Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 78
Filtrar
Mais filtros










Filtros aplicados
Base de dados
Intervalo de ano de publicação
1.
Med Res Rev ; 44(1): 66-137, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37222435

RESUMO

The demand for novel, fast-acting, and effective antimalarial medications is increasing exponentially. Multidrug resistant forms of malarial parasites, which are rapidly spreading, pose a serious threat to global health. Drug resistance has been addressed using a variety of strategies, such as targeted therapies, the hybrid drug idea, the development of advanced analogues of pre-existing drugs, and the hybrid model of resistant strains control mechanisms. Additionally, the demand for discovering new potent drugs grows due to the prolonged life cycle of conventional therapy brought on by the emergence of resistant strains and ongoing changes in existing therapies. The 1,2,4-trioxane ring system in artemisinin (ART) is the most significant endoperoxide structural scaffold and is thought to be the key pharmacophoric moiety required for the pharmacodynamic potential of endoperoxide-based antimalarials. Several derivatives of artemisinin have also been found as potential treatments for multidrug-resistant strain in this area. Many 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes derivatives have been synthesised as a result, and many of these have shown promise antimalarial activity both in vivo and in vitro against Plasmodium parasites. As a consequence, efforts to develop a functionally straight-forward, less expensive, and vastly more effective synthetic pathway to trioxanes continue. This study aims to give a thorough examination of the biological properties and mode of action of endoperoxide compounds derived from 1,2,4-trioxane-based functional scaffolds. The present system of 1,2,4-trioxane, 1,2,4-trioxolane, and 1,2,4,5-tetraoxane compounds and dimers with potentially antimalarial activity will be highlighted in this systematic review (January 1963-December 2022).


Assuntos
Antimaláricos , Artemisininas , Tetraoxanos , Humanos , Antimaláricos/química , Artemisininas/farmacologia , Artemisininas/química , Plasmodium falciparum , Revisões Sistemáticas como Assunto , Tetraoxanos/farmacologia , Tetraoxanos/química
2.
Eur J Med Chem ; 244: 114774, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36306538

RESUMO

The artemisinin resistance has posed a serious threat against malaria elimination lately. Past few years have seen important development of several peroxide based medicinal compounds and their derivatives such as trioxanes and tetraoxanes. Here, we report a rapid, one-pot method for synthesizing a new series of N-sulfonylpiperidine dispiro-1,2,4,5-tetraoxane analogs with diverse substitution on the tetraoxane ring i.e., various substituted alkyl and aryl sulfonyl chlorides, as well as cyclic, acyclic and aryl substituted ketones. All the synthesized tetraoxanes were characterized by spectroscopic (1H NMR,13C NMR), and spectrometric (High-resolution mass spectrometry) techniques and quantify by High Performance Liquid Chromatography (HPLC) analysis. The structure of compound 19 was confirmed by single crystal XRD. From the overall preliminary in vitro data, analogs 14, 16, 19, 20, 24, 41, and 44 exhibited potential IC50 values in the nanomolar range between 4.7 ± 0.3 to 12.9 ± 1.1 nM against P. falciparum (Pf3D7) strains of human malaria parasite. Furthermore, these selective analogs were evaluated in vivo for their antimalarial potential against P. berghei and results revealed that analogue 24 rapidly kills the infected cell at asexual erythrocytic stage, with activity comparable to positive control chloroquine.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Tetraoxanos , Camundongos , Humanos , Animais , Tetraoxanos/química , Antimaláricos/química , Plasmodium berghei , Plasmodium falciparum , Malária/tratamento farmacológico , Malária/parasitologia , Malária Falciparum/tratamento farmacológico
3.
Molecules ; 27(17)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36080174

RESUMO

Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane-pyrazole (OZ1, OZ2) and tetraoxane-pyrazole (T1, T2) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane-pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania promastigotes, while tetraoxane-pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound OZ1•HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide-pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of Leishmania. Our preliminary biological findings encourage further optimization of peroxide-pyrazole hybrids to identify a promising antileishmanial lead.


Assuntos
Antiprotozoários , Leishmania infantum , Leishmania , Leishmaniose , Tetraoxanos , Antiprotozoários/química , Humanos , Leishmaniose/tratamento farmacológico , Pirazóis/química , Tetraoxanos/farmacologia , Tetraoxanos/uso terapêutico
4.
ChemMedChem ; 17(20): e202200328, 2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36045616

RESUMO

Bridged aminoperoxides, for the first time, were investigated for the in vitro antimalarial activity against the chloroquine-resistant Plasmodium falciparum strain K1 and for their cytotoxic activities against immortalized human normal liver (LO2) and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer cell lines. Aminoperoxides exhibit good cytotoxicity against lung A549 cancer cell line. Synthetic ozonides were shown to have high activity against the chloroquine-resistant P. falciparum. A cyclic voltammetry study of peroxides was performed, and most of the compounds did not show a direct correlation in oxidative capacity-activity. Peroxides were analyzed for ROS production to understand their mechanism of action. However, none of the compounds has an impact on ROS generation, suggesting that ozonides induce apoptosis in HepG2 cells through ROS-independent dysfunction pathway.


Assuntos
Antimaláricos , Antagonistas do Ácido Fólico , Tetraoxanos , Humanos , Antimaláricos/farmacologia , Espécies Reativas de Oxigênio , Plasmodium falciparum , Peróxidos/farmacologia , Cloroquina
5.
Chempluschem ; 87(8): e202200207, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-36000152

RESUMO

Plasmodium falciparum artemisinin-resistance boosted the quest for novel plasmodial "fast killers," uncovering antimalarial candidates OZ439 and E209, whose peroxide precursors are 1,2,4-trioxolane (1) and 1,2,4,5-tetraoxane (2), differing solely in the pharmacophore (trioxolane or tetraoxane). Combining X-ray crystallography and vibrational spectroscopy, along with Hirshfeld surface analysis and calculations (CE-B3LYP/6-31G(d,p)) of pairwise interaction energies of intermolecular contacts existing in the crystal structure, may deepen the understanding of relative reactivity and properties of these endoperoxides classes. In the crystal, the tetraoxane ring in 2 and the trioxolane-adamantyl fragment in 1 are disordered, with molecules 1 and 2 existing as two distinct, stable conformations. Whereas the dominant C-H⋅⋅⋅O H-bonds in 1 connect an adamantyl C-H and O1 or O2 of the trioxolane ring, in 2 they involve the carbonyl oxygen, acting as a double acceptor from phenyl ring C-H groups. C-H⋅⋅⋅O and C-H⋅⋅⋅π H-bonds define the molecular packing of 2, while C-H⋅⋅⋅H-C van der Waals interactions determine the packing of 1. The dispersive component dominates the interaction energies calculated for the most representative molecular pairs.


Assuntos
Antimaláricos , Tetraoxanos , Antimaláricos/química , Antimaláricos/farmacologia , Antiparasitários , Estrutura Molecular , Peróxidos/química , Tetraoxanos/química , Tetraoxanos/farmacologia
6.
Int J Mol Sci ; 23(3)2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35163703

RESUMO

This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used for the construction and evaluation of pharmacophoric models. The pharmacophore-based virtual screening was performed on the Molport® database (~7.9 million compounds) and obtained 313 structures. Additionally, a pharmacokinetic study was developed, obtaining 174 structures with 99% confidence for human intestinal absorption and penetration into the blood-brain barrier (BBB); posteriorly, a study of toxicological properties was realized. Toxicological predictions showed that the selected molecules do not present a risk of hepatotoxicity, carcinogenicity, mutagenicity, and skin irritation. Only 54 structures were selected for molecular docking studies, and five structures showed binding affinity (ΔG) values satisfactory for ACE2 receptors (PDB 6M0J), in which the molecule MolPort-007-913-111 had the best ΔG value of -8.540 Kcal/mol, followed by MolPort-002-693-933 with ΔG = -8.440 Kcal/mol. Theoretical determination of biological activity was realized for 54 structures, and five molecules showed potential protease inhibitors. Additionally, we investigated the Mpro receptor (6M0K) for the five structures via molecular docking, and we confirmed the possible interaction with the target. In parallel, we selected the TopsHits 9 with antiviral potential that evaluated synthetic accessibility for future synthesis studies and in vivo and in vitro tests.


Assuntos
Hidroxicloroquina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Tetraoxanos/farmacologia , Antivirais/farmacologia , Sítios de Ligação , Biologia Computacional/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Hidroxicloroquina/análogos & derivados , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Inibidores de Proteases/farmacologia , Ligação Proteica/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Tratamento Farmacológico da COVID-19
7.
Molecules ; 26(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208832

RESUMO

The rapid emergence of drug resistance to the current antimalarial agents has led to the urgent need for the discovery of new and effective compounds. In this work, a series of 5-phenoxy primaquine analogs with 8-aminoquinoline core (7a-7h) was synthesized and investigated for their antimalarial activity against Plasmodium falciparum. Most analogs showed improved blood antimalarial activity compared to the original primaquine. To further explore a drug hybrid strategy, a conjugate compound between tetraoxane and the representative 5-phenoxy-primaquine analog 7a was synthesized. In our work, the hybrid compound 12 exhibited almost a 30-fold increase in the blood antimalarial activity (IC50 = 0.38 ± 0.11 µM) compared to that of primaquine, with relatively low toxicity against mammalian cells (SI = 45.61). Furthermore, we found that these 5-phenoxy primaquine analogs and the hybrid exhibit significant heme polymerization inhibition, an activity similar to that of chloroquine, which could contribute to their improved antimalarial activity. The 5-phenoxy primaquine analogs and the tetraoxane hybrid could serve as promising candidates for the further development of antimalarial agents.


Assuntos
Antimaláricos , Eritrócitos/parasitologia , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/crescimento & desenvolvimento , Primaquina , Tetraoxanos , Adulto , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Eritrócitos/metabolismo , Eritrócitos/patologia , Feminino , Humanos , Malária Falciparum/metabolismo , Malária Falciparum/patologia , Masculino , Pessoa de Meia-Idade , Primaquina/análogos & derivados , Primaquina/síntese química , Primaquina/química , Primaquina/farmacologia , Tetraoxanos/síntese química , Tetraoxanos/química , Tetraoxanos/farmacologia
8.
J Org Chem ; 86(15): 10608-10620, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34279102

RESUMO

A novel protocol for the preparation of non-symmetrical 1,2,4,5-tetraoxanes and 1,2,4-trioxanes, promoted by the heterogeneous silica sulfuric acid (SSA) catalyst, is reported. Different ketones react under mild conditions with gem-dihydroperoxides or peroxysilyl alcohols/ß-hydroperoxy alcohols to generate the corresponding endoperoxides in good yields. Our mechanistic proposal, assisted by molecular orbital calculations, at the ωB97XD/def2-TZVPP/PCM(DCM)//B3LYP/6-31G(d) level of theory, enhances the role of SSA in the cyclocondensation step. This novel procedure differs from previously reported methods by using readily available and inexpensive reagents, with recyclable properties, thereby establishing a valid alternative approach for the synthesis of new biologically active endoperoxides.


Assuntos
Tetraoxanos , Catálise , Compostos Heterocíclicos , Dióxido de Silício , Ácidos Sulfúricos
9.
Eur J Med Chem ; 219: 113408, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33989911

RESUMO

Emergence and spread of Plasmodium falciparum resistant to artemisinin-based combination therapy has led to a situation of haste in the scientific and pharmaceutical communities. Sincere efforts are redirected towards finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. Extensive research yielded the concept of "Chimeric Bitherapy (CB)" which involves the linking of two molecules with individual pharmacological activity and exhibit dual mode of action into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs and are more effective compared to the multi-component drugs because of the lower occurrence of drug-drug adverse effects. This review is an attempt to congregate complete survey on endoperoxide based hybrid antiplasmodial molecules that will give glimpse on the future directions for successful development and discovery of useful antimalarial hybrid drugs.


Assuntos
Antimaláricos/química , Malária/tratamento farmacológico , Acridinas/química , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Artemisininas/química , Artemisininas/uso terapêutico , Desenho de Fármacos , Meia-Vida , Humanos , Quinolinas/química , Tetraoxanos/química
10.
SAR QSAR Environ Res ; 31(9): 677-695, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32854545

RESUMO

A set of 23 steroidal 1,2,4,5-tetraoxane analogues were studied using quantum-chemical method (B3LYP/6-31 G*) and multivariate analyses (PCA, HCA, KNN and SIMCA) in order to calculate the properties and correlate them with antimalarial activity (log RA) against Plasmodium falciparum clone D-6 from Sierra Leone. PCA results indicated 99.94% of the total variance and it was possible to divide the compounds into two classes: less and more active. Descriptors responsible for separating were: highest occupied molecular orbital energy (HOMO), bond length (O1-O2), Mulliken electronegativity (χ) and Bond information content (BIC0). We use HCA, KNN and SIMCA to explain relationships between molecular properties and biological activity of a training set and to predict antimalarial activity (log RA) of 13 compounds (#24-36) with unknown biological activity. We apply molecular docking simulations to identify intermolecular interactions with a selected biological target. The results obtained in multivariate analysis aided in the understanding of the activity of the new compound's design (#24-36). Thus, through chemometric analyses and docking molecular study, we propose theoretical synthetic routes for the most promising compounds 28, 30, 32 and 36 that can proceed to synthesis steps and in vitro and in vivo assays.


Assuntos
Antimaláricos/química , Desenho de Fármacos , Plasmodium falciparum/efeitos dos fármacos , Tetraoxanos/química , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade
11.
Chem Biodivers ; 17(6): e2000142, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32294320

RESUMO

Leishmaniasis is a neglected disease, caused by a parasite of Leishmania genus and widespread in the tropical and subtropical areas of the world. Currents drugs are limited due to their toxicity and parasite resistance. Therefore, the discovery of new treatment, more effective and less toxic, is urgent. In this study, we report the synthesis of six gem-dihydroperoxides (2a-2f), with yields ranging from 10 % to 90 %, utilizing a new methodology. The dihydroperoxides were converted into ten tetroxanes (3a-3j), among which six (3b, 3c, 3d, 3g, 3h and 3j) showed activity against intracellular amastigotes of Leishmania amazonensis. The cytotoxicity of all compounds was also evaluated against canine macrophages (DH82), human hepatoma (HepG2) and monkey renal cells (BGM). Most compounds were more active and less toxic than potassium antimonyl tartrate trihydrate, used as positive control. Amongst all tetroxanes, 3b (IC50 =0.64 µm) was the most active, being more selective than positive control in relation to DH82, HepG2 and BGM cells. In summary, the results revealed a hit compound for the development of new drugs to treat leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Tetraoxanos/química , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cães , Haplorrinos , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Tetraoxanos/síntese química , Tetraoxanos/farmacologia
12.
Molecules ; 25(3)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31979089

RESUMO

A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.


Assuntos
Antiprotozoários/química , Antiprotozoários/uso terapêutico , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/patogenicidade , Tetraoxanos/química , Tetraoxanos/uso terapêutico , Animais , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Camundongos , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Fosforilcolina/uso terapêutico
13.
Med Chem ; 16(3): 392-402, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31208310

RESUMO

BACKGROUND: With few exceptions, existing tuberculosis drugs were developed many years ago and resistance profiles have emerged. This has created a need for new drugs with discrete modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner similar to that which has proven highly successful in malaria therapy. OBJECTIVE: To develop an alternative approach to the incorporation of bacterial siderophores that results in the creation of antitubercular peroxidic leads for subsequent development as novel agents against tuberculosis. METHODS: Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro. RESULTS: The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic structure results in antitubercular activity in vitro. The same effect is not observed in the absence of the pyrimidine or with other heteroaromatic substituents. CONCLUSION: The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound. This will be a useful approach for creating oxidative drugs to target tuberculosis.


Assuntos
Antituberculosos/farmacologia , Artemisininas/farmacologia , Tetraoxanos/farmacologia , Animais , Antituberculosos/síntese química , Artemisininas/síntese química , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Ratos , Tetraoxanos/síntese química
14.
Chemistry ; 26(21): 4734-4751, 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-31774931

RESUMO

The catalyst H3+x PMo12-x +6 Mox +5 O40 supported on SiO2 was developed for peroxidation of 1,3- and 1,5-diketones with hydrogen peroxide with the formation of bridged 1,2,4,5-tetraoxanes and bridged 1,2,4-trioxolanes (ozonides) with high yield based on isolated products (up to 86 and 90 %, respectively) under heterogeneous conditions. Synthesis of peroxides under heterogeneous conditions is a rare process and represents a challenge for this field of chemistry, because peroxides tend to decompose on the surface of a catalyst . A new class of antifungal agents for crop protection, that is, cyclic peroxides: bridged 1,2,4,5-tetraoxanes and bridged ozonides, was discovered. Some ozonides and tetraoxanes exhibit a very high antifungal activity and are superior to commercial fungicides, such as Triadimefon and Kresoxim-methyl. It is important to note that none of the fungicides used in agricultural chemistry contains a peroxide fragment.


Assuntos
Fungicidas Industriais/química , Compostos Heterocíclicos/química , Peróxido de Hidrogênio/química , Cetonas/química , Peróxidos/síntese química , Dióxido de Silício/química , Tetraoxanos/síntese química , Catálise , Fungicidas Industriais/síntese química , Peróxidos/química , Tetraoxanos/química
15.
PLoS Negl Trop Dis ; 13(3): e0007235, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30908481

RESUMO

Visceral leishmaniasis (VL) is a major problem worldwide and causes significant morbidity and mortality. Existing drugs against VL have limitations, including their invasive means of administration long duration of treatment regimens. There are also concerns regarding increasing treatment relapses as well as the identification of resistant clinical strains with the use of miltefosine, the sole oral drug for VL. There is, therefore, an urgent need for new alternative oral drugs for VL. In the present study, we show the leishmanicidal effect of a novel, oral antimalarial endoperoxide N-251. In our In vitro studies, N-251 selectively and specifically killed Leishmania donovani D10 amastigotes with no accompanying toxicity toward the host cells. In addition, N-251 exhibited comparable activities against promastigotes of L. donovani D10, as well as other L. donovani complex parasites, suggesting a wide spectrum of activity. Furthermore, even after a progressive infection was established in mice, N-251 significantly eliminated amastigotes when administered orally. Finally, N-251 suppressed granuloma formation in mice liver through parasite death. These findings indicate the therapeutic effect of N-251 as an oral drug, hence suggest N-251 to be a promising lead compound for the development of a new oral chemotherapy against VL.


Assuntos
Antimaláricos/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Compostos de Espiro/administração & dosagem , Tetraoxanos/administração & dosagem , Animais , Antimaláricos/farmacologia , Antiprotozoários/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Leishmania donovani/fisiologia , Leishmaniose Visceral/patologia , Fígado/patologia , Camundongos Endogâmicos BALB C , Compostos de Espiro/farmacologia , Tetraoxanos/farmacologia , Resultado do Tratamento
16.
Bioorg Med Chem ; 26(11): 2996-3005, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29779669

RESUMO

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.


Assuntos
Antimaláricos/uso terapêutico , Malária , Morfolinas/síntese química , Plasmodium falciparum , Tetraoxanos/síntese química , Administração Oral , Animais , Antimaláricos/síntese química , Antimaláricos/química , Modelos Animais de Doenças , Estabilidade de Medicamentos , Humanos , Concentração Inibidora 50 , Malária/tratamento farmacológico , Camundongos , Morfolinas/química , Morfolinas/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Ratos , Tetraoxanos/química , Tetraoxanos/uso terapêutico
17.
Steroids ; 129: 17-23, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29180289

RESUMO

A series of new steroidal peroxides - 3'-trifluoromethylated 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes based on deoxycholic acid were prepared via the reactions of the Griesbaum coozonolysis and peroxycondensation, respectively. 1,2,4-Trioxolanes were synthesized by the interaction of methyl O-methyl-3-oximino-12α-acetoxy-deoxycholate with CF3C(O)CH3 or CF3C(O)Ph and O3 as the mixtures of four possible stereoisomers at ratios of 1:2:2:1 and in yields of 50% and 38%, respectively. The major diastereomer of methyl 12α-acetoxy-5ß-cholan-24-oate-3-spiro-5'-(3'-methyl-3'-trifluoromethyl-1',2',4'-trioxolane) was isolated via crystallization of a mixture of stereoisomers from hexane and its (3S,3'R)-configuration was determined using X-ray crystallographic analysis. Peroxycondensation of methyl 3-bishydroperoxy-12α-acetoxy-deoxycholate with CF3C(O)CH3 or acetone led to 1,2,4,5-tetraoxanes in yields of 44% and 37%, respectively. Antimalarial activity of these new steroidal peroxides was evaluated in vitro against the chloroquine-sensitive (CQS) T96 and chloroquine-resistant (CQR) K1 strains of Plasmodium falciparum. Deoxycholic acid 3'-trifluoromethylated 1,2,4,5-tetraoxane demonstrated a good IC50 value against CQR-strain (IC50 (K1) = 7.6 nM) of P. falciparum. Tetraoxane with the acetone subunit demonstrated the best results among all tested peroxides with an IC50 value of 3 nM against the CQ-resistant K1 strain. In general, 1,2,4-trioxolanes of deoxycholic acid are less active than 1,2,4,5-tetraoxanes.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Ácido Desoxicólico/química , Furanos/síntese química , Furanos/farmacologia , Tetraoxanos/síntese química , Tetraoxanos/farmacologia , Antimaláricos/química , Técnicas de Química Sintética , Furanos/química , Metilação , Modelos Moleculares , Conformação Molecular , Plasmodium falciparum/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Tetraoxanos/química
18.
Parasitol Int ; 66(5): 619-621, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28571765

RESUMO

Metronidazole is well known for medicine against Trichomonas vaginalis infection, but it has side effects though it is effective, and especially because reports of metronidazole-tolerant species are increasing, the development of new medicine is being required. Here, we noticed the killing effects of endoperoxide compounds, N-89 and N-251 as new antimalarial drug candidates, on T. vaginalis and searched the possibility of development of new medicine. We added each of metronidazole, artemisinin, and two of new endoperoxides (N-89 and N-251) to metronidazole-resistant and -sensitive species and compared its anti-trichomonal efficacy. For metronidazole, IC50 value, 50% of killing concentration for T. vaginalis, was very low for metronidazole-sensitive isolates (11.7 to 22.8µM), but was high for metronidazole-resistant ones (182.9 to 730.4µM). The IC50 values of N-89 and N-251 were 41.0 to 60.0µM, and 82.0 to 300.0µM for metronidazole-sensitive and -resistant isolates, respectively. In conclusion, we found the endoperoxides, N-89 and N-251, have anti-trichomonal effect against metronidazole-resistant T. vaginalis as well as metronidazole-sensitive ones. These results indicate that the anti-trichomonal effects for our endoperoxides are equivalent or better in metronidazole-resistant T. vaginalis in comparison to metronidazole.


Assuntos
Antiprotozoários/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos de Espiro/farmacologia , Tetraoxanos/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Artemisininas/farmacologia , Resistência a Medicamentos , Compostos Heterocíclicos com 2 Anéis/síntese química , Concentração Inibidora 50 , Metronidazol/farmacologia , Compostos de Espiro/síntese química , Tetraoxanos/síntese química
19.
Nat Commun ; 8: 15159, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28537265

RESUMO

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Proteínas de Protozoários/metabolismo , Tetraoxanos/química , Tetraoxanos/farmacologia , Animais , Antimaláricos/química , Cães , Relação Dose-Resposta a Droga , Resistência a Medicamentos/genética , Eritrócitos/parasitologia , Feminino , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Plasmodium falciparum/genética , Plasmodium vivax/genética , Ratos , Ratos Sprague-Dawley , Tetraoxanos/farmacocinética , Transgenes
20.
Parasitol Int ; 66(1): 917-924, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27771462

RESUMO

The new synthetic compound 1,2,6,7-tetraoxaspiro[7.11]nonadecan (N-89), a novel anti-malaria drug candidate, is also a promising drug candidate against schistosomiasis with killing effects against juvenile stage of S. mansoni. In order to investigate how N-89 kills schistosomes, we used a derivative of N-89, 6-(1,2,6,7-tetraoxaspiro[7.11] nonadec-4-yl)hexan-1-ol (N-251), which enables us to conjugate with fluorescent reagents. Firstly, N-251 showed strong killing effects to larvae of S. mansoni in vitro. Ultrastructural analysis showed the disruptions of the lysosome-like organelles or the acetabular glands, followed by cytoplasmic lysis inside the worm body in N-251-treated group under electron microscopy. For rhodamine-conjugated N-251 and organelle markers, we observed that N-251 accumulated in acidic organelle. In addition, LysoTracker signals in these acidic organelles disappeared in N-251-treated group over time. Finally, we observed that the activity of cathepsin B, a lysosome-specific enzyme, was also decreased together with alternation of acidic organelle marker signal by N-251-treated group. These results suggested that our synthesized compounds induced the dysfunction or the disruption of acidic lysosome-like organelles and finally led to worm death.


Assuntos
Lisossomos/efeitos dos fármacos , Organelas/efeitos dos fármacos , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/crescimento & desenvolvimento , Esquistossomicidas/farmacologia , Compostos de Espiro/farmacologia , Tetraoxanos/farmacologia , Animais , Catepsina B/metabolismo , Descoberta de Drogas , Compostos Heterocíclicos com 2 Anéis/farmacologia , Larva/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Lisossomos/patologia , Lisossomos/ultraestrutura , Microscopia Eletrônica de Transmissão , Organelas/química , Organelas/ultraestrutura , Rodaminas/química , Schistosoma mansoni/ultraestrutura , Compostos de Espiro/metabolismo , Tetraoxanos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...