RESUMO
Malaria is a life-threatening disease that affects tropical and subtropical regions worldwide. Various drugs were used to treat malaria, including artemisinin and derivatives, antibiotics (tetracycline, doxycycline), quinolines (chloroquine, amodiaquine), and folate antagonists (sulfadoxine and pyrimethamine). Since the malarial parasites developed drug resistance, there is a need to develop new chemical entities with high efficacy and low toxicity. In this context, 1,2,4,5-tetraoxanes emerged as an essential scaffold and have shown promising antimalarial activity. To improve activity and overcome resistance to various antimalarial drugs; 1,2,4,5-tetraoxanes were fused with various aryl/heteroaryl/alicyclic/spiro moieties (steroid-based 1,2,4,5-tetraoxanes, triazine-based 1,2,4,5-tetraoxanes, aminoquinoline-based 1,2,4,5-tetraoxanes, dispiro-based 1,2,4,5-tetraoxanes, piperidine-based 1,2,4,5-tetraoxanes and diaryl-based 1,2,4,5-tetraoxanes). The present review aims to focus on covering the relevant literature published during the past 30 years (1992-2022). We summarize the most significant in vitro, in vivo results and structure-activity relationship studies of 1,2,4,5-tetraoxane-based hybrids as antimalarial agents. The structural evolution of different hybrids can provide the framework for the future development of 1,2,4,5-tetraoxane-based hybrids to treat malaria.
Assuntos
Antimaláricos , Tetraoxanos , Antimaláricos/farmacologia , Antimaláricos/química , Relação Estrutura-Atividade , Humanos , Tetraoxanos/farmacologia , Tetraoxanos/química , Animais , Malária/tratamento farmacológico , Peróxidos/química , Peróxidos/farmacologia , Plasmodium falciparum/efeitos dos fármacosRESUMO
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/químicaRESUMO
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 farmacológicoRESUMO
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-Hâ â â 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-Hâ â â O and C-Hâ â â π H-bonds define the molecular packing of 2, while C-Hâ â â 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/farmacologiaRESUMO
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/farmacologiaRESUMO
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/químicaRESUMO
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-AtividadeRESUMO
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 =0.64â 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/farmacologiaRESUMO
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 terapêuticoRESUMO
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/químicaRESUMO
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 0.84â¯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 terapêuticoRESUMO
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)â¯=â¯7.6â¯nM) of P. falciparum. Tetraoxane with the acetone subunit demonstrated the best results among all tested peroxides with an IC50 value of 3â¯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/químicaRESUMO
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 , TransgenesRESUMO
Praziquantel is currently the only drug available to treat schistosomiasis. Since drug resistance would be a major barrier for the increasing global attempts to eliminate schistosomiasis as a public health problem, efforts should go hand in hand with the discovery of novel treatment options. Synthetic peroxides might offer a good direction since their antischistosomal activity has been demonstrated in the laboratory. We studied 19 bridged 1,2,4,5-tetraoxanes, 2 tricyclic monoperoxides, 11 bridged 1,2,4-trioxolanes, 12 silyl peroxides, and 4 hydroxylamine derivatives against newly transformed schistosomula (NTS) and adult Schistosoma mansoni in vitro. Schistosomicidal compounds were tested for cytotoxicity followed by in vivo studies of the most promising compounds. Tricyclic monoperoxides, trioxolanes, and tetraoxanes revealed the highest in vitro activity against NTS (IC50s 0.4-20.2 µM) and adult schistosomes (IC50s 1.8-22.8 µM). Tetraoxanes showed higher cytotoxicity than antischistosomal activity. Selected trioxolane and tricyclic monoperoxides were tested in mice harboring an adult S. mansoni infection. The highest activity was observed for two trioxolanes, which showed moderate worm burden reductions (WBR) of 44.3% and 42.9% (p>0.05). Complexation of the compounds with ß-cyclodextrin with the aim to improve solubility and gastrointestinal absorption did not increase in vivo antischistosomal efficacy. The high in vitro antischistosomal activity of trioxolanes and tricyclic monoperoxides is a promising basis for future investigations, with the focus on improving in vivo efficacy.
Assuntos
Descoberta de Drogas , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/química , Esquistossomicidas/uso terapêutico , Animais , Feminino , Humanos , Hidroxilamina/química , Hidroxilamina/farmacologia , Hidroxilamina/uso terapêutico , Camundongos , Peróxidos/química , Peróxidos/farmacologia , Peróxidos/uso terapêutico , Esquistossomicidas/farmacologia , Tetraoxanos/química , Tetraoxanos/farmacologia , Tetraoxanos/uso terapêuticoRESUMO
The reaction of ß,δ-triketones with an ethereal solution of H2O2 catalyzed by heteropoly acids in the presence of a polar aprotic co-solvent proceeds via three pathways to form three classes of peroxides: tricyclic monoperoxides, bridged tetraoxanes, and a pair of stereoisomeric ozonides. The reaction is unusual in that produces bridged tetraoxanes and ozonides with one of the three carbonyl groups remaining intact. In the synthesis of bridged tetraoxanes, the peroxide ring is formed by the reaction of hydrogen peroxide with two carbonyl groups at the ß positions. The synthesis of ozonides from ketones and hydrogen peroxide is a unique process in which the ozonide ring is formed with the participation of two carbonyl groups at the δ positions. Rearrangements of ozonides were found for the first time after more than one century of their active investigation. Ozonides are interconverted with each other and rearranged into tricyclic monoperoxides, whereas ozonides and tricyclic monoperoxides are transformed into bridged tetraoxanes. The individual reaction products were isolated by column chromatography and characterized by NMR spectroscopy, mass spectrometry, and elemental analysis. One representative of each class of peroxides was characterized by X-ray diffraction.
Assuntos
Compostos Heterocíclicos/síntese química , Peróxido de Hidrogênio/química , Cetonas/química , Peróxidos/síntese química , Ciclização , Compostos Heterocíclicos/química , Peróxidos/química , Tetraoxanos/síntese química , Tetraoxanos/química , Difração de Raios XRESUMO
The chromatographic behavior of mixed 1,2,4,5-tetraoxanes, cholic and deoxycholic acid derivatives with distinct biological activity, was examined by high-performance thin-layer chromatography in order to correlate their structure and retention. Chromatographic systems were consisted of RP-18 or CN-silica as stationary phase, and binary mixtures of water with methanol, dioxane or acetone as mobile phase. Based on the respective retentions, the lipophilicity of the investigated compounds was determined. Multiple linear regression and partial least squares have been used to select variables that best describe the behavior of the investigated compounds in chromatographic systems and to quantify influences of most important parameters. The validation and cross-validation of the QSRR model suggest its applicability for prediction and understanding of retention of congeners. The models indicate the importance of nonpolar properties of the solutes and their ability for hydrophobic interactions, as well as the importance of proton donating abilities, hydrophilic and π interactions pointing out on that way the possible separation mechanism in the studied chromatographic systems. Observed correlations between structure and biological activity of mixed 1,2,4,5-tetraoxanes, indicate that the antimalarial activity against W2 and D6 Plasmodium falciparum strains, is governed by hydrophobic feature (measured with lipophilicity parameter), hydrophilic feature (measured with HLB, %HS, HB and HBA descriptors), and electronic feature (HOMO).
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Plasmodium falciparum/efeitos dos fármacos , Tetraoxanos/química , Tetraoxanos/farmacologia , Cromatografia em Camada Fina , Modelos Químicos , Estrutura Molecular , Relação Quantitativa Estrutura-AtividadeRESUMO
Cyclic organic peroxides are a broad and highly sought-after class of peroxide compounds that present high reactivity and even explosive character. The unusually high reactivity of these peroxides can generally be attributed to the rupture of O-O bonds. Cyclic diperoxides are a very interesting series of substituted compounds in which tetroxane is the most prominent member. Gas-phase thermolysis of the simplest substituted member of the series [3-methyl-1,2,4,5-tetroxane or methylformaldehyde diperoxide (MFDP)] has been observed to yield one acetaldehyde, one formaldehyde, and one oxygen molecule as reaction products. DFT at the 6-311 + G** level of theory using the BHANDHLYP correlation-exchange functional was applied via the Gaussian09 program to calculate the critical points of the potential energy surface (PES) of this reaction. Equatorial and axial isomers were studied. The singlet state PES of MFDP was calculated, and an open diradical structure was found to be the first intermediate in a stepwise reaction. Two PESs were subsequently obtained: singlet state (S) and triplet state (T) PESs. After that, two alternative stepwise reactions were found to be possible: 1) one in which either an acetaldehyde, or 2) formaldehyde molecule is initially formed. For second one, exothermic reactions were observed for both the S and T PESs. The reaction products include a oxygen molecule in either S or T state, with the T reaction being the most exothermic. When calculations were performed at the CASSCF(10,10)/6-311 + G** level, spin-orbit coupling permitted S to T crossing at the open diradical intermediate stage, a non-adiabatic reaction was observed, and lower activation energies and higher exothermicity were generally seen for the T PES than for the S PES. These results were compared with the corresponding results for tetroxane. The spin-orbit coupling of MFDP and tetroxane yielded identical values, so it appears that the methyl substituent does not have any effect on this coupling.
Assuntos
Simulação por Computador , Explosões , Modelos Químicos , Modelos Moleculares , Temperatura , Tetraoxanos/química , Acetaldeído/química , Transferência de Energia , Formaldeído/química , Gases , Estrutura Molecular , Oxigênio/químicaRESUMO
The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of Plasmodium parasites. Our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. In this study, we adapted this approach to a novel class of falcipain inhibitors: peptidomimetic pyrimidine nitriles. Pyrimidine tetraoxane hybrids displayed potent nanomolar activity against three strains of Plasmodium falciparum and falcipain-2, combined with low cytotoxicity. In vivo, a decrease in parasitemia and an increase in survival of mice infected with Plasmodium berghei was observed when compared to control. All tested compounds combined good blood stage activity with significant effects on liver stage parasitemia, a most welcome feature for any new class of antimalarial drug.
Assuntos
Antimaláricos/síntese química , Nitrilas/síntese química , Peptidomiméticos/síntese química , Pirimidinas/síntese química , Tetraoxanos/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Linhagem Celular , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Malária/tratamento farmacológico , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Nitrilas/química , Nitrilas/farmacologia , Estresse Oxidativo , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Tetraoxanos/química , Tetraoxanos/farmacologiaRESUMO
With the emergence of resistance to artemesinin, the need for new antimalarial compounds is pressing. Several research groups have made significant contributions to the exploration of the use of 1,2,4,5-tetraoxanes and 1,2,4- trioxanes as synthetic analogues of artemesinin. This short review highlights the recent developments in this field detailing both biological results and useful synthetic methodology. In addition, the current understanding of the mode of action of this class of compounds has been described.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Malária/tratamento farmacológico , Peróxidos/química , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Tetraoxanos/farmacologia , Antimaláricos/síntese química , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tetraoxanos/síntese química , Tetraoxanos/químicaRESUMO
The synthesis of a range of mono spiro and dispiro 1,2,4,5-tetraoxane dimers is described. Selected molecules were examined in in vitro assays to determine their antimalarial and anticancer potential. Our studies reveal that several molecules possess potent nanomolar antimalarial and single digit micromolar antiproliferative IC(50)s versus colon (HT29-AK and leukemia (HL60) cell lines.