Synthesis and NMR Studies of Novel 2-Eteroarylbenzofuran Derivatives

The 19th International Electronic Conference on Synthetic Organic Chemistry session General Organic SynthesisThe benzofuran scaffold is ubiquitous in the area of pharmacologically active agents and isolated natural products. Natural products possessing the 2-substituted moiety exhibit a broad range of pharmacological activities such as antimicrobial, anti-inflammatory, antifungal, antipsychotic, antilipidemic, analgesic, cytotoxic and central nervous system stimulant. Also, benzofuran nucleus has been recently described as a good scaffold for designing potent and relatively non-selective MAOIs. The synthesis and identification of novel 2-eteroarylbenzofuran derivatives with electron-donating and electron-withdrawing substituents are reported in this work. The key step for the formation of the benzofuran moiety was achieved by an intramolecular Wittig reaction between ortho-hydroxybenzyltriphosphonium salts and the appropriate aroyl chlorides. Their complete structural characterization was performed using one-dimensional and two- dimensional resonance techniques. The acquired data constitute a valuable database for the unambiguous identification of eteroarylbenzofuran library developed with the aim of our medicinal chemistry progra

Synthesis of new phthalazinedione derivatives

The 15th International Electronic Conference on Synthetic Organic Chemistry session General Organic SynthesisIn the past few decades, the synthesis of new heterocyclic compounds has been a subject of great interest due to their wide applicability. Among a large variety of heterocyclic compounds, heterocycles containing phthalazine moiety were reported to possess anticonvulsant, cardiotonic, and vasorelaxant activities. Therefore, a number of methods have been reported for the synthesis of phthalazine derivatives. Despite the available methods, the development of new synthetic methods for the efficient preparation of heterocycles containing phthalazine ring fragment is therefore an interesting challenge. With these precedents and with the aim of preparing new derivatives with potential pharmacological activity, we have synthesized new phthalazinedione derivatives by introducing halogenoalkyl substituents in one of the NH-nucleophilic groups. So, we started with 4-chloro-phthalic anhydride, which reacted with methyl- hydrazine, in MW mild conditions. After purification, we obtained two different isomers of phthalizediones, 8-chloro-2-methyl-2, 3-dihydro-phthalazine-1, 4-dione and 8-chloro-3-methyl-2, 3-dihydro-phthalazine-1,4-dione. Then halogenoalkyl substituents with different chain length were introduced in the nitrogen group in a very efficient way. Finally halogen atom of alkyl chains was replaced by an azide group. The described synthetic route will allow us to condense a nitrogen heterocyclic ring on the phatalazinone moiety and obtain a new tricyclic scaffold with promising pharmacological propertie

Computational Drug Target Screening through Protein Interaction Profiles

The development of computational methods to discover novel drug-target interactions on a large scale is of great interest. We propose a new method for virtual screening based on protein interaction profile similarity to discover new targets for molecules, including existing drugs. We calculated Target Interaction Profile Fingerprints (TIPFs) based on ChEMBL database to evaluate drug similarity and generated new putative compound-target candidates from the non-intersecting targets in each pair of compounds. A set of drugs was further studied in monoamine oxidase B (MAO-B) and cyclooxygenase-1 (COX-1) enzyme through molecular docking and experimental assays. The drug ethoxzolamide and the natural compound piperlongumine, present in Piper longum L, showed hMAO-B activity with IC50 values of 25 and 65μM respectively. Five candidates, including lapatinib, SB-202190, RO-316233, GW786460X and indirubin-3′-monoxime were tested against human COX-1. Compounds SB-202190 and RO-316233 showed a IC50 in hCOX-1 of 24 and 25μM respectively (similar range as potent inhibitors such as diclofenac and indomethacin in the same experimental conditions). Lapatinib and indirubin3′-monoxime showed moderate hCOX-1 activity (19.5% and 28% of enzyme inhibition at 25μM respectively). Our modeling constitutes a multi-target predictor for large scale virtual screening with potential in lead discovery, repositioning and drug safetyThis study was supported by grant R01 LM006910 (GH) “Discovering and Applying Knowledge in Clinical Databases” from the U.S. National Library of Medicine, “Angeles Alvariño, Plan Galego de Investigación, Innovación e Crecemento 2011–2015 (I2C)” and European Social Fund (ESF)S

Design, Synthesis and Pharmacological Evaluation of New Coumarin Derivatives as Monoamine Oxidase A and B Inhibitors

The 12th International Electronic Conference on Synthetic Organic Chemistry session Bioorganic Chemistry and Natural ProductsWith the aim to find out the structural features for the MAO inhibitory activity and selectivity, in the present communication we report the design, synthesis and pharmacological evaluation of a new series of coumarin derivatives with 4-methyl or cycloalkene or benzene ring condensed in the 3,4 position. The substituents in this new scaffold were introduced in the 5, 7 and/or 8 positions of the coumarin moiety. The synthesized compounds 1-13 were evaluated as MAO A and B inhibitors using clorgyline and selegiline, respectively, as reference inhibitors, showing, most of them, activities in the nanomolar range. Compounds 6 (IC50 = 1.18 nM) and 10 (IC50 = 1.48 nM), show higher activity than selegiline (IC50 = 19.60 nM), and high MAO-B selectivity with 100-fold and 1600-fold inhibition levels, with respect to the MAO-A isoformWe are grateful to the Xunta de Galicia (INCITE07PXI203030ES, PGIDIT05BTF20302PR and INCITE08PXIB203022PR) and Ministerio de Sanidad y Consumo (FIS PI061537 and PI061457) for financial support

Curcumin–Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin–coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11–18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H2O2 in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtainedThis research was funded by Consellería de Cultura, Educación e Ordenación Universitaria (EM2014/016) and Centro Singular de Investigación de Galicia and the European Regional De-velopment Fund (ERDF) (accreditation 2016–2019, ED431G/05)S

Synthesis and vasorelaxant and platelet antiaggregatory activities of a new series of 6-Halo-3-phenylcoumarins

A series of 6-halo-3-hydroxyphenylcoumarins (resveratrol-coumarins hybrid derivatives) was synthesized in good yields by a Perkin reaction followed by hydrolysis. The new compounds were evaluated for their vasorelaxant activity in intact rat aorta rings pre-contracted with phenylephrine (PE), as well as for their inhibitory effects on platelet aggregation induced by thrombin in washed human platelets. These compounds concentration-dependently relaxed vascular smooth muscle and some of them showed a platelet antiaggregatory activity that was up to thirty times higher than that shown by trans-resveratrol and some other previously synthesized derivativesWe thank Progetto di Ricerca Scientifica 2007-Università di Cagliari and Fondazione del Banco di Sardegna, Spanish Ministerio de Sanidad y Consumo (FISS PI061537, PI061457), Xunta de Galicia (Spain; INCITE08PXIB203022PR) and Spanish Ministerio de Ciencia e Innovación (FISS PS09/00618). D. Vina acknowledges sponsorships for a tenure-track research position at the University of Santiago de Compostela from the Isidro Parga Pondal Programme of the “Dirección Xeral de Investigación e Desenvolvemento, Xunta de Galicia”. E. Quezada thanks for a postdoctoral grant from FCT (Portugal). Verónica García-Morales thanks for a predoctoral grant (FPU, AP2008-02609, Spanish Ministerio de Ciencia e Innovación). C. Picciau thanks for a predoctoral grant Master & Back-Regione SardegnaS

Tyrosinase inhibitor activity of coumarin-resveratrol hybrids

In the present work we report on the contribution of the coumarin moiety to tyrosinase inhibition. Coumarin-resveratrol hybrids 1-8 have been resynthesized to investigate the structure-activity relationships and the IC50 values of these compounds were measured. The results showed that these compounds exhibited tyrosinase inhibitory activity. Compound 3-(3’,4’,5’-trihydroxyphenyl)-6,8-dihydroxycoumarin (8)is the most potentcompound (0.27 mM), more so than umbelliferone (0.42 mM), used as reference compound. The kinetic studies revealed that compound 8 caused non-competitive tyrosinase inhibitionWe thank Progetto di Ricerca Scientifica 2007-Università di Cagliari and Fondazione del Banco di Sardegna, Xunta de Galicia (PGIDIT05PXIB20304PR) and Ministerio de Sanidad y Consumo (FIS PI061537 and PI061457) for financial supportS