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Herein we report the synthesis of ten newly substituted 3-phenyl-5-aryl-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidin-4,6,11-triones (“benzochromenopyrimidines”) in a one-step reaction, by reacting ethyl 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-carboxylates with aniline, and triethyl orthoformate, under acidic catalyst and solvent-free conditions. These benzochromenopyrimidines were submitted to biological evaluation for in vitro anti-cancer activity, several derivatives showing higher activity than commonly used chemotherapeutic agents such as oxaliplatin, 5-fluorouracil, and paclitaxel. In particular, the 5-(2-Methoxyphenyl)-3-phenyl-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11-trione was identified as the most potent inhibitor among all the new ligands, showing significant cytotoxic activity against all the cancer cell lines tested [human colon cancer cell lines, LoVo and HCT-116; human lung cancer cells (A549 line)], as evidenced by the significant decrease in IC values, while maintaining low cytotoxicity against normal cells. These promising results suggest that this compound deserves further investigation as a potential hit compound for the development of a selective anticancer drug in cancer therapy.

The synthesis, antioxidant capacity, and anti-inflammatory activity of four novel N-benzyl-2-[4-(aryl)-1H-1,2,3-triazol-1-yl]ethan-1-imine oxides 10a–d are reported herein. The nitrones 10a–d were tested for their antioxidant properties and their ability to inhibit soybean lipoxygenase (LOX). Four diverse antioxidant tests were used for in vitro antioxidant assays, namely, interaction with the stable free radical DPPH (1,1-diphenyl-2-picrylhydrazyl radical) as well as with the water-soluble azo compound AAPH (2,2′-azobis(2-amidinopropane) dihydrochloride), competition with DMSO for hydroxyl radicals, and the scavenging of cationic radical ABTS•+ (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical cation). Nitrones 10b, 10c, and 10d, having the 4-fluorophenyl, 2,4-difluorophenyl, and 4-fluoro-3-methylphenyl motif, respectively, exhibited high interaction with DPPH (64.5–81% after 20 min; 79–96% after 60 min), whereas nitrone 10a with unfunctionalized phenyl group showed the lowest inhibitory potency (57% after 20 min, 78% after 60 min). Nitrones 10a and 10d, decorated with phenyl and 4-fluoro-3-methylphenyl motif, respectively, appeared the most potent inhibitors of lipid peroxidation. The results obtained from radical cation ABTS•+ were not significant, since all tested compounds 10a–d showed negligible activity (8–46%), much lower than Trolox (91%). Nitrone 10c, bearing the 2,4-difluorophenyl motif, was found to be the most potent LOX inhibitor (IC50 = 10 μM).

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.

En la línea de las ediciones anteriores, los resultados obtenidos con el proyecto "INSILITOX" han sido muy positivos. Por esta razón, el equipo se ha propuesto continuar optimizando la página web añadiendo nuevos recursos que apoyen la formación de los estudiantes, tanto de Grado como de Posgrado, en este entorno multilingüe de aprendizaje virtual adaptativo.

In our search for new neuroprotective agents for stroke therapy to improve the pharmacological profile of the compound quinolylnitrone QN23, we have prepared and studied sixteen new, related and easily available quinolylnitrones. As a result, we have identified compounds QN4 and QN15 as promising candidates showing high neuroprotection power in a cellular experimental model of ischemia. Even though they were found to be less active than our current lead compound QN23, QN4 and QN15 provide an improved potency and, particularly for QN4, an expanded range of tolerability and improved solubility compared to the parent compound. A computational DFT-based analysis has been carried out to understand the antioxidant power of quinolylnitrones QN23, QN4 and QN15. Altogether, these results show that subtle, simple modifications of the quinolylnitrone scaffold are tolerated, providing high neuroprotective activity and optimization of the pharmacological potency required for an improved design and future drug developments in the field., Instituto de Salud Carlos III, European Regional Development Fund (FEDER), grant number PI18/0255 and RETICS RD21/0006/0019, MINECO (Government of Spain) grant number SAF-2015-65586-R to J.M.-C., Depto. de Química Orgánica, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, Fac. de Medicina, TRUE, pub

In our search for new neuroprotective agents for stroke therapy to improve the pharmacological profile of the compound quinolylnitrone QN23, we have prepared and studied sixteen new, related and easily available quinolylnitrones. As a result, we have identified compounds QN4 and QN15 as promising candidates showing high neuroprotection power in a cellular experimental model of ischemia. Even though they were found to be less active than our current lead compound QN23, QN4 and QN15 provide an improved potency and, particularly for QN4, an expanded range of tolerability and improved solubility compared to the parent compound. A computational DFT-based analysis has been carried out to understand the antioxidant power of quinolylnitrones QN23, QN4 and QN15. Altogether, these results show that subtle, simple modifications of the quinolylnitrone scaffold are tolerated, providing high neuroprotective activity and optimization of the pharmacological potency required for an improved design and future drug developments in the field, Instituto de Salud Carlos III, European Regional Development Fund (FEDER), Ministerio de Asuntos Económicos y Transformación Digital (MINECO), Depto. de Química Orgánica, Fac. de Ciencias Químicas, TRUE, pub

Herein we report that 4-aminopyrimidine-5-carbonitriles 3 a–i were efficiently synthesized by reacting suitable 2-(ethoxyalkylene)malononitriles 1 a–c with easily available amidine hydrochlorides 2 a–d, in good yields using a simple synthetic scheme. To predict their pharmacological properties a comprehensive in silico analysis was conducted. Consequently, appropriate compounds 3 a–h were screened for their antiproliferative activity against two colorectal-cancer-cell lines and one lung cancer cell line. These analyses revealed that 4-amino-6-methyl-2-(p-tolyl) pyrimidine-5-carbonitrile (3 c) and 4-amino-2-(4-chlorophenyl)-6-methyl pyrimidine-5-carbonitrile (3 h) exhibited the most potent inhibitory activity against human LoVo and HCT-116 cancer cells, and that the most potent inhibitory activity against human A549 cells was observed for compound 3 h.

Herein it is summarized and critically discussed the different methods reported in the current literature and patents for the synthesis of 3-nitrooxypropanol (3-NOP). Among the small molecules 3-NOP is possibly one of the smallest (chemical formula: C3H7NO4; molecular weight: 121.09) showing interesting biological properties. Particularly, 3-NOP is an efficient inhibitor of methyl CoM reductase, an enzyme that catalyzes the last step of methanogenesis in anaerobic systems (e.g., ruminants), and a potent methane mitigant, able to reduce greenhouse gas emissions and climate change. 3-NOP is the active ingredient of Bovaer, a feed additive for ruminants. Furthermore, 3-NOP has been incorporated in a number of nitrate esters as NO-donors, showing diverse pharmacological activities for the treatment of inflammation or cardiovascular diseases. 1 Introduction 2 Synthetic Approaches to 3-NOP Based on the Nitrating Agent 3 From 3-NOP to Bovaer 4 Conclusions.

Great effort has been devoted to the synthesis of novel multi-target directed tacrine derivatives in the search of new treatments for Alzheimer’s disease (AD). Herein we describe the proof of concept of MBA121, a compound designed as a tacrine–ferulic acid hybrid, and its potential use in the therapy of AD. MBA121 shows good β-amyloid (Aβ) anti-aggregation properties, selective inhibition of human butyrylcholinesterase, good neuroprotection against toxic insults, such as Aβ1–40, Aβ1–42, and H2O2, and promising ADMET properties that support translational developments. A passive avoidance task in mice with experimentally induced amnesia was carried out, MBA121 being able to significantly decrease scopolamine-induced learning deficits. In addition, MBA121 reduced the Aβ plaque burden in the cerebral cortex and hippocampus in APPswe/PS1ΔE9 transgenic male mice. Our in vivo results relate its bioavailability with the therapeutic response, demonstrating that MBA121 is a promising agent to treat the cognitive decline and neurodegeneration underlying AD.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for this disease. For this purpose, new MTDLs were designed and synthesized in three steps by simple and cost-efficient procedures targeting calcium channel blockade, cholinesterase inhibition, and antioxidant activity. The biological and physicochemical results collected in this study allowed us the identification two sulfonamide-dihydropyridine hybrids showing simultaneous cholinesterase inhibition, calcium channel blockade, antioxidant capacity and Nrf2-ARE activating effect, that deserve to be further investigated for AD therapy.

Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.

[EN] The present invention relates to a series of N-sulfonlyurea derivative compounds, compounds of general formula (I), with pharmacological inhibitory activity of the NLRP3 inflammasome. The use of the compounds of general formula (I) as agents for treating preferably human diseases that involve an inflammatory process, preferably involving what are known as inflammasomes, preferably of the NLRP3 type, is claimed. These diseases include neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, inflammatory diseases, metabolic diseases, autoimmune diseases and generally any pathology caused by impaired biological functions in which the NLRP3 inflammasome is involved. The present invention has been developed in the field of pharmaceutical industry., [ES] La presente invención se refiere a una serie de compuestos derivados de N-sulfonilureas, compuestos de fórmula general (I), con actividad farmacológica inhibidora del inflamasoma NLRP3. Se reivindica el uso de los compuestos referidos con la fórmula general (I) como agentes para el tratamiento de enfermedades preferentemente humanas que cursan con proceso inflamatorio, preferentemente mediado por lo que se conoce como inflamasoma, preferentemente del tipo denominado NLRP3. Entre estas enfermedades se encuentran las denominadas neurodegenerativas, como el Alzheimer y el Parkinson, las enfermedades inflamatorias, la enfermedades metabólicas, las autoinmunes y, en general, cualquier patología producida por la alteración de las funciones biológicas donde está implicado el inflamasoma NLRP3. La presente invención se puede enmarcar en el campo de la industria farmacéutica., [FR] La présente invention se rapporte à une série de composés dérivés de N-sulfonylurées, de composés de formule générale (I), ayant une activité pharmacologique inhibitrice de l'inflammasome NLRP3. L'invention porte également sur l'utilisation desdits composés ayant la formule générale (I) en tant qu'agents pour le traitement de maladies de préférence humaines qui peuvent accompagner un processus inflammatoire, de préférence médié par ce qu'on appelle l'inflammasome, de préférence du type appelé NLRP3. Parmi ces maladies on trouve les maladies neurodégénératives, comme la maladie d'Alzheimer et la maladie de Parkinson, les maladies inflammatoires, les maladies métaboliques, les maladies autoimmunes et, en général, toute pathologie produite par l'altération des fonctions biologiques dans lesquelles est impliqué l'inflammasome NLRP3. La présente invention peut se situer dans le domaine de l'industrie pharmaceutique.