RESUMEN
This study aims the characterization of several tianeptine transformation products in ultrapure water by simulated sunlight irradiation. Tianeptine was completely degraded after 106 h of exposition following pseudo-first-order kinetics (half-life time = 12.0 ± 2.4 h). Furthermore, an ultra-high-performance liquid chromatography coupled with a high-resolution quadrupole time-of-flight-mass spectrometry method was developed and fully validated taking into account different method performance parameters for the quantification of tianeptine in river water up to a concentration of 400 pg L-1. Following a non-targeted approach based on mass data-independent acquisition, eight different transformation products not previously reported in the literature were identified and accordingly elucidated, proposing a photodegradation mechanism based on the accurate tandem mass spectrometry information acquired. Irradiation experiments were replicated for a tianeptine solution prepared in a blank river water sample, resulting in the formation of the same transformation products and similar degradation kinetics. In addition, a toxicity assessment of the photoproducts was performed by in silico method, being generally all TPs of comparable toxicity to the precursor except for TP1, and showing a similar persistence in the environment except for TP2 and TP6, while TP4 was the only TP predicted as mutagenic. The developed method was applied for the analysis of four river water samples.
Asunto(s)
Fotólisis , Espectrometría de Masas en Tándem , Tiazepinas , Contaminantes Químicos del Agua , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/química , Cromatografía Líquida de Alta Presión , Tiazepinas/química , Tiazepinas/análisis , Ríos/química , Cinética , Luz SolarRESUMEN
To discover new multifunctional agents for the treatment of cardiovascular diseases, we designed and synthesized a series of compounds with a cyclopropyl alcohol moiety and evaluated them in biochemical assays. Biological screening identified derivatives with dual activity: preventing Ca2+ leak through ryanodine receptor 2 (RyR2) and enhancing cardiac sarco-endoplasmic reticulum (SR) Ca2+ load by activation of Ca2+-dependent ATPase 2a (SERCA2a). The compounds that stabilize RyR2 at micro- and nanomolar concentrations are either structurally related to RyR-stabilizing drugs or Rycals or have structures similar to them. The novel compounds also demonstrate a good ability to increase ATP hydrolysis mediated by SERCA2a activity in cardiac microsomes, e.g., the half-maximal effective concentration (EC50) was as low as 383 nM for compound 12a, which is 1,4-benzothiazepine with two cyclopropanol groups. Our findings indicate that these derivatives can be considered as new lead compounds to improve cardiac function in heart failure.
Asunto(s)
Canal Liberador de Calcio Receptor de Rianodina , Retículo Sarcoplasmático , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Miocitos Cardíacos , Canal Liberador de Calcio Receptor de Rianodina/farmacología , Retículo Sarcoplasmático/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Tiazepinas/química , Tiazepinas/farmacologíaRESUMEN
A series of novel 2,3,4,5-tetrahydrobenzothiazepine appended α-aminophosphonate derivatives were synthesized by subjecting 2,3-dihydrobenzothiazepine to Pudovik reaction using diethyl phosphite. Tested derivatives exhibited better AChE inhibition (0.86-12.85 µM) when compared to BuChE (3.13-19.36 µM). Derivative 5f (IC50 = 0.86 ± 0.08 µM), 5g (IC50 = 1.05 ± 0.06 µM) and 5d (IC50 = 1.64 ± 0.06 µM) exhibited higher AChE inhibitory activity as compared to standard drug galantamine (IC50 = 2.15 ± 0.05 µM). Similarly, derivative 5e (IC50 = 3.13 ± 0.11 µM) and 5f (IC50 = 3.64 ± 0.06 µM) demonstrated comparable BuChE inhibitory activity to reference drug galantamine (IC50 = 3.86 ± 0.03 µM). Further, enzyme kinetic studies were carried out for the most active molecule i.e. derivative 5f (for AChE) and derivative 5e (for BuChE) and the results imply that derivatives 5f and 5e show mixed-type inhibition with Ki values of 1.779 µM and 3.851 µM respectively. Enzyme reversibility inhibition studies demonstrated that all the tested derivatives possess reversible inhibitor characteristics. In addition, % hemolysis studies were carried out using human red blood cells (hRBCs) and the results demonstrated that the synthesized derivatives were biocompatible in nature as they impart very less cytotoxicity to hRBCs (CC50 > 1000 µg/mL). Also, cell viability studies for tested derivatives revealed no cytotoxicity in N2a cells. Moreover, molecular docking studies revealed that derivative 5e and 5f bind to the PAS and CAS of the AChE. ADME predictions suggested that synthesized derivatives have high possibility of being drug-like.
Asunto(s)
Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Simulación del Acoplamiento Molecular , Organofosfonatos/farmacología , Tiazepinas/farmacología , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Eritrocitos/efectos de los fármacos , Humanos , Estructura Molecular , Organofosfonatos/química , Relación Estructura-Actividad , Tiazepinas/síntesis química , Tiazepinas/químicaRESUMEN
Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with interaction volume of 50 µM2% and 31 µM2% at 95% confidence interval, respectively. On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from -50 µM2 % to -176 µM2 % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations.
Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Antivirales/química , Antivirales/uso terapéutico , Descubrimiento de Drogas/métodos , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Quinazolinas/química , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/virología , Bibliotecas de Moléculas Pequeñas , Sulfonas , Tiazepinas/química , Tiazepinas/farmacología , Tiazepinas/uso terapéutico , Inhibidores de Proteínas Virales de Fusión/química , Inhibidores de Proteínas Virales de Fusión/farmacología , Inhibidores de Proteínas Virales de Fusión/uso terapéuticoRESUMEN
In this work, a series of diaryl benzo[b][1,4]thiazepine derivatives D1-D36 were synthesized and screened as tubulin polymerization inhibitors with anti-tumor potency. They were designed by introducing the seven-member ring benzothiazepine as the linker for CA-4 modification for the first time. Among them, the hit compound D8 showed potential on inhibiting the growth of several cancer cell lines (IC50 values: 1.48 µM for HeLa, 1.47 µM for MCF-7, 1.52 µM for HT29 and 1.94 µM for A549), being comparable with the positive controls Colchicine and CA-4P. The calculated IC50 value of D8 as an tubulin polymerization inhibitor was 1.20 µM. The results of the flow cytometry assay revealed that D8 could induce the mitotic catastrophe and the death of living cancer cells. D8 also indicated the anti-vascular activity. The possible binding pattern was implied by docking simulation, inferring the possibility of introducing interactions with the nearby tubulin chain. Since the novel structural trial has been conducted with preliminary discussion, this work might stimulate new ideas in further modification of tubulin-related anti-cancer agents and therapeutic approaches.
Asunto(s)
Antineoplásicos/farmacología , Tiazepinas/farmacología , Moduladores de Tubulina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Polimerizacion/efectos de los fármacos , Relación Estructura-Actividad , Tiazepinas/síntesis química , Tiazepinas/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/químicaRESUMEN
Neprilysin (NEP) and angiotensin-converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide and kinin systems and renin-angiotensin-aldosterone system, respectively. They play an important role in blood pressure regulation and reducing the risk of heart failure. Vasopeptidase inhibitors omapatrilat and sampatrilat possess dual activity against these enzymes by blocking the ACE-dependent conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependent degradation of vasodilator atrial natriuretic peptide. Here, we report crystal structures of omapatrilat, sampatrilat, and sampatrilat-ASP (a sampatrilat analogue) in complex with NEP at 1.75, 2.65, and 2.6 Å, respectively. A detailed analysis of these structures and the corresponding structures of ACE with these inhibitors has provided the molecular basis of dual inhibitor recognition involving the catalytic site in both enzymes. This new information will be very useful in the design of safer and more selective vasopeptidase inhibitors of NEP and ACE for effective treatment in hypertension and heart failure.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Diseño de Fármacos , Mesilatos/metabolismo , Neprilisina/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Piridinas/metabolismo , Tiazepinas/metabolismo , Tirosina/análogos & derivados , Inhibidores de la Enzima Convertidora de Angiotensina/química , Antihipertensivos/química , Antihipertensivos/metabolismo , Cristalografía por Rayos X/métodos , Mesilatos/química , Neprilisina/química , Peptidil-Dipeptidasa A/química , Unión Proteica/fisiología , Estructura Secundaria de Proteína , Piridinas/química , Tiazepinas/química , Tirosina/química , Tirosina/metabolismoRESUMEN
Latrunculia sponges represent a rich source of discorhabdin-type pyrroloiminoquinone alkaloids, a few of which comprise a dimeric structure. The anticancer-activity-guided isolation of the n-hexane subextract of the Antarctic deep-sea sponge Latrunculia biformis yielded the known compound (-)-(1R,2R,6R,8S,6'S)-discorhabdin B dimer (1) and two new derivatives, (-)-(1S,2R,6R,8S,6'S)-discorhabdin B dimer (2) and (-)-(1R,2R,6R,8S,6'S)-16',17'-dehydrodiscorhabdin B dimer (3). The chemical structures of compounds 1-3 were elucidated by means of HR-ESIMS, NMR, [ï¡], ECD spectroscopy, and a comparison with the previously reported discorhabdin analogs. Compounds 1 and 2 showed significant in vitro anticancer activity against the human colon cancer cell line (HCT-116), with IC50 values of 0.16 and 2.01 µM, respectively. Compared to monomeric discorhabdins, dimeric discorhabdins are very rare in Nature. This study adds two new discorhabdin dimers (2 and 3) to this small pyrroloiminoquinone subfamily. This is also the first report of compound 1 as a natural product and the first assessment of its in vitro anticancer activity.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Poríferos/química , Quinolonas/química , Quinolonas/farmacología , Tiazepinas/química , Tiazepinas/farmacología , Animales , Productos Biológicos , Neoplasias del Colon , Doxorrubicina/farmacología , Células HCT116 , Humanos , Concentración 50 Inhibidora , Queratinocitos , Estructura MolecularRESUMEN
BACKGROUND: Despite the availability of a variety of chemotherapeutic agents, cancer is still one of the leading causes of death worldwide because of the problems with existing chemotherapeutic agents like objectionable side effects, lack of selectivity, and resistance. Hence, there is an urgent need for the development of novel anticancer agents with high usefulness, fewer side effects, devoid of resistance and superior selectivity. OBJECTIVE: The objective of this study is to synthesize a series of novel 1,5-benzothiazepine derivatives and evaluate their anticancer activity employing biological and computational methods. METHODS: Twenty new benzothiazepines (BT1-BT20) were prepared by condensing different 1-(4- isobutylphenyl)ethanone chalcones with 2-amiothiophenol and evaluated for their anticancer activity by MTT assay against three cell lines including HT-29 (colon cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer). These compounds were also tested for their inhibitory action against EGFR (Epidermal Growth Factor Receptor) tyrosine kinase enzyme by taking into account of their excellent action against colon and breast cancer cell lines. Further, the structural features responsible for the activity were identified by Pharmacophorebased modelling using Schrodinger's PHASETM software. RESULTS: Among the 20 benzothiazepine derivatives, three compounds viz., BT18, BT19 and BT20 exhibited promising activity against the cell lines tested and the activity of BT20 was more than the standard methotrexate. Again the above three compounds showed excellent inhibitory activity with the percentage inhibition of 64.5, 57.3 and 55.8 respectively against EGFR (Epidermal Growth Factor Receptor) tyrosine kinase. PHASE identified a five-point AHHRR model for the proposed activity and the computational studies provided insights into the structural requirements for the anticancer activity and the results were consistent with the observed in vitro activity data. CONCLUSION: These novel benzothiazepines will be useful as lead molecules for the further development of new cancer therapies against colon and breast cancers.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Tiazepinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Tiazepinas/síntesis química , Tiazepinas/químicaRESUMEN
BACKGROUND & OBJECTIVE: Quinazolines and their fused systems are noteworthy in pharmaceutical chemistry due to their wide range of biological activities. METHODS: A direct and efficient approach for the synthesis of new series of fused quinazolines with triazole, thiazole, benzimidazole and tetrazole has been preceded via the reaction of quinazoline thione derivative with halogenated compounds or cyclocondensation of arylidene of quinazoline derivative with heterocyclic amines. Also, dibenzo[b,e][1,4]thiazepine derivatives was synthesized through the reaction of 2,6-bis-(2-chloro-benzylidene)-cyclohexanone with o-aminothiophenol. RESULTS: The structures of all new synthesized heterocyclic compounds were confirmed and discussed on the bases of spectral data. The utility of the preparation and design of the above mentioned compounds has been shown to be clear in the results of their antimicrobial activity which revealed that some derivatives have potent activity exceeding or similar to the activity of the reference drugs. CONCLUSION: The insertion of triazole or thiazole moieties to be fused with quinazoline ring helps to enhance its antimicrobial activity.
Asunto(s)
Quinazolinas/química , Quinazolinas/síntesis química , Quinazolinas/farmacología , Tiazepinas/química , Tiazepinas/síntesis química , Tiazepinas/farmacología , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Azoles/síntesis química , Azoles/química , Azoles/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Two multitarget hybrids, derived from an aza-analogue of CGP37157, a mitochondrial Na+ /Ca2+ exchanger antagonist, and lipoic acid were designed in order to combine in a single molecule the antioxidant and Nrf2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The hybrid derivatives showed Nrf2 induction and radical scavenging properties, leading to a good neuroprotective profile against oxidative stress, together with an interesting antineuroinflammatory activity. The results obtained show differences in activity depending on the configuration of the chiral center of LA.
Asunto(s)
Antioxidantes/farmacología , Fármacos Neuroprotectores/farmacología , Tiazepinas/farmacología , Ácido Tióctico/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/química , Línea Celular , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Fármacos Neuroprotectores/química , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tiazepinas/química , Ácido Tióctico/químicaRESUMEN
The sponge genus Latrunculia is a prolific source of discorhabdin type pyrroloiminoquinone alkaloids. In the continuation of our research interest into this genus, we studied the Antarctic deep-sea sponge Latrunculia biformis that showed potent in vitro anticancer activity. A targeted isolation process guided by bioactivity and molecular networking-based metabolomics yielded three known discorhabdins, (-)-discorhabdin L (1), (+)-discorhabdin A (2), (+)-discorhabdin Q (3), and three new discorhabdin analogs (-)-2-bromo-discorhabdin D (4), (-)-1-acetyl-discorhabdin L (5), and (+)-1-octacosatrienoyl-discorhabdin L (6) from the MeOH-soluble portion of the organic extract. The chemical structures of 1-6 were elucidated by extensive NMR, HR-ESIMS, FT-IR, [α]D, and ECD (Electronic Circular Dichroism) spectroscopy analyses. Compounds 1, 5, and 6 showed promising anticancer activity with IC50 values of 0.94, 2.71, and 34.0 µM, respectively. Compounds 1-6 and the enantiomer of 1 ((+)-discorhabdin L, 1e) were docked to the active sites of two anticancer targets, topoisomerase I-II and indoleamine 2,3-dioxygenase (IDO1), to reveal, for the first time, the binding potential of discorhabdins to these proteins. Compounds 5 and 6 are the first discorhabdin analogs with an ester function at C-1 and 6 is the first discorhabdin bearing a long-chain fatty acid at this position. This study confirms Latrunculia sponges to be excellent sources of chemically diverse discorhabdin alkaloids.
Asunto(s)
Alcaloides/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Poríferos/química , Quinonas/química , Compuestos de Espiro/química , Tiazepinas/química , Células A549 , Animales , Regiones Antárticas , Antineoplásicos/química , Línea Celular Tumoral , Células HCT116 , Células HT29 , Células Hep G2 , Humanos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , EstereoisomerismoRESUMEN
The formation of a thrombus is a key event in thromboembolic disorders, that contribute to high mortality and morbidity in affected patients. In the present study, we synthesized a library of novel substituted 3,3-dibutyl-8-methoxy-2,3-dihydrobenzo [b] [1,4] thiazepin-4(5H)-one derivatives which were tested for their platelet aggregation and thrombin inhibitory activity. Among the tested compounds, 3,3-dibutyl-7-(2-chlorophenyl)-8-methoxy-2,3-dihydrobenzo[b] [1,4]thiazepin-4(5H)-one (DCT) displayed the maximum thrombin inhibition with an IC50 value of 3.85⯵M and thus DCT was chosen for further studies. Next, the effect of DCT on primary hemostasis was evaluated using agonist-induced platelet aggregation model. The lead compound inhibited the collagen- or ADP- or thrombin-induced platelet aggregation in a dose-dependent manner. Furthermore, DCT prolonged the process of clot formation when evaluating plasma re-calcification time (320⯱â¯11â¯sec at 5⯵g DCT), activated partial thromboplastin time (58.0⯱â¯0.01â¯sec at 2⯵g), and prothrombin time (14.7⯱â¯0.01â¯sec at 5⯵g). Molecular docking studies suggested that the benzothiazepinones evaluated here consistently display hydrogen bonding with Ser214 of thrombin, which is similar to that of the co-crystallized ligand (1-(2R)-2-amino-3-phenyl-propanoyl-N-(2,5dichlorophenyl)methylpyrrolidine-2-carboxamide). DCT displayed additional hydrogen bonding to Ser195 and π-π interactions between its methoxyphenyl groups and Trp60, thereby providing a structural rationale for the observed biological effect.
Asunto(s)
Inhibidores de Serina Proteinasa/farmacología , Tiazepinas/farmacología , Trombina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/química , Relación Estructura-Actividad , Tiazepinas/síntesis química , Tiazepinas/química , Trombina/metabolismoRESUMEN
Glycogen synthase kinase-3ß (GSK-3ß) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory mediated diseases in animal models. Non-ATP competitive inhibitors inherently have better therapeutical value due to their higher specificity than ATP competitive ones. In this paper, we designed and synthesized a series of new BTZ derivatives as non-ATP competitive GSK-3ß inhibitors. Kinetic analysis revealed two typical compounds 6j and 3j showed the different non-ATP competitive mechanism of substrate competition or allosteric modulation to GSK-3ß, respectively. As expected, the two compounds showed good specificity in a panel test of 16 protein kinases, even to the closest enzymes, like CDK-1/cyclin B and CK-II. The in vivo results proved that both compounds can greatly attenuate the LPS-induced acute lung injury (ALI) and diminish inflammation response in mice by inhibiting the mRNA expression of IL-1ß and IL-6. Western blot analysis demonstrated that they negatively regulated GSK-3ß, and the mechanism of the observed beneficial effects of the inhibitors may involve both the increased phosphorylation of the Ser9 residue on GSK-3ß and protein expression of Sirtuin 1 (SIRT1). The results support that such novel BTZ compounds have a protective role in LPS-induced ALI, and might be attractive candidates for further development of inflammation pharmacotherapy, which greatly thanks to their inherently high selectivities by the non-ATP competitive mode of action. Finally, we proposed suggesting binding modes by Docking study to well explain the impacts of compounds on the target site.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Tiazepinas/química , Tiazepinas/uso terapéutico , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/patología , Animales , Antiinflamatorios/farmacología , Cristalografía por Rayos X , Descubrimiento de Drogas , Glucógeno Sintasa Quinasa 3 beta/inmunología , Humanos , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Tiazepinas/farmacologíaRESUMEN
A series of bezofuran appended 1,5-benzothiazepine compounds 7a-v was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. All analogs exhibited varied BChE inhibitory activity with IC50 value ranging between 1.0⯱â¯0.01 and 72⯱â¯2.8⯵M when compared with the standard donepezil (IC50, 2.63⯱â¯0.28⯵M). Among the synthesized derivatives, compounds 7l, 7m and 7k exhibited the highest BChE inhibition with IC50 values of 1.0, 1.0 and 1.8⯵M, respectively. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 7l with BChE. In addition, docking studies confirmed the results obtained through in vitro experiments and showed that most potent compounds bind to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. The synthesized compounds were also evaluated for their in vitro antibacterial and antifungal activities. The results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms and showed high activity against both gram positive and gram negative bacteria and fungi.
Asunto(s)
Antiinfecciosos/síntesis química , Benzofuranos/química , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Diseño de Fármacos , Tiazepinas/química , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Antiinfecciosos/farmacología , Sitios de Unión , Butirilcolinesterasa/química , Dominio Catalítico , Inhibidores de la Colinesterasa/farmacología , Hongos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Concentración 50 Inhibidora , Cinética , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Tiazepinas/farmacologíaRESUMEN
American trypanosomiasis or Chagas disease (CD) is a vector borne pathology caused by the parasite Trypanosoma cruzi (T. cruzi), which remains a serious global health problem. The current available treatment for CD is limited to two nitroderivatives with limited efficacy and several side effects. The rational design of ergosterol synthetic route inhibitors (e.g. CYP51 inhibitors) represents a promising strategy for fungi and trypanosomatids, exhibiting excellent anti-T.cruzi activity in pre-clinical assays. In the present work, we evaluate through different approaches (molecular docking, structure activity relationships, CYP51 inhibitory assay, and phenotypic screenings in vitro and in vivo) the potency and selectivity of a novel CYP51 inhibitor (compound 1) and its analogues against T.cruzi infection. Regarding anti-parasitic effect, compound 1 was active in vitro with EC50 3.86 and 4.00⯵M upon intracellular (Tulahuen strain) and bloodstream forms (Y strain), respectively. In vivo assays showed that compound 1 reduced in 43% the parasitemia peak but, unfortunately failed to promote animal survival. In order to promote an enhancement at the potency and pharmacological properties, 17 new analogues were purchased and screened in vitro. Our findings demonstrated that five compounds were active against intracellular forms, highlighting compounds 1e and 1f, with EC50 2.20 and 2.70⯵M, respectively, and selectivity indices (SI)â¯=â¯50 and 36, respectively. Against bloodstream trypomastigotes, compound 1f reached an EC50 value of 20.62⯵M, in a similar range to Benznidazole, but with low SI (3). Although improved the solubility of compound 1, the analogue 1f did not enhance the potency in vitro neither promote better in vivo efficacy against mouse model of acute T.cruzi infection arguing for the synthesis of novel pyrazolo[3,4-e][1,4]thiazepin derivatives aiming to contribute for alternative therapies for CD.
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Inhibidores de 14 alfa Desmetilasa/química , Pirazolonas/química , Tiazepinas/química , Inhibidores de 14 alfa Desmetilasa/uso terapéutico , Animales , Enfermedad de Chagas/tratamiento farmacológico , Ratones , Simulación del Acoplamiento Molecular , Parasitemia/tratamiento farmacológico , Pirazolonas/farmacología , Relación Estructura-Actividad , Tasa de Supervivencia , Tiazepinas/farmacología , Trypanosoma cruzi/efectos de los fármacosRESUMEN
A series of new of furan derivatised [1,4] benzothiazepine analogues were synthesized starting from 1-(furan-2-yl)ethanone. 1-(Furan-2-yl)ethanone was converted into chalcones by its reaction with various aromatic aldehydes, then were reacted with 2-aminobenzenethiol in acidic conditions to obtain the title compounds in good yields. The synthesized new compounds were characterized by 1H NMR, 13C NMR, Mass spectral studies and elemental analyses. All the new compounds were evaluated for their in vitro VRV-PL-8a and H+/K+ ATPase inhibitor properties. Preliminary studies revealed that, some molecules amongst the designed series showed promising VRV-PL-8a and H+/K+ ATPase inhibitor properties. Further, rigid body docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This finding presents a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorder that can mitigate the ulcer inducing side effect shown by other NSAIDs.
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Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Fosfolipasas A2 Grupo II/antagonistas & inhibidores , ATPasa Intercambiadora de Hidrógeno-Potásio/química , Tiazepinas/síntesis química , Tiazepinas/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Sitios de Unión , Chalconas/química , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Furanos/química , Fosfolipasas A2 Grupo II/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Conformación Molecular , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Inhibidores de la Bomba de Protones/síntesis química , Inhibidores de la Bomba de Protones/química , Inhibidores de la Bomba de Protones/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Tiazepinas/química , Tiazepinas/metabolismoRESUMEN
Benzo[d][1,3]dioxoles 1,4-thiazepines remarkable antitumor activities, benzo[d][1,3]dioxoles-fused 1,4-thiazepines, which combine two biologically active heterocyclic cores, are expected to be of pharmacological interest, We therefore envisaged that integrating 1,4-thiazepine and benzo[d][1,3]dioxole moieties in one molecular platform could potentially produce novel compounds with significant synergistic antitumor properties. A series of novel benzo[d][1,3]dioxoles-fused 1,4-thiazepines, designed via molecular hybridization approach, were synthesized in very good yields using one-pot condensation of 3,4-methylenedioxyaniline, aldehydes, and α-mercaptocarboxylic acids under solvent-free condition. The anti-proliferative activities of all the synthesized compounds were assessed on two different human cancer cell lines (Esophageal squamous cell carcinoma Ec9706 and Eca109), and the results showed that compound 4e showed the best anti-tumor activity with IC50 values of 8.23 µM and 16.22 µM against Ec9706 and Eca109 cell lines, respectively, which was 2-3 times more potent than 5-Fluorouracil (IC50 = 23.26 µM and 30.25 µM against Ec9706 and Eca109 respectively). These novel benzo[d][1,3]dioxoles fused with bioactive heterocyclic skeletons may find their pharmaceutical applications after further investigations.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Dioxoles/química , Diseño de Fármacos , Tiazepinas/síntesis química , Tiazepinas/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Humanos , Relación Estructura-Actividad , Tiazepinas/químicaRESUMEN
In our previous work, a series of novel benzothiazepine derivatives containing pyridine moiety were successfully synthesized through chalcone 1,3-dipolar cycloaddition and determined their antiviral activity against tobacco mosaic virus (TMV). Bioassay results indicated that most of these target compounds exhibited improved curative, protection, and inactivation activity in vivo than the commercial agent ningnanmycin. Particularly, compound 3m exhibited marked curative activity against TMV, with an EC50 value of 352.2 µM, which was even better than that of ningnanmycin. The compound was identified as the most promising candidate for inhibiting plant virus and an excellent compound with antiviral activities against TMV. Structure-activity relationship experiment indicated that the 1,5-benzothiazepine moiety is crucial for potent anti-TMV activity.
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Diseño de Fármacos , Tiazepinas/química , Tiazepinas/farmacología , Virus del Mosaico del Tabaco/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
Selective inhibitors of histone deacetylase 6 (HDAC6) are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Herein, the synthesis of ten new benzohydroxamic acids, constructed by employing the tetrahydrobenzothiazepine core as a privileged pharmacophoric unit, is described. This is the first report on the synthesis and isolation of octahydrodibenzothiazepines and octahydro-6H-benzocycloheptathiazepines, which were then used to develop a new class of HDAC6 inhibitors. Evaluations of their HDAC-inhibiting activity resulted in the identification of cis-N-(4-hydroxycarbamoylbenzyl)-1,2,3,4,4a,5,11,11a-octahydrodibenzo[b,e][1,4]thiazepine-10,10-dioxide and cis-N-(4-hydroxycarbamoylbenzyl)-7-trifluoromethyl-1,2,3,4,4a,5,11,11a-octahydrodibenzo[b,e][1,4]thiazepine-10,10-dioxide as highly potent and selective HDAC6 inhibitors with activity in the low nanomolar range, which also show excellent selectivity on the enzymatic and cellular levels. Furthermore, four promising inhibitors were subjected to an Ames fluctuation assay, which revealed no mutagenic effects associated with these structures.
Asunto(s)
Inhibidores de Histona Desacetilasas/síntesis química , Histona Desacetilasas/metabolismo , Tiazepinas/química , Sitios de Unión , Cicloheptanos/química , Ciclohexanos/química , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/química , Humanos , Concentración 50 Inhibidora , Isomerismo , Simulación de Dinámica Molecular , Tiazepinas/síntesis químicaRESUMEN
During brain ischemia, oxygen and glucose deprivation induces calcium overload, extensive oxidative stress, neuroinflammation, and, finally, massive neuronal loss. In the search of a neuroprotective compound to mitigate this neuronal loss, we have designed and synthesized a new multitarget hybrid (ITH14001) directed at the reduction of calcium overload by acting on two regulators of calcium homeostasis; the mitochondrial Na+/Ca2+ exchanger (mNCX) and L-type voltage dependent calcium channels (VDCCs). This compound is a hybrid of CGP37157 (mNCX inhibitor) and nimodipine (L-type VDCCs blocker), and its pharmacological evaluation revealed a moderate ability to selectively inhibit both targets. These activities conferred concentration-dependent neuroprotection in two models of Ca2+ overload, such as toxicity induced by high K+ in the SH-SY5Y cell line (60% protection at 30 µM) and veratridine in hippocampal slices (26% protection at 10 µM). It also showed neuroprotective effect against oxidative stress, an activity related to its nitrogen radical scavenger effect and moderate induction of the Nrf2-ARE pathway. Its Nrf2 induction capability was confirmed by the increase of the expression of the antioxidant and anti-inflammatory enzyme heme-oxygenase I (3-fold increase). In addition, the multitarget profile of ITH14001 led to anti-inflammatory properties, shown by the reduction of nitrites production induced by lipopolysaccharide in glial cultures. Finally, it showed protective effect in two acute models of cerebral ischemia in hippocampal slices, excitotoxicity induced by glutamate (31% protection at 10 µM) and oxygen and glucose deprivation (76% protection at 10 µM), reducing oxidative stress and iNOS deleterious induction. In conclusion, our hybrid derivative showed improved neuroprotective properties when compared to its parent compounds CGP37157 and nimodipine.