo- (4-BrSalA, C7H5BrO3) and 3,5-dibromosalicylic acid (3,5-Br2SalA, C7H4Br2O3)] are reported. All the structures are related to the parent 11-Aza:SalA cocrystal (monoclinic P21) reported previously. The 5-BrSalA analogue is isostructural with the parent, with lattice expansion along the c axis. The 4-BrSalA and 3,5-Br2SalA cocrystals retain the highly preserved 21 stacks of the molecular pairs, but these pack with a varying degree of slippage with respect to neighbouring stacks, altering the close contacts between them, and represent two potential alternative homostructural arrangements for the parent compound. Structure redeterminations of the bromosalicylic acids 5-BrSalA, 4-BrSalA and 3,5-Br2SalA at 100 K show that the packing efficiency of the cocrystals need not be higher than the parent coformers, based on specific-volume calculations, attributable to the strong O-H...O=C hydrogen bonds of 2.54 Šin the cocrystals.


Assuntos
Antimaláricos/química , Salicilatos/química , Antimaláricos/farmacologia , Cristalografia por Raios X , Ligação de Hidrogênio , Salicilatos/farmacologia , Solubilidade
8.
Front Cell Infect Microbiol ; 11: 685866, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178724

RESUMO

Malaria is a parasitic disease that represents a public health problem worldwide. Protozoans of the Plasmodium genus are responsible for causing malaria in humans. Plasmodium species have a complex life cycle that requires post-translational modifications (PTMs) to control cellular activities temporally and spatially and regulate the levels of critical proteins and cellular mechanisms for maintaining an efficient infection and immune evasion. SUMOylation is a PTM formed by the covalent linkage of a small ubiquitin-like modifier protein to the lysine residues on the protein substrate. This PTM is reversible and is triggered by the sequential action of three enzymes: E1-activating, E2-conjugating, and E3 ligase. On the other end, ubiquitin-like-protein-specific proteases in yeast and sentrin-specific proteases in mammals are responsible for processing SUMO peptides and for deconjugating SUMOylated moieties. Further studies are necessary to comprehend the molecular mechanisms and cellular functions of SUMO in Plasmodium. The emergence of drug-resistant malaria parasites prompts the discovery of new targets and antimalarial drugs with novel mechanisms of action. In this scenario, the conserved biological processes regulated by SUMOylation in the malaria parasites such as gene expression regulation, oxidative stress response, ubiquitylation, and proteasome pathways, suggest PfSUMO as a new potential drug target. This mini-review focuses on the current understanding of the mechanism of action of the PfSUMO during the coordinated multi-step life cycle of Plasmodium and discusses them as attractive new target proteins for the development of parasite-specific inhibitors and therapeutic intervention toward malaria disease.


Assuntos
Antimaláricos , Malária , Plasmodium , Animais , Antimaláricos/farmacologia , Humanos , Malária/tratamento farmacológico , Plasmodium falciparum , Sumoilação
9.
Front Cell Infect Microbiol ; 11: 691121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178727

RESUMO

Parasites of the phylum Apicomplexa impact humans in nearly all parts of the world, causing diseases including to toxoplasmosis, cryptosporidiosis, babesiosis, and malaria. Apicomplexan parasites have complex life cycles comprised of one or more stages characterized by rapid replication and biomass amplification, which enables accelerated evolutionary adaptation to environmental changes, including to drug pressure. The emergence of drug resistant pathogens is a major looming and/or active threat for current frontline chemotherapies, especially for widely used antimalarial drugs. In fact, resistant parasites have been reported against all modern antimalarial drugs within 15 years of clinical introduction, including the current frontline artemisinin-based combination therapies. Chemotherapeutics are a major tool in the public health arsenal for combatting the onset and spread of apicomplexan diseases. All currently approved antimalarial drugs have been discovered either through chemical modification of natural products or through large-scale screening of chemical libraries for parasite death phenotypes, and so far, none have been developed through a gene-to-drug pipeline. However, the limited duration of efficacy of these drugs in the field underscores the need for new and innovative approaches to discover drugs that can counter rapid resistance evolution. This review details both historical and current antimalarial drug discovery approaches. We also highlight new strategies that may be employed to discover resistance-resistant drug targets and chemotherapies in order to circumvent the rapid evolution of resistance in apicomplexan parasites.


Assuntos
Antimaláricos , Malária , Parasitos , Animais , Antimaláricos/farmacologia , Descoberta de Drogas , Resistência a Medicamentos , Humanos , Malária/tratamento farmacológico , Plasmodium falciparum
10.
Nat Commun ; 12(1): 3160, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039976

RESUMO

Despite the high burden of Plasmodium vivax malaria in South Asian countries, the genetic diversity of circulating parasite populations is not well described. Determinants of antimalarial drug susceptibility for P. vivax in the region have not been characterised. Our genomic analysis of global P. vivax (n = 558) establishes South Asian isolates (n = 92) as a distinct subpopulation, which shares ancestry with some East African and South East Asian parasites. Signals of positive selection are linked to drug resistance-associated loci including pvkelch10, pvmrp1, pvdhfr and pvdhps, and two loci linked to P. vivax invasion of reticulocytes, pvrbp1a and pvrbp1b. Significant identity-by-descent was found in extended chromosome regions common to P. vivax from India and Ethiopia, including the pvdbp gene associated with Duffy blood group binding. Our investigation provides new understanding of global P. vivax population structure and genomic diversity, and genetic evidence of recent directional selection in this important human pathogen.


Assuntos
Genes de Protozoários , Malária Vivax/parasitologia , Plasmodium vivax/genética , Seleção Genética , África Oriental , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Ásia , Resistência a Medicamentos/genética , Sistema do Grupo Sanguíneo Duffy , Loci Gênicos , Humanos , Malária Vivax/sangue , Malária Vivax/tratamento farmacológico , Filogenia , Filogeografia , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/patogenicidade , Polimorfismo de Nucleotídeo Único , Proteínas de Protozoários/genética , Reticulócitos/parasitologia
11.
Nat Commun ; 12(1): 3196, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045457

RESUMO

Malaria parasites have a complex life cycle featuring diverse developmental strategies, each uniquely adapted to navigate specific host environments. Here we use single-cell transcriptomics to illuminate gene usage across the transmission cycle of the most virulent agent of human malaria - Plasmodium falciparum. We reveal developmental trajectories associated with the colonization of the mosquito midgut and salivary glands and elucidate the transcriptional signatures of each transmissible stage. Additionally, we identify both conserved and non-conserved gene usage between human and rodent parasites, which point to both essential mechanisms in malaria transmission and species-specific adaptations potentially linked to host tropism. Together, the data presented here, which are made freely available via an interactive website, provide a fine-grained atlas that enables intensive investigation of the P. falciparum transcriptional journey. As well as providing insights into gene function across the transmission cycle, the atlas opens the door for identification of drug and vaccine targets to stop malaria transmission and thereby prevent disease.


Assuntos
Anopheles/parasitologia , Estágios do Ciclo de Vida/genética , Malária Falciparum/transmissão , Mosquitos Vetores/parasitologia , Plasmodium falciparum/genética , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Feminino , Interações Hospedeiro-Parasita/genética , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Masculino , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , RNA-Seq , Análise de Célula Única , Especificidade da Espécie , Transcriptoma/efeitos dos fármacos
12.
ACS Infect Dis ; 7(6): 1818-1832, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34044540

RESUMO

The Ubiquitin Proteasome System is the main proteolytic pathway in eukaryotic cells, playing a role in key cellular processes. The essentiality of the Plasmodium falciparum proteasome is well validated, underlying its potential as an antimalarial target, but selective compounds are required to avoid cytotoxic effects in humans. Almost 550000 compounds were tested for the inhibition of the chymotrypsin-like activity of the P. falciparum proteasome using a Proteasome-GLO luminescence assay. Hits were confirmed in an orthogonal enzyme assay using Rho110-labeled peptides, and selectivity was assessed against the human proteasome. Four nonpeptidomimetic chemical families with some selectivity for the P. falciparum proteasome were identified and characterized in assays of proteasome trypsin and caspase activities and in parasite growth inhibition assays. Target engagement studies were performed, validating our approach. Hits identified are good starting points for the development of new antimalarial drugs and as tools to better understand proteasome function in P. falciparum.


Assuntos
Antimaláricos , Malária Falciparum , Antimaláricos/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum , Inibidores de Proteassoma/farmacologia
13.
Int J Infect Dis ; 107: 234-241, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33940188

RESUMO

BACKGROUND: Recent studies showed the first emergence of the R561H artemisinin-associated resistance marker in Africa, which highlights the importance of continued molecular surveillance to assess the selection and spread of this and other drug resistance markers in the region. METHOD: In this study, we used targeted amplicon deep sequencing of 116 isolates collected in two areas of Cameroon to genotype the major drug resistance genes, k13, crt, mdr1, dhfr, and dhps, and the cytochrome b gene (cytb) in Plasmodium falciparum. RESULTS: No confirmed or associated artemisinin resistance markers were observed in Pfk13. In comparison, both major and minor alleles associated with drug resistance were found in Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps. Notably, a high frequency of other nonsynonymous mutations was observed across all the genes, except for Pfcytb, suggesting continued selection pressure. CONCLUSIONS: The results from this study supported the continued use of artemisinin-based combination therapy and administration of sulfadoxine-pyrimethamine for intermittent preventive therapy in pregnant women, and for seasonal chemoprevention in these study sites in Cameroon.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos/genética , Marcadores Genéticos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Alelos , Camarões , Feminino , Genótipo , Humanos , Mutação , Plasmodium falciparum/isolamento & purificação , Gravidez
14.
J Med Chem ; 64(10): 6581-6595, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33979164

RESUMO

Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction. As a proof-of-concept, the utility of this novel amino AOCOM ether prodrug approach was demonstrated on an antimalarial compound series representing a variety of antimalarial 4(1H)-quinolones, which entered and failed preclinical development over the last decade. With the amino AOCOM ether prodrug moiety, the 3-aryl-4(1H)-quinolone preclinical candidate was shown to provide single-dose cures in a rodent malaria model at an oral dose of 3 mg/kg, without the use of an advanced formulation technique.


Assuntos
Antimaláricos/química , Éteres/química , Pró-Fármacos/química , Quinolonas/química , Administração Oral , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Ciclização , Modelos Animais de Doenças , Feminino , Meia-Vida , Concentração de Íons de Hidrogênio , Malária/tratamento farmacológico , Malária/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium falciparum/efeitos dos fármacos , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Quinolonas/farmacocinética , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Solubilidade , Relação Estrutura-Atividade
15.
Antimicrob Agents Chemother ; 65(7): e0271720, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33903109

RESUMO

The artemisinin-based combination therapies (ACTs) used to treat Plasmodium falciparum in Africa are threatened by the emergence of parasites in Asia that carry variants of the Kelch 13 (K13) locus with delayed clearance in response to ACTs. Single nucleotide polymorphisms (SNPs) in other molecular markers, such as ap2mu and ubp1, were associated with artemisinin resistance in rodent malaria and clinical failure in African malaria patients. Here, we characterized the polymorphisms in pfmdr1, pfcrt, pfK13, pfubp1, and pfap2mu among African isolates reported in Shandong and Guangxi provinces in China. Among 144 patients with P. falciparum returning from Africa from 2014 to 2018, pfmdr1 N86Y (8.3%) and pfcrt K76T (2.1%) were the major mutant alleles. The most common genotype for pfcrt was I74E75T76 (8.3%), followed by E75T76 (2.1%). For K13 polymorphisms, a limited number of mutated alleles were observed, and A578S was the most frequently detected allele in 3 isolates (2.1%). A total of 27.1% (20/144) of the isolates were found to contain pfubp1 mutations, including 6 nonsynonymous and 2 synonymous mutations. The pfubp1 genotypes associated with artemisinin resistance were D1525E (10.4%) and E1528D (8.3%). Furthermore, 11 SNPs were identified in pfap2mu, and S160N was the major polymorphism (4.2%). Additionally, 4 different types of insertions were found in pfap2mu, and the codon AAT, encoding aspartic acid, was more frequently observed at codons 226 (18.8%) and 326 (10.7%). Moreover, 4 different types of insertions were observed in pfubp1 at codon 1520, which was the most common (6.3%). These findings indicate a certain degree of variation in other potential molecular markers, such as pfubp1 and pfap2mu, and their roles in either the parasite's mechanism of resistance or the mode of action should be evaluated or elucidated further.


Assuntos
Antimaláricos , Malária Falciparum , África , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Ásia , China , Resistência a Medicamentos/genética , Humanos , Malária Falciparum/tratamento farmacológico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo
16.
J Parasitol ; 107(2): 284-288, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33844839

RESUMO

Malaria remains one of the most important infectious diseases in the world. In 2017 alone, approximately 219 million people were infected with malaria, and 435,000 people died of this disease. Plasmodium falciparum, which causes falciparum malaria, is becoming resistant to artemisinin (ART) in Southeast Asia; therefore, new antimalarial drugs are urgently needed. Some excellent antimalarial drugs, such as quinine and ART, were originally obtained from plants. Hence, we analyzed the antimalarial effects of marine natural products to find new antimalarial agents. We used a malaria growth inhibition assay to determine the antimalarial ability and half-maximal inhibitory concentration (IC50) values of the marine organism-derived compounds. Three compounds (kapakahine A, kapakahine B, and kulolide-1) showed antimalarial effects, and one (kapakahine F) showed selective antimalarial effects on the Dd2 clone. Although the IC50 values obtained for these compounds were greater than that of ART, their potency against P. falciparum is sufficient to warrant further investigation of these compounds as possible drug leads.


Assuntos
Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Toxinas Marinhas/farmacologia , Peptídeos Cíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/química , Antimaláricos/uso terapêutico , Humanos , Concentração Inibidora 50 , Toxinas Marinhas/química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/uso terapêutico
17.
J Nat Med ; 75(3): 633-642, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33822287

RESUMO

Two new bisindole alkaloids, bisnaecarpamines A (1) and B (2), possessing a vobasine-sarpagine type skeleton were isolated from the bark of Tabernaemontana macrocarpa Jack. Their structures were elucidated by extensive spectroscopic methods and chemical correlation. The absolute configurations of compounds 1 and 2 were established using TDDFT-ECD calculation of the selected isomers. Bisnaecarpamine A exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC50 value of 28.8 µM.


Assuntos
Alcaloides/química , Antimaláricos/química , Tabernaemontana/química , Alcaloides/farmacologia , Antimaláricos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Alcaloides Indólicos , Indonésia , Estrutura Molecular , Casca de Planta/química , Plasmodium falciparum/efeitos dos fármacos
18.
Molecules ; 26(5)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801371

RESUMO

A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC50 values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects.


Assuntos
Antimaláricos/farmacologia , Antiprotozoários/farmacologia , Cumarínicos/química , Compostos Ferrosos/química , Oxazinas/química , Plasmodium falciparum/efeitos dos fármacos , Trypanosoma brucei brucei/efeitos dos fármacos , Antimaláricos/química , Antiprotozoários/química , Proliferação de Células , Sobrevivência Celular , Feminino , Humanos , Técnicas In Vitro , Estrutura Molecular , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Células Tumorais Cultivadas
19.
J Med Chem ; 64(8): 5198-5215, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33844521

RESUMO

A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.


Assuntos
Antimaláricos/química , Benzimidazóis/química , Hemeproteínas/metabolismo , Bases de Mannich/química , Microtúbulos/metabolismo , Administração Oral , Animais , Antimaláricos/metabolismo , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Modelos Animais de Doenças , Desenho de Fármacos , Resistência a Medicamentos/efeitos dos fármacos , Estabilidade de Medicamentos , Meia-Vida , Hemeproteínas/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária/tratamento farmacológico , Malária/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Microtúbulos/efeitos dos fármacos , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/fisiologia , Relação Estrutura-Atividade
20.
J Med Chem ; 64(8): 4478-4497, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33792339

RESUMO

Malaria-causing Plasmodium parasites are developing resistance to antimalarial drugs, providing the impetus for new antiplasmodials. Although pantothenamides show potent antiplasmodial activity, hydrolysis by pantetheinases/vanins present in blood rapidly inactivates them. We herein report the facile synthesis and biological activity of a small library of pantothenamide analogues in which the labile amide group is replaced with a heteroaromatic ring. Several of these analogues display nanomolar antiplasmodial activity against Plasmodium falciparum and/or Plasmodium knowlesi, and are stable in the presence of pantetheinase. Both a known triazole and a novel isoxazole derivative were further characterized and found to possess high selectivity indices, medium or high Caco-2 permeability, and medium or low microsomal clearance in vitro. Although they fail to suppress Plasmodium berghei proliferation in vivo, the pharmacokinetic and contact time data presented provide a benchmark for the compound profile likely required to achieve antiplasmodial activity in mice and should facilitate lead optimization.


Assuntos
Antimaláricos/química , Isoxazóis/química , Ácido Pantotênico/análogos & derivados , Tiadiazóis/química , Triazóis/química , Animais , Antimaláricos/metabolismo , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Estabilidade de Medicamentos , Eritrócitos/citologia , Eritrócitos/parasitologia , Feminino , Meia-Vida , Humanos , Malária Falciparum/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Ácido Pantotênico/química , Ácido Pantotênico/metabolismo , Ácido Pantotênico/farmacologia , Ácido Pantotênico/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium knowlesi/efeitos dos fármacos , Relação Estrutura-Atividade
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