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1.
Molecules ; 26(4)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671751

RESUMO

Green synthetic protocol refers to the development of processes for the sustainable production of chemicals and materials. For the synthesis of various biologically active compounds, energy-efficient and environmentally benign processes are applied, such as microwave irradiation technology, ultrasound-mediated synthesis, photo-catalysis (ultraviolet, visible and infrared irradiation), molecular sieving, grinding and milling techniques, etc. Thesemethods are considered sustainable technology and become valuable green protocol to synthesize new drug molecules as theyprovidenumerous benefits over conventional synthetic methods.Based on this concept, oxadiazole derivatives are synthesized under microwave irradiation technique to reduce the formation of byproduct so that the product yield can be increased quantitatively in less reaction time. Hence, the synthesis of drug molecules under microwave irradiation follows a green chemistry approach that employs a set of principles to minimize or remove the utilization and production of hazardous toxic materials during the design, manufacture and application of chemical substances.This approach plays a major role in controlling environmental pollution by utilizing safer solvents, catalysts, suitable reaction conditions and thereby increases the atom economy and energy efficiency. Oxadiazole is a five-membered heterocyclic compound that possesses one oxygen and two nitrogen atoms in the ring system.Oxadiazole moiety is drawing considerable interest for the development of new drug candidates with potential therapeutic activities including antibacterial, antifungal, antiviral, anticonvulsant, anticancer, antimalarial, antitubercular, anti-asthmatic, antidepressant, antidiabetic, antioxidant, antiparkinsonian, analgesic and antiinflammatory, etc. This review focuses on different synthetic approaches of oxadiazole derivatives under microwave heating method and study of their various biological activities.


Assuntos
Oxidiazóis/síntese química , Micro-Ondas , Estrutura Molecular , Oxidiazóis/química , Oxidiazóis/farmacologia
2.
Molecules ; 26(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673047

RESUMO

The analysis of stability of biologically active compounds requires an accurate determination of their structure. We have found that 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles are generally unstable in the presence of acids and bases and are rearranged into the salts of spiropyrazolinium compounds. Hence, there is a significant probability that it is the rearranged products that should be attributed to biological activity and not the primarily screened 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles. A series of the 2-amino-8-oxa-1,5-diazaspiro[4.5]dec-1-en-5-ium (spiropyrazoline) benzoates and chloride was synthesized by Boulton-Katritzky rearrangement of 5-substituted phenyl-3-[2-(morpholin-1-yl)ethyl]-1,2,4-oxadiazoles and characterized using FT-IR and NMR spectroscopy and X-ray diffraction. Spiropyrazolylammonium chloride demonstrates in vitro antitubercular activity on DS (drug-sensitive) and MDR (multidrug-resistant) of MTB (M. tuberculosis) strains (1 and 2 µg/mL, accordingly) equal to the activity of the basic antitubercular drug rifampicin; spiropyrazoline benzoates exhibit an average antitubercular activity of 10-100 µg/mL on MTB strains. Molecular docking studies revealed a series of M. tuberculosis receptors with the energies of ligand-receptor complexes (-35.8--42.8 kcal/mol) close to the value of intermolecular pairwise interactions of the same cation in the crystal of spiropyrazolylammonium chloride (-35.3 kcal/mol). However, only in complex with transcriptional repressor EthR2, both stereoisomers of the cation realize similar intermolecular interactions.


Assuntos
Antituberculosos/química , Benzoatos/química , Oxidiazóis/química , Tuberculose/tratamento farmacológico , Antituberculosos/farmacologia , Benzoatos/farmacologia , Cloretos/química , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Oxidiazóis/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo , Relação Estrutura-Atividade , Tuberculose/microbiologia
3.
SAR QSAR Environ Res ; 32(3): 175-190, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33618568

RESUMO

Cannabinoid receptor has been shown to be overexpressed in various types of cancers, especially non-small cell lung cancer. As a result, it could be used as novel target for anticancer treatments. Because receptor-dependent 4D-QSAR generates conformational ensemble profiles of compounds by molecular dynamics simulations at the binding site of the enzyme, this work describes the synthesis, biological activity evaluation and 4D-QSAR studies of 4,5-dihydro-1,3,4-oxadiazole derivatives targeting cannabinoid receptor. Compared with WIN55,212-2, compound 5 f showed the best antiproliferative activity. The receptor-dependent 4D-QSAR model was generated by multiple linear regression method using QSARINS. Leave-n-out cross-validation and chemical applicability domain were performed to analyse the independent test set and to verify the robustness of the model. The best 4D-QSAR model showed the following statistics: r2 = 0.8487, Q2LOO = 0.7667, Q2LNO = 0.7524, and r2Pred = 0.8358.


Assuntos
Oxidiazóis/farmacologia , Relação Quantitativa Estrutura-Atividade , Receptores de Canabinoides/efeitos dos fármacos , Células A549 , Proliferação de Células/efeitos dos fármacos , Humanos , Conformação Molecular , Simulação de Dinâmica Molecular , Oxidiazóis/síntese química , Oxidiazóis/química
4.
Biomed Pharmacother ; 134: 111162, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33360932

RESUMO

Non-specific histone deacetylase (HDAC) inhibition reduces high blood pressure in essential hypertensive animal models. However, the exact HDAC isoforms that play a critical role in controlling hypertension are not known. Here, we investigated the role of HDAC5 in vascular contraction, hypertrophy, and oxidative stress in the context of angiotensin II (Ang II)-induced hypertension. Genetic deletion of HDAC5 and treatment with class IIa HDAC inhibitors (TMP269 and TMP195) prevented Ang II-induced increases in blood pressure and arterial wall thickness. Hdac5-knockout mice were also resistant to the thromboxane A2 agonist (U46619)-induced vascular contractile response. Furthermore, the expression of Rho-associated protein kinase (ROCK) 2 was downregulated in the aortas of Ang II-treated Hdac5-knockout mice. Knockdown of HDAC5, RhoA, or ROCK2 reduced collagen gel contraction, whereas silencing of ROCK1 increased it. VSMC hypertrophy reduced on knocking down HDAC5, ROCK1, and ROCK2. Here we showed that genetic deletion of HDAC5 and pharmacological inhibition of class IIa HDACs ameliorated Ang II-induced ROS generation. Moreover, ROCK1 and ROCK2, the downstream targets of HDAC5, influenced ROS generation. The relative protein levels of HDAC5, ROCK1, and ROCK2 were increased both in the cytoplasm and nuclear fraction in response to Ang II stimulation in vascular smooth muscle cells. Inhibition of HDAC5 expression or activity reduced vascular hypertrophy, vasoconstriction, and oxidative stress in the Ang II-induced hypertension model. These findings indicate that HDAC5 may serve as a potential target in the treatment of hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Benzamidas/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Hipertensão/prevenção & controle , Músculo Liso Vascular/efeitos dos fármacos , Oxidiazóis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Angiotensina II , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Aorta Torácica/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Histona Desacetilases/deficiência , Histona Desacetilases/genética , Hipertensão/induzido quimicamente , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
5.
PLoS One ; 15(12): e0232864, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33373369

RESUMO

Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses (Margolis et al. 2003, 2006); therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of 3.0 ± 4.6 nM. PF-04455242 exhibited partial antagonist activity asymptoting at 55% blockade (IC50 = 6.7 ± 15.1 nM). In 3/8 of neurons, 1 µM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO and DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within circuits implicated in the neurobehavioral disorders of interest.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Receptores Opioides kappa/antagonistas & inibidores , Analgésicos Opioides/farmacologia , Animais , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Neurônios Dopaminérgicos/metabolismo , Eletrofisiologia , D-Penicilina (2,5)-Encefalina/farmacologia , Masculino , Mesencéfalo/metabolismo , Antagonistas de Entorpecentes/farmacologia , Oxidiazóis/farmacologia , Técnicas de Patch-Clamp/métodos , Piperidinas/farmacologia , Pirrolidinas/farmacologia , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Sulfonamidas/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos
6.
PLoS One ; 15(9): e0238178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32946441

RESUMO

Mycobacterium abscessus (M. abscessus), a rapidly growing mycobacterium, is an emergent opportunistic pathogen responsible for chronic bronchopulmonary infections in individuals with respiratory diseases such as cystic fibrosis. Most treatments of M. abscessus pulmonary infections are poorly effective due to the intrinsic resistance of this bacteria against a broad range of antibiotics including anti-tuberculosis agents. Consequently, the number of drugs that are efficient against M. abscessus remains limited. In this context, 19 oxadiazolone (OX) derivatives have been investigated for their antibacterial activity against both the rough (R) and smooth (S) variants of M. abscessus. Several OXs impair extracellular M. abscessus growth with moderated minimal inhibitory concentrations (MIC), or act intracellularly by inhibiting M. abscessus growth inside infected macrophages with MIC values similar to those of imipenem. Such promising results prompted us to identify the potential target enzymes of the sole extra and intracellular inhibitor of M. abscessus growth, i.e., compound iBpPPOX, via activity-based protein profiling combined with mass spectrometry. This approach led to the identification of 21 potential protein candidates being mostly involved in M. abscessus lipid metabolism and/or in cell wall biosynthesis. Among them, the Ag85C protein has been confirmed as a vulnerable target of iBpPPOX. This study clearly emphasizes the potential of the OX derivatives to inhibit the extracellular and/or intracellular growth of M. abscessus by targeting various enzymes potentially involved in many physiological processes of this most drug-resistant mycobacterial species.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Mycobacterium abscessus/efeitos dos fármacos , Oxidiazóis/química , Oxidiazóis/farmacologia , Animais , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/microbiologia , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium abscessus/crescimento & desenvolvimento , Células RAW 264.7
7.
J Med Chem ; 63(15): 8216-8230, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32786237

RESUMO

Herein, we disclose three structurally differentiated γ-secretase modulators (GSMs) based on an oxadiazine scaffold. The analogues from series I potently inhibit the generation of Aß42 in vitro when the substituents at 3 and 4 positions of the oxadiazine moiety adopt an α orientation (cf. 11). To address the concern around potential reactivity of the exocyclic double bond present in series I toward nucleophilic attack, compounds containing either an endocyclic double bond, such as 20 (series II), or devoid of an olefinic moiety, such as 27 (series III), were designed and validated as novel GSMs. Compound 11 and azepine 20 exhibit robust lowering of CSF Aß42 in rats treated with a 30 mg/kg oral dose.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Alcenos/química , Alcenos/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Sítios de Ligação/fisiologia , Células HEK293 , Humanos , Oxidiazóis/química , Oxidiazóis/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/líquido cefalorraquidiano , Ratos , Relação Estrutura-Atividade
8.
Toxicol Lett ; 331: 242-253, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32579994

RESUMO

Dysregulated bile acid (BA) homeostasis is an extremely significant pathological phenomenon of intrahepatic cholestasis, and the accumulated BA could further trigger hepatocyte injury. Here, we showed that the expression of sphingosine-1-phosphate receptor 1 (S1PR1) was down-regulated by α-naphthylisothiocyanate (ANIT) in vivo and in vitro. The up-regulated S1PR1 induced by SEW2871 (a specific agonist of S1PR1) could improve ANIT-induced deficiency of hepatocyte tight junctions (TJs), cholestatic liver injury and the disrupted BA homeostasis in mice. BA metabolic profiles showed that SEW2871 not only reversed the disruption of plasma BA homeostasis, but also alleviated BA accumulation in the liver of ANIT-treated mice. Further quantitative analysis of 19 BAs showed that ANIT increased almost all BAs in mice plasma and liver, all of which were restored by SEW2871. Our data demonstrated that the top performing BAs were taurine conjugated bile acids (T-), especially taurocholic acid (TCA). Molecular mechanism studies indicated that BA transporters, synthetase, and BAs nuclear receptors (NRs) might be the important factors that maintained BA homeostasis by SEW2871 in ANIT-induced cholestasis. In conclusion, these results demonstrated that S1PR1 selective agonists might be the novel and potential effective agents for the treatment of intrahepatic cholestasis by recovering dysregulated BA homeostasis.


Assuntos
1-Naftilisotiocianato/toxicidade , Ácidos e Sais Biliares/sangue , Colestase/prevenção & controle , Fígado/efeitos dos fármacos , Oxidiazóis/farmacologia , Receptores de Esfingosina-1-Fosfato/agonistas , Tiofenos/farmacologia , Animais , Ácidos e Sais Biliares/metabolismo , Colestase/induzido quimicamente , Colestase/metabolismo , Regulação para Baixo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Homeostase , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Receptores de Esfingosina-1-Fosfato/genética , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
9.
Life Sci ; 254: 117819, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32442451

RESUMO

AIMS: Vascular dysfunction plays a key role in sepsis but the role of perivascular adipose tissue (PVAT) in this condition is relatively unknown. MAIN METHODS: Sepsis was induced by cecal ligation and puncture (CLP). The responses of the aorta and superior mesenteric artery to norepinephrine in the presence or absence of PVAT were evaluated. Fluorescent probes measured the production of nitric oxide (NO) and reactive oxygen species (ROS). NO synthases (NOS) and ß3-adrenoceptor expression were detected by immunofluorescence and S-nitrosylation by the biotin switch assay. KEY FINDINGS: Aorta and superior mesenteric arteries from septic animals with intact PVAT showed a worsened response to the vasoconstrictor compared to vessels without PVAT. PVAT from the aorta (APVAT) produced NO and ROS whereas PVAT from the superior mesenteric artery (MPVAT) produced only ROS. Septic APVAT exhibited a higher density of NOS-1 and NOS-3. S-nitrosylation was found in APVAT. Donor (PVAT obtained from normal or septic rats):Host (normal vessel without PVAT) experiments showed that L-NAME, ODQ and ß3-adrenergic receptor antagonist blocked the septic APVAT anti-contractile effect. None of these compounds affected MPVAT; tempol, but not apocynin, blocked its anti-contractile effect. SIGNIFICANCE: PVAT contributes to the anti-contractile effect in the aorta and mesenteric artery of septic rats through different pathways. ß3-Adrenergic receptor and NO appear to be key mediators of this effect in APVAT, but not in MPVAT where ROS seem to be a relevant mediator. Therefore, PVAT is a relevant player of sepsis vascular dysfunction.


Assuntos
Aorta/metabolismo , Artérias Mesentéricas/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Adrenérgicos beta 3/fisiologia , Sepse/fisiopatologia , Acetofenonas/farmacologia , Tecido Adiposo/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Óxidos N-Cíclicos/farmacologia , Feminino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/metabolismo , Norepinefrina/farmacologia , Oxidiazóis/farmacologia , Fenótipo , Quinoxalinas/farmacologia , Ratos , Receptores Adrenérgicos beta 3/biossíntese , Marcadores de Spin , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia
10.
PLoS One ; 15(5): e0233468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469975

RESUMO

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Transtornos da Memória/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Oxidiazóis/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/psicologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Epigênese Genética/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacocinética , Oxidiazóis/química , Oxidiazóis/farmacocinética , Ratos , Ratos Sprague-Dawley
11.
Artigo em Inglês | MEDLINE | ID: mdl-32164965

RESUMO

Azilsartan is used for treatment of the high blood pressure (hypertension). Reducing high blood pressure enables avoid strokes, heart attacks and problems of kidneys. Azilsartan comes under the name angiotensin receptor blocker (ARBs) as a class of drugs. It acts by relaxing blood vessels to make it easier for blood to flow. Azilsartan Medoxomil's a comprehensive profile containing the description, formulae, Elemental Analysis, Uses and application. Furthermore, methods and schemes are outlined for the preparation of the drug substance. The physical properties of the medication include constant of ionization, solubility, X-ray powder diffraction pattern, differential scanning calorimetry, thermal conduct and spectroscopic studies are investigated. The methods employed in bulk medicines and/or in pharmaceutical formulations to analyze the drug substance include spectrophotometric, electrochemical and the chromatographic methods. Other studies on this drug substance include drug stability, Pharmaceutical Applications, Mechanism of Action, Pharmacodynamics, and a Dosing Information are reviewed. At the end of this profile, there are more than sixty references were listed.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Benzimidazóis/farmacologia , Oxidiazóis/farmacologia , Pressão Sanguínea , Estabilidade de Medicamentos , Humanos , Hipertensão/tratamento farmacológico
12.
Eur J Med Chem ; 193: 112219, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32203788

RESUMO

Two new series of 1,3,4-oxadiazole benzenesulfonamide hybrids 3 and 4, having twenty novel compounds, have been designed and synthesized in order to assess their inhibition potential as CAIs against hCA I, II, IX, and XII. 'Tail approach' strategy has been used to design the aromatic sulfonamide scaffolds with carbonyl and amide linker. Excellent inhibitory activity against hCA I has been exhibited by compounds 3g and 4j, 3.5 magnitude of order better than reference drug AAZ (KI = 250 nM). Moreover, compound 4j (KI = 7.9 nM) effectively inhibited glaucoma-associated hCA II isoform as well as tumor-associated hCA IX isoform with KI = 16.3 nM. Further hCA XII was weakly inhibited by all the compounds with KI values ranging from 0.23 µM to 3.62 µM. Interestingly structure-activity relationship (SAR) study indicates that N-(3-nitrophenyl)-2-((5-(4-sulfamoylphenyl)-1,3,4-oxadiazol-2-yl)thio)acetamide (4j) is a potent compound to be investigated further for antiglaucoma and antitumor activity. The chemistry of the nature of different substitutions on the 1,3,4-oxadiazole bearing benzenesulfonamide substituted aromatic ring for potency and selectivity over one hCA isoform versus others is deliberated in the present study. In this context, the 1,3,4-oxadiazole motif can be a valuable tool worth developing for the procurement of novel and potent selective CAIs potentially useful for the management of a variety of diseases as chemotherapeutic agents.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Oxidiazóis/farmacologia , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Oxidiazóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
13.
Cancer Sci ; 111(5): 1774-1784, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32112605

RESUMO

The signal transducer and activator of transcription 3 (STAT3) signaling pathway is a key mediator of cancer cell proliferation, survival and invasion. Aberrant STAT3 has been demonstrated in various malignant cancers. YHO-1701 is a novel quinolinecarboxamide derivative generated from STX-0119. Here, we examined the effect of YHO-1701 on STAT3 and evaluated antitumor activity of YHO-1701 as a single agent and in combination. YHO-1701 inhibited STAT3-SH2 binding to phospho-Tyr peptide selectively and more potently than STX-0119 in biochemical assays. Molecular docking studies with STAT3 suggested more stable interaction of YHO-1701 with the SH2 domain. YHO-1701 exhibited approximately 10-fold stronger activity than STX-0119 in abrogating the STAT3 signaling pathway of human oral cancer cell line SAS. YHO-1701 also blocked multi-step events by inhibiting STAT3 dimerization and suppressed STAT3 promoter activity. As expected, YHO-1701 exerted strong antiproliferative activity against human cancer cell lines addicted to STAT3 signaling. Orally administered YHO-1701 showed statistically significant antitumor effects with long exposure to high levels of YHO-1701 at tumor sites in SAS xenograft models. Moreover, combination regimen with sorafenib led to significantly stronger antitumor activity. In addition, the suppression level of survivin (a downstream target) was superior for the combination as compared with monotherapy groups within tumor tissues. Thus, YHO-1701 had a favorable specificity for STAT3 and pharmacokinetics after oral treatment; it also contributed to the enhanced antitumor activity of sorafenib. The evidence presented here provides justification using for this approach in future clinical settings.


Assuntos
Antineoplásicos/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Interleucina-6/sangue , Camundongos , Simulação de Acoplamento Molecular , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Multimerização Proteica/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Fator de Transcrição STAT3/química , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Survivina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Domínios de Homologia de src
15.
J Agric Food Chem ; 68(8): 2340-2346, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32017553

RESUMO

Ralstonia solanacearum is an extremely destructive and rebellious phytopathogen that can cause bacterial wilt diseases in more than 200 plant species. To explore and discover the potential targets in R. solanacearum for the purpose of developing new agrochemicals targeting this infection, here, we exploited a typical activity-based protein profiling technique for target discovery in R. solanacearum based on an activity-based probe 1 derived from bioactive oxadiazole sulfones. A total of 65 specific targets were identified with high confidence through a quantitative chemical proteomic approach. Three representative proteins (glycine cleavage system H protein, thiol peroxidase, and dihydrolipoamide S-succinyltransferase) were validated as the targets by using the immunoblotting analysis with their respective antibodies. Additionally, the in vitro interaction between the recombinant thiol peroxidase and probe 1 further confirmed that this protein was a target of oxadiazole sulfones. We anticipated that these discovered protein targets in R. solanacearum can stimulate the discovery and development of novel agrochemicals targeting bacterial infections caused by R. solanacearum.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Oxidiazóis/farmacologia , Doenças das Plantas/microbiologia , Ralstonia solanacearum/efeitos dos fármacos , Sulfonas/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteômica , Ralstonia solanacearum/genética , Ralstonia solanacearum/metabolismo
16.
J Med Chem ; 63(5): 2511-2526, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32017849

RESUMO

Small molecule mitochondrial uncouplers are emerging as a new class of molecules for the treatment of nonalcoholic steatohepatitis. We utilized BAM15, a potent protonophore that uncouples the mitochondria without depolarizing the plasma membrane, as a lead compound for structure-activity profiling. Using oxygen consumption rate as an assay for determining uncoupling activity, changes on the 5- and 6-position of the oxadiazolopyrazine core were introduced. Our studies suggest that unsymmetrical aniline derivatives bearing electron withdrawing groups are preferred compared to the symmetrical counterparts. In addition, alkyl substituents are not tolerated, and the N-H proton of the aniline ring is responsible for the protonophore activity. In particular, compound 10b had an EC50 value of 190 nM in L6 myoblast cells. In an in vivo model of NASH, 10b decreased liver triglyceride levels and showed improvement in fibrosis, inflammation, and plasma ALT. Taken together, our studies indicate that mitochondrial uncouplers have potential for the treatment of NASH.


Assuntos
Diaminas/uso terapêutico , Mitocôndrias Hepáticas/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pirazinas/uso terapêutico , Desacopladores/uso terapêutico , Animais , Diaminas/química , Diaminas/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Oxidiazóis/química , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Consumo de Oxigênio/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacologia , Desacopladores/química , Desacopladores/farmacologia
17.
PLoS One ; 15(1): e0227876, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31935275

RESUMO

Candida krusei is one of the most common agents of invasive candidiasis and candidemia worldwide, leading to high morbidity and mortality rates. This species has become a problem due to its intrinsic resistance and reduced susceptibility to azoles and polyenes. Moreover, the number of antifungal drugs available for candidiasis treatment is limited, demonstrating the urgent need for the discovery of novel alternative therapies. In this work, the in vivo and in vitro activities of a new oxadiazole (LMM11) were evaluated against C. krusei. The minimum inhibitory concentration ranged from 32 to 64 µg/mL with a significant reduction in the colony forming unit (CFU) count (~3 log10). LMM11 showed fungicidal effect, similar to amphotericin, reducing the viable cell number (>99.9%) in the time-kill curve. Yeast cells presented morphological alterations and inactive metabolism when treated with LMM11. This compound was also effective in decreasing C. krusei replication inside and outside macrophages. A synergistic effect between fluconazole and LMM11 was observed. In vivo treatment with the new oxadiazole led to a significant reduction in CFU (0.85 log10). Furthermore, histopathological analysis of the treated group exhibited a reduction in the inflammatory area. Taken together, these results indicate that LMM11 is a promising candidate for the development of a new antifungal agent for the treatment of infections caused by resistant Candida species such as C. krusei.


Assuntos
Antifúngicos/química , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Oxidiazóis/química , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Candida/patogenicidade , Candidíase/microbiologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Oxidiazóis/farmacologia , Células-Tronco/efeitos dos fármacos
18.
Eur J Med Chem ; 189: 112046, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31962263

RESUMO

Studying the structure-activity relationships (SAR) of oxadiazolylthiazole antibiotics unexpectedly led us to identify ethylenediamine- and propylenediamine-analogs as potential antimycotic novel lead structures. Replacement of the ethylenediamine moiety for the lead compound 7 with cis-diaminocyclohexyl group (compound 18) significantly enhanced the antifungal activity. In addition to the high safety margin of 18 against mammalian cells, it showed highly selective broad-spectrum activity against fungal cells without inhibiting the human normal microbiota. The antifungal activity of 18 was investigated against 20 drug-resistant clinically important fungi, including Candida species, Cryptococcus, and Aspergillus fumigatus strains. In addition to the low MIC values that mostly ranged between 0.125 and 2.0 µg/mL, compound 18 outperformed fluconazole in disrupting mature Candida biofilm.


Assuntos
Antifúngicos/farmacologia , Oxidiazóis/farmacologia , Tiazóis/farmacologia , Antifúngicos/toxicidade , Aspergillus/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Células CACO-2 , Candida/efeitos dos fármacos , Candida/fisiologia , Cryptococcus/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Oxidiazóis/toxicidade , Estereoisomerismo , Tiazóis/toxicidade
19.
Chem Biodivers ; 17(2): e1900659, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31995280

RESUMO

Breast Cancer (BCa) is the most often diagnosed cancer among women who were in the late 1940's. Breast cancer growth is largely dependent on the expression of estrogen and progesterone receptor. Breast cancer cells may have one, both, or none of these receptors. The treatment for breast cancer may involve surgery, hormonal therapy (Tamoxifen, an aromatase inhibitor, etc.) and oral chemotherapeutic drugs. The molecular docking technique reported the findings on the potential binding modes of the 2-(2-bromo-3-nitrophenyl)-5-phenyl-1,3,4-oxadiazole derivatives with the estrogen receptor (PDB ID: 3ERT). The 1,3,4-oxadiazole derivatives 4a-4j have been synthesized and described by spectroscopic method. 2-(2-Bromo-6-nitrophenyl)-5-(4-bromophenyl)-1,3,4-oxadiazole (4c) was reconfirmed by single-crystal XRD. All the compounds have been tested in combination with generic Imatinib pharmaceutical drug against breast cancer cell lines isolated from Caucasian woman MCF-7, MDA-MB-453 and MCF-10A non-cancer cell lines. The compounds with the methoxy (in 4c) and methyl (in 4j) substitution were shown to have significant cytotoxicity, with 4c showing dose-dependent activation and decreased cell viability. The mechanism of action was reported by induced apoptosis and tested by a DNA enzyme inhibitor experiment (ELISA) for Methyl Transferase. Molecular dynamics simulations were made for hit molecule 4c to study the stability and interaction of the protein-ligand complex. The toxicity properties of ADME were calculated for all the compounds. All these results provide essential information for further clinical trials.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Oxidiazóis/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Mesilato de Imatinib/farmacologia , Conformação Molecular , Simulação de Acoplamento Molecular , Oxidiazóis/metabolismo , Oxidiazóis/farmacologia , Relação Estrutura-Atividade
20.
J Med Chem ; 63(4): 1660-1670, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31990537

RESUMO

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.


Assuntos
HDL-Colesterol/metabolismo , Inibidores Enzimáticos/farmacologia , Cetonas/farmacologia , Lipase/antagonistas & inibidores , Oxidiazóis/farmacologia , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Cetonas/síntese química , Cetonas/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Relação Estrutura-Atividade
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