Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.244
Filtrar
1.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205228

RESUMO

BACKGROUND: Artemether-lumefantrine is a highly effective artemisinin-based combination therapy that was adopted in Mali as first-line treatment for uncomplicated Plasmodium falciparum malaria. This study was designed to measure the efficacy of artemether-lumefantrine and to assess the selection of the P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multi-drug resistance 1 (pfmdr1) genotypes that have been associated with drug resistance. METHODS: A 28-day follow-up efficacy trial of artemether-lumefantrine was conducted in patients aged 6 months and older suffering from uncomplicated falciparum malaria in four different Malian areas during the 2009 malaria transmission season. The polymorphic genetic markers MSP2, MSP1, and Ca1 were used to distinguish between recrudescence and reinfection. Reinfection and recrudescence were then grouped as recurrent infections and analyzed together by PCR-restriction fragment length polymorphism (RFLP) to identify candidate markers for artemether-lumefantrine tolerance in the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multi-drug resistance 1 (pfmdr1) gene. RESULTS: Clinical outcomes in 326 patients (96.7%) were analyzed and the 28-day uncorrected adequate clinical and parasitological response (ACPR) rate was 73.9%. The total PCR-corrected 28-day ACPR was 97.2%. The pfcrt 76T and pfmdr1 86Y population prevalence decreased from 49.3% and 11.0% at baseline (n = 337) to 38.8% and 0% in patients with recurrent infection (n = 85); p = 0.001), respectively. CONCLUSION: Parasite populations exposed to artemether-lumefantrine in this study were selected toward chloroquine-sensitivity and showed a promising trend that may warrant future targeted reintroduction of chloroquine or/and amodiaquine.


Assuntos
Combinação Arteméter e Lumefantrina/administração & dosagem , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Protozoários/genética , Alelos , Combinação Arteméter e Lumefantrina/efeitos adversos , Artemisininas/administração & dosagem , Artemisininas/efeitos adversos , Criança , Pré-Escolar , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Resistência a Medicamentos/genética , Feminino , Humanos , Malária Falciparum/genética , Malária Falciparum/parasitologia , Malária Falciparum/patologia , Masculino , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade
2.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199336

RESUMO

The natural compound ravenelin was isolated from the biomass extracts of Exserohilum rostratum fungus, and its antimicrobial, antiplasmodial, and trypanocidal activities were evaluated. Ravenelin was isolated by column chromatography and HPLC and identified by NMR and MS. The susceptibility of Gram-positive and Gram-negative bacteria strains to ravenelin was determined by microbroth dilution assay. Cytotoxicity was evaluated in hepatocarcinoma cells (HepG2) and BALB/c peritoneal macrophages by using MTT. SYBR Green I-based assay was used in the asexual stages of Plasmodium falciparum. Trypanocidal activity was tested against the epimastigote and intracellular amastigote forms of Trypanosoma cruzi. Ravenelin was active against Gram-positive bacteria strains, with emphasis on Bacillus subtilis (MIC value of 7.5 µM). Ravenelin's antiparasitic activities were assessed against both the epimastigote (IC50 value of 5 ± 1 µM) and the intracellular amastigote forms of T. cruzi (IC50 value of 9 ± 2 µM), as well as against P. falciparum (IC50 value of 3.4 ± 0.4 µM). Ravenelin showed low cytotoxic effects on both HepG2 (CC50 > 50 µM) and peritoneal macrophage (CC50 = 185 ± 1 µM) cells with attractive selectivity for the parasites (SI values > 15). These findings indicate that ravenelin is a natural compound with both antibacterial and antiparasitic activities, and considerable selectivity indexes. Therefore, ravenelin is an attractive candidate for hit-to-lead development.


Assuntos
Antibacterianos/farmacologia , Antiprotozoários/farmacologia , Ascomicetos/química , Macrófagos Peritoneais/citologia , Xantonas/farmacologia , Animais , Antibacterianos/química , Antiprotozoários/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Biomassa , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células Hep G2 , Humanos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Xantonas/química
3.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: covidwho-1256561

RESUMO

Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite Plasmodium falciparum, aspartyl proteases of P. falciparum (plasmepsins) and the Sars-CoV-2 viral proteases. Despite some unfulfilled expectations over previous decades, the three reviewed targets clearly demonstrate that selective protease inhibitors provide effective therapeutic solutions for the two most impacting infectious diseases nowadays-malaria and COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Ácido Aspártico Endopeptidases/metabolismo , COVID-19/enzimologia , COVID-19/metabolismo , Humanos , Malária/enzimologia , Malária/metabolismo , Plasmodium falciparum/patogenicidade , SARS-CoV-2/patogenicidade
4.
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
5.
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
6.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071206

RESUMO

Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite Plasmodium falciparum, aspartyl proteases of P. falciparum (plasmepsins) and the Sars-CoV-2 viral proteases. Despite some unfulfilled expectations over previous decades, the three reviewed targets clearly demonstrate that selective protease inhibitors provide effective therapeutic solutions for the two most impacting infectious diseases nowadays-malaria and COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Ácido Aspártico Endopeptidases/metabolismo , COVID-19/enzimologia , COVID-19/metabolismo , Humanos , Malária/enzimologia , Malária/metabolismo , Plasmodium falciparum/patogenicidade , SARS-CoV-2/patogenicidade
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
Mar Drugs ; 19(4)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805935

RESUMO

Novel drug leads for malaria therapy are urgently needed because of the widespread emergence of resistance to all available drugs. Screening of the Harbor Branch enriched fraction library against the Plasmodium falciparum chloroquine-resistant strain (Dd2) followed by bioassay-guided fractionation led to the identification of two potent antiplasmodials; a novel diterpene designated as bebrycin A (1) and the known C21 degraded terpene nitenin (2). A SYBR Green I assay was used to establish a Dd2 EC50 of 1.08 ± 0.21 and 0.29 ± 0.02 µM for bebrycin A and nitenin, respectively. Further analysis was then performed to assess the stage specificity of the inhibitors antiplasmodial effects on the Dd2 intraerythrocytic life cycle. Exposure to bebrycin A was found to block parasite maturation at the schizont stage if added any time prior to late schizogony at 42 hours post invasion, (HPI). In contrast, early life cycle exposure to nitenin (prior to 18 HPI) was identified as crucial to parasite inhibition, suggesting nitenin may target the maturation of the parasite during the transition from ring to early trophozoite (6-18 HPI), a novel property among known antimalarials.


Assuntos
Antozoários/metabolismo , Antimaláricos/farmacologia , Diterpenos/farmacologia , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Poríferos/metabolismo , Animais , Antimaláricos/isolamento & purificação , Diterpenos/isolamento & purificação , Células Hep G2 , Humanos , Estágios do Ciclo de Vida , Malária Falciparum/parasitologia , Estrutura Molecular , Plasmodium falciparum/crescimento & desenvolvimento , Relação Estrutura-Atividade , Fatores de Tempo
15.
Molecules ; 26(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919319

RESUMO

A radical approach to late-stage functionalization using photoredox and Diversinate™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC50 values ranging from 0.3 to >20 µM; none of the compounds displayed any toxicity against HEK293 at 80 µM.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Técnicas de Química Sintética , Pirazinas/química , Pirazinas/farmacologia , Álcoois/química , Antimaláricos/síntese química , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Pirazinas/síntese química , Relação Estrutura-Atividade
16.
J Med Chem ; 64(9): 6085-6136, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33876936

RESUMO

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.


Assuntos
Antimaláricos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Pirróis/farmacologia , Animais , Antimaláricos/química , Inibidores Enzimáticos/química , Camundongos , Plasmodium falciparum/efeitos dos fármacos , Pirróis/química , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 217: 113330, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33744688

RESUMO

Presently, artemisinin-based combination therapy (ACT) is the first-line therapy of Plasmodium falciparum malaria. With the emergence of malaria parasites that are resistant to ACT, alternative antimalarial therapies are urgently needed. In line with this, we designed and synthesised a series of novel N-(7-chloroquinolin-4-yl)-N'-(4,6-diphenylpyrimidin-2-yl)alkanediamine hybrids (6a-7c) and evaluated their inhibitory activity against the NF54 chloroquine-susceptible strain as a promising class of antimalarial compounds. The antiplasmodial screening revealed that seven analogues showed promising to good activity with half-maximal inhibitory concentration (IC50) = 0.32 µM-4.30 µM. Compound 7a with 1,4-diamine butyl linker and 4-hydroxyl phenyl on fourth and sixth position of pyrimidine core showed the most prominent activity with an IC50 value of 0.32 ± 0.06 µM, with a favourable safety profile of 9.79 to human kidney epithelial (HEK293) cells. The remaining six analogues showed moderate activity with IC50 values ranging from 7.50 µM to 83.01 µM. We further investigated the binding affinities of the molecules to two essential cytosolic P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z. Compound 7a exhibited the highest binding affinity for both PfHsp70s with KD in a lower nanomolar range (4.4-11.4 nM). Furthermore, molecular docking revealed that compounds 6, 6k, 7b and 7a exhibited better fitness in PfHsp70-1 with compound 7a showing the highest and lowest binding scores of -9.8 kcal/mol. Therefore, we speculate that PfHsp70-1 is one of the targets of these inhibitors. The bioisoteric replacement of the groups at phenyl ring at the fourth and sixth position of the pyrimidine core had a constructive association with antiplasmodial activity. The promising antiplasmodial activity of the synthesised analogues illustrates how crucial molecular hybridisation is as a strategy in the development of quinoline-pyrimidine hybrids as prospective antiprotozoal agents.


Assuntos
Antimaláricos/farmacologia , Desenho de Fármacos , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/farmacologia , Quinolinas/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Pirimidinas/química , Quinolinas/química , Relação Estrutura-Atividade , Termodinâmica
18.
Mar Drugs ; 19(3)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33670878

RESUMO

Malaria is an infectious disease caused by protozoan parasites of the Plasmodium genus through the bite of female Anopheles mosquitoes, affecting 228 million people and causing 415 thousand deaths in 2018. Artemisinin-based combination therapies (ACTs) are the most recommended treatment for malaria; however, the emergence of multidrug resistance has unfortunately limited their effects and challenged the field. In this context, the ocean and its rich biodiversity have emerged as a very promising resource of bioactive compounds and secondary metabolites from different marine organisms. This systematic review of the literature focuses on the advances achieved in the search for new antimalarials from marine sponges, which are ancient organisms that developed defense mechanisms in a hostile environment. The principal inclusion criterion for analysis was articles with compounds with IC50 below 10 µM or 10 µg/mL against P. falciparum culture. The secondary metabolites identified include alkaloids, terpenoids, polyketides endoperoxides and glycosphingolipids. The structural features of active compounds selected in this review may be an interesting scaffold to inspire synthetic development of new antimalarials for selectively targeting parasite cell metabolism.


Assuntos
Antimaláricos/isolamento & purificação , Malária Falciparum/tratamento farmacológico , Poríferos/metabolismo , Animais , Antimaláricos/administração & dosagem , Antimaláricos/farmacologia , Desenvolvimento de Medicamentos , Resistência a Múltiplos Medicamentos , Humanos , Concentração Inibidora 50 , Plasmodium falciparum/efeitos dos fármacos , Metabolismo Secundário
19.
J Med Chem ; 64(7): 4150-4162, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33759519

RESUMO

Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine 23, which exhibited significantly improved in vitro metabolic stability (8 and 42 µL/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer 23 was also observed to suppress parasitemia in the Peters 4-day test with a mean ED50 value of 1.85 mg/kg/day and exhibited a fast-killing profile, revealing a new class of orally available antimalarial compounds of considerable interest.


Assuntos
Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Triazinas/uso terapêutico , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Células CACO-2 , Feminino , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacocinética
20.
J Med Chem ; 64(6): 3035-3047, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33666415

RESUMO

3-Hydroxypropanamidines are a new promising class of highly active antiplasmodial agents. The most active compound 22 exhibited excellent antiplasmodial in vitro activity with nanomolar inhibition of chloroquine-sensitive and multidrug-resistant parasite strains ofPlasmodium falciparum (with IC50 values of 5 and 12 nM against 3D7 and Dd2 strains, respectively) as well as low cytotoxicity in human cells. In addition, 22 showed strong in vivo activity in thePlasmodium berghei mouse model with a cure rate of 66% at 50 mg/kg and a cure rate of 33% at 30 mg/kg in the Peters test after once daily oral administration for 4 consecutive days. A quick onset of action was indicated by the fast drug absorption shown in mice. The new lead compound was also characterized by a high barrier to resistance and inhibited the heme detoxification machinery in P. falciparum.


Assuntos
Amidinas/química , Amidinas/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Amidinas/farmacocinética , Amidinas/uso terapêutico , Animais , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Linhagem Celular , Desenho de Fármacos , Humanos , Malária/tratamento farmacológico , Camundongos , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Propano/química , Propano/farmacocinética , Propano/farmacologia , Propano/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...