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1.
Nat Prod Res ; : 1-7, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33703954

RESUMO

Malaria is an infectious illness, affecting vulnerable populations in Third World countries. Inspired by natural products, indole alkaloids have been used as a nucleus to design new antimalarial drugs. So, eighteen oxindole derivatives, aza analogues were obtained with moderate to excellent yields. Also, the saturated derivatives of oxindole and aza derivatives via H2/Pd/C reduction were obtained in good yields, leading to racemic mixtures of each compound. Next, the inhibitory activity against P. falciparum of 18 compounds were tested, founding six compounds with IC50 < 20 µM. The most active of these compounds was 8c; however, their unsaturated derivative 7c was inactive. Then, a structure-activity relationship analysis was done, founding that focused LUMO lobe on the specific molecular zone is related to inhibitory activity against P. falciparum. Finally, we found a potential inhibition of lactate dehydrogenase by oxindole derivatives, using molecular docking virtual screening.

2.
Eur J Med Chem ; 209: 112941, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33158577

RESUMO

In this work, we designed and synthesized 35 new triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors (3D7 strain). Thirty compounds exhibited anti-P. falciparum activity, with IC50 values ranging from 0.030 to 9.1 µM. The [1,2,4]triazolo[1,5-a]pyrimidine derivatives were more potent than the pyrazolo[1,5-a]pyrimidine and quinoline analogues. Compounds 20, 21, 23 and 24 were the most potent inhibitors, with IC50 values in the range of 0.030-0.086 µM and were equipotent to chloroquine. In addition, the compounds were selective, showing no cytotoxic activity against the human hepatoma cell line HepG2. All [1,2,4]triazolo[1,5-a]pyrimidine derivatives inhibited PfDHODH activity in the low micromolar to low nanomolar range (IC50 values of 0.08-1.3 µM) and did not show significant inhibition against the HsDHODH homologue (0-30% at 50 µM). Molecular docking studies indicated the binding mode of [1,2,4]triazolo[1,5-a]pyrimidine derivatives to PfDHODH, and the highest interaction affinities for the PfDHODH enzyme were in agreement with the in vitro experimental evaluation. Thus, the most active compounds against P. falciparum parasites 20 (R = CF3, R1 = F; IC50 = 0.086 µM), 21 (R = CF3; R1 = CH3; IC50 = 0.032 µM), 23, (R = CF3, R1 = CF3; IC50 = 0.030 µM) and 24 (R = CF3, 2-naphthyl; IC50 = 0.050 µM) and the most active inhibitor against PfDHODH 19 (R = CF3, R1 = Cl; IC50 = 0.08 µM - PfDHODH) stood out as new lead compounds for antimalarial drug discovery. Their potent in vitro activity against P. falciparum and the selective inhibition of the PfDHODH enzyme strongly suggest that this is the mechanism of action underlying this series of new [1,2,4]triazolo[1,5-a]pyrimidine derivatives.


Assuntos
Antimaláricos/síntese química , Inibidores Enzimáticos/química , Malária Falciparum/tratamento farmacológico , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Pirimidinas/síntese química , Quinolinas/síntese química , Triazóis/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Cloroquina/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Plasmodium falciparum/efeitos dos fármacos , Ligação Proteica , Pirimidinas/farmacologia , Quinolinas/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologia
3.
Bioorg Med Chem ; 27(6): 1002-1008, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30737133

RESUMO

Malaria remains a major public health problem worldwide, and it is responsible for high rates of morbidity and mortality. Resistance to current antimalarial drugs has been identified, and new drugs are urgently needed. In this study, we designed and synthesized seventeen novel quinolines based on the structures of mefloquine ((2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol) and amodiaquine (4-((7-chloroquinolin-4-yl)amino)-2-((diethylamino)methyl)phenol) using ring bioisosteric replacement and molecular hybridization of the functional groups. The compounds were evaluated in vitro against Plasmodium falciparum and in vivo in mice infected with P. berghei. All derivatives presented anti-P. falciparum activity with IC50 values ranging from 0.083 to 33.0 µM. The compound with the best anti-P. falciparum activity was N-(5-methyl-4H-1,2,4-triazol-3-yl)-2,8-bis(trifluoromethyl)quinolin-4-amine (12) which showed an IC50 of 0.083 µM. The three most active compounds were selected for antimalarial activity tests against P. berghei-infected mice. Compound 12 was the most active on the 5th day after infection, reducing parasitemia by 66%, which is consistent with its in vitro activity. This is an important result as 12, a simpler molecule than mefloquine, does not contain the stereogenic center, and consequently, its synthesis in the laboratory is easier and less expensive. This system proved promising for the design of potential antimalarial compounds.


Assuntos
Antimaláricos/farmacologia , Malária/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/uso terapêutico , Linhagem Celular , Descoberta de Drogas , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Halogenação , Haplorrinos , Humanos , Metilação , Camundongos , Quinolinas/química , Quinolinas/uso terapêutico
4.
ACS Med Chem Lett ; 10(1): 137-141, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30655961

RESUMO

Malaria is a major tropical disease where important needs are to mitigate symptoms and to prevent the establishment of infection. Cyclopeptides containing N-methyl amino acids with in vitro activity against erythrocytic forms as well as liver stage are presented. The synthesis, parasitological characterization, physicochemical properties, in vivo evaluation, and mice pharmacokinetics are described.

5.
Int J Parasitol Drugs Drug Resist ; 8(3): 459-464, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30396013

RESUMO

In spite of recent efforts to eradicate malaria in the world, this parasitic disease is still considered a major public health problem, with a total of 216 million cases of malaria and 445,000 deaths in 2016. Artemisinin-based combination therapies remain effective in most parts of the world, but recent cases of resistance in Southeast Asia have urged for novel approaches to treat malaria caused by Plasmodium falciparum. In this work, we present chloroquine analogs that exhibited high activity against sensitive and chloroquine-resistant P. falciparum blood parasites and were also active against P. berghei infected mice. Among the compounds tested, DAQ, a chloroquine analog with a more linear side chain, was shown to be the most active in vitro and in vivo, with low cytotoxicity, and therefore may serve as the basis for the development of more effective chloroquine analogs to aid malaria eradication.


Assuntos
Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Cloroquina/análogos & derivados , Cloroquina/química , Desenho de Fármacos , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/isolamento & purificação , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Resistência a Medicamentos , Células Hep G2 , Humanos , Malária/tratamento farmacológico , Camundongos , Testes de Sensibilidade Parasitária
6.
J Nat Prod ; 81(1): 188-202, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29297684

RESUMO

The isolation and identification of a series of new pseudoceratidine (1) derivatives from the sponge Tedania brasiliensis enabled the evaluation of their antiparasitic activity against Plasmodium falciparum, Leishmania (Leishmania) amazonensis, Leishmania (Leishmania) infantum, and Trypanosoma cruzi, the causative agents of malaria, cutaneous leishmaniasis, visceral leishmaniasis, and Chagas disease, respectively. The new 3-debromopseudoceratidine (4), 20-debromopseudoceratidine (5), 4-bromopseudoceratidine (6), 19-bromopseudoceratidine (7), and 4,19-dibromopseudoceratidine (8) are reported. New tedamides A-D (9-12), with an unprecedented 4-bromo-4-methoxy-5-oxo-4,5-dihydro-1H-pyrrole-2-carboxamide moiety, are also described. Compounds 4 and 5, 6 and 7, 9 and 10, and 11 and 12 have been isolated as pairs of inseparable structural isomers differing in their sites of bromination or oxidation. Tedamides 9+10 and 11+12 were obtained as optically active pairs, indicating an enzymatic formation rather than an artifactual origin. N12-Acetylpseudoceratidine (2) and N12-formylpseudoceratidine (3) were obtained by derivatization of pseudoceratidine (1). The antiparasitic activity of pseudoceratidine (1) led us to synthesize 23 derivatives (16, 17, 20, 21, 23, 25, 27-29, 31, 33, 35, 38, 39, 42, 43, 46, 47, 50, and 51) with variations in the polyamine chain and aromatic moiety in sufficient amounts for biological evaluation in antiparasitic assays. The measured antimalarial activity of pseudoceratidine (1) and derivatives 4, 5, 16, 23, 25, 31, and 50 provided an initial SAR evaluation of these compounds as potential leads for antiparasitics against Leishmania amastigotes and against P. falciparum. The results obtained indicate that pseudoceratidine represents a promising scaffold for the development of new antimalarial drugs.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Antiparasitários/química , Antiparasitários/farmacologia , Poríferos/química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos
7.
Mem Inst Oswaldo Cruz ; 110(7): 906-13, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26560981

RESUMO

Several species of Aspidosperma plants are used to treat diseases in the tropics, including Aspidosperma ramiflorum, which acts against leishmaniasis, an activity that is experimentally confirmed. The species, known as guatambu-yellow, yellow peroba, coffee-peroba and matiambu, grows in the Atlantic Forest of Brazil in the South to the Southeast regions. Through a guided biofractionation of A. ramiflorum extracts, the plant activity against Plasmodium falciparum was evaluated in vitro for toxicity towards human hepatoma G2 cells, normal monkey kidney cells and nonimmortalised human monocytes isolated from peripheral blood. Six of the seven extracts tested were active at low doses (half-maximal drug inhibitory concentration < 3.8 µg/mL); the aqueous extract was inactive. Overall, the plant extracts and the purified compounds displayed low toxicity in vitro. A nonsoluble extract fraction and one purified alkaloid isositsirikine (compound 5) displayed high selectivity indexes (SI) (= 56 and 113, respectively), whereas compounds 2 and 3 were toxic (SI < 10). The structure, activity and low toxicity of isositsirikine in vitro are described here for the first time in A. ramiflorum, but only the neutral and precipitate plant fractions were tested for activity, which caused up to 53% parasitaemia inhibition of Plasmodium berghei in mice with blood-induced malaria. This plant species is likely to be useful in the further development of an antimalarial drug, but its pharmacological evaluation is still required.


Assuntos
Antimaláricos/farmacologia , Aspidosperma/química , Extratos Vegetais/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/isolamento & purificação , Antimaláricos/toxicidade , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Parasitária
8.
Chem Biol Drug Des ; 84(3): 325-32, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24803084

RESUMO

Malaria is one of the most prevalent parasitic diseases in the world. The global importance of this disease, current vector control limitations, and the absence of an effective vaccine make the use of therapeutic antimalarial drugs the main strategy to control malaria. Chloroquine is a cost-effective antimalarial drug with a relatively robust safety profile, or therapeutic index. However, chloroquine is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of chloroquine-resistant strains, which have also been reported for Plasmodium vivax. However, the activity of 1,2,3-triazole derivatives against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum has been reported in the literature. To enhance the anti-P. falciparum activity of quinoline derivatives, we synthesized 11 new quinoline-1H-1,2,3-triazole hybrids with different substituents in the 4-positions of the 1H-1,2,3-triazole ring, which were assayed against the W2-chloroquine-resistant P. falciparum clone. Six compounds exhibited activity against the P. falciparum W2 clone, chloroquine-resistant, with IC50 values ranging from 1.4 to 46 µm. None of these compounds was toxic to a normal monkey kidney cell line, thus exhibiting good selectivity indexes, as high 351 for one compound (11).


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Plasmodium falciparum/fisiologia , Quinolinas/química , Quinolinas/farmacologia , Triazóis/química , Animais , Antimaláricos/síntese química , Apoptose/efeitos dos fármacos , Cloroquina/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Eritrócitos/parasitologia , Haplorrinos , Humanos , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/síntese química
9.
Malar J ; 13: 142, 2014 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-24731256

RESUMO

BACKGROUND: Several species of Aspidosperma (Apocynaceae) are used as treatments for human diseases in the tropics. Aspidosperma olivaceum, which is used to treat fevers in some regions of Brazil, contains the monoterpenoid indole alkaloids (MIAs) aspidoscarpine, uleine, apparicine, and N-methyl-tetrahydrolivacine. Using bio-guided fractionation and cytotoxicity testing in a human hepatoma cell line, several plant fractions and compounds purified from the bark and leaves of the plant were characterized for specific therapeutic activity (and selectivity index, SI) in vitro against the blood forms of Plasmodium falciparum. METHODS: The activity of A. olivaceum extracts, fractions, and isolated compounds was evaluated against chloroquine (CQ)-resistant P. falciparum blood parasites by in vitro testing with radiolabelled [3H]-hypoxanthine and a monoclonal anti-histidine-rich protein (HRPII) antibody. The cytotoxicity of these fractions and compounds was evaluated in a human hepatoma cell line using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, and the SI was calculated as the ratio between the toxicity and activity. Two leaf fractions were tested in mice with Plasmodium berghei. RESULTS: All six fractions from the bark and leaf extracts were active in vitro at low doses (IC50 < 5.0 µg/mL) using the anti-HRPII test, and only two (the neutral and basic bark fractions) were toxic to a human cell line (HepG2). The most promising fractions were the crude leaf extract and its basic residue, which had SIs above 50. Among the four pure compounds evaluated, aspidoscarpine in the bark and leaf extracts showed the highest SI at 56; this compound, therefore, represents a possible anti-malarial drug that requires further study. The acidic leaf fraction administered by gavage to mice with blood-induced malaria was also active. CONCLUSION: Using a bio-monitoring approach, it was possible to attribute the anti-P. falciparum activity of A. olivaceum to aspidoscarpine and, to a lesser extent, N-methyl-tetrahydrolivacine; other isolated MIA molecules were active but had lower SIs due to their higher toxicities. These results stood in contrast to previous work in which the anti-malarial activity of other Aspidosperma species was attributed to uleine.


Assuntos
Antimaláricos/farmacologia , Aspidosperma/química , Alcaloides Indólicos/farmacologia , Extratos Vegetais/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/isolamento & purificação , Antimaláricos/toxicidade , Brasil , Sobrevivência Celular/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/toxicidade , Testes de Sensibilidade Parasitária , Casca de Planta/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Folhas de Planta/química
10.
PLoS One ; 9(3): e91191, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24651068

RESUMO

DNA topoisomerase I from Plasmodium falciparum (PfTopoI), a potential selective target for chemotherapy and drug development against malaria, is used here, together with human Topo I (HssTopoI), for docking, molecular dynamics (MD) studies and experimental assays. Six synthetic isoflavonoid derivatives and the known PfTopoI inhibitors camptothecin and topotecan were evaluated in parallel. Theoretical results suggest that these compounds dock in the binding site of camptothecin and topotecan inside both enzymes and that LQB223 binds selectively in PfTopoI. In vitro tests against P. falciparum blood parasites corroborated the theoretical findings. The selectivity index (SI) of LQB223 ≥ 98 suggests that this molecule is the most promising in the group of compounds tested. In vivo experiments in mice infected with P. berghei showed that LQB223 has an antimalarial activity similar to that of chloroquine.


Assuntos
Antimaláricos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Isoflavonas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Inibidores da Topoisomerase/farmacologia , Animais , Antimaláricos/química , Antimaláricos/uso terapêutico , Camptotecina/química , Camptotecina/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Isoflavonas/química , Isoflavonas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Parasitos/efeitos dos fármacos , Plasmodium berghei/efeitos dos fármacos , Termodinâmica , Inibidores da Topoisomerase/química , Topotecan/química , Topotecan/farmacologia
11.
Molecules ; 17(7): 8285-302, 2012 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-22781441

RESUMO

According to the World Health Organization, half of the World's population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiting factor, and the search for new drugs is important. We have designed and synthesized new 2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidine derivatives based on bioisosteric replacement of functional groups on the anti-malarial compounds mefloquine and amodiaquine. This approach enabled us to investigate the impact of: (i) ring bioisosteric replacement; (ii) a CF3 group substituted at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold and (iii) a range of amines as substituents at the 7-position of the of heterocyclic ring; on in vitro activity against Plasmodium falciparum. P. falciparum dihydroorotate dehydrogenase (PfDHODH) through strong hydrogen bonds. The presence of a trifluoromethyl group at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine ring led to increased drug activity. Thirteen compounds were found to be active, with IC50 values ranging from 0.023 to 20 µM in the anti-HRP2 and hypoxanthine assays. The selectivity index (SI) of the most active derivatives 5, 8, 11 and 16 was found to vary from 1,003 to 18,478.


Assuntos
Antimaláricos/farmacologia , Azóis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Azóis/síntese química , Azóis/química , Morte Celular/efeitos dos fármacos , Cloroquina/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Células Hep G2 , Humanos , Modelos Moleculares , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Quinolinas/química
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