Pedro Besada

New pyridazinone derivatives with vasorelaxant and platelet antiaggregatory activities

New 6-substituted and 2,6-disubstituted pyridazinone derivatives were obtained starting from easily accessible alkyl furans by using oxidation with singlet oxygen to give 4-methoxy or 4-hydroxybutenolides, key intermediates of this synthetic strategy. The new pyridazinone derivatives have been studied as vasorelaxant and antiplatelet agents. Analysis of biological data revealed the silyl ethers (4a-i) and N,O-dibenzyl derivatives (6g-i) as the most active compounds.

Phthalazin-1(2H)-one as a remarkable scaffold in drug discovery

Phthalazinones are an important kind of nitrogen atom containing heterocyclic compounds due to their synthetic and pharmacological versatility. This fused heterocycle system represents a common structural feature for many bioactive compounds showing a variety of pharmacological activities such as anticancer, anti-diabetic, anti-asthmatic, antihistaminic, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant or antimicrobial agents, which makes it an attractive scaffold for the design and development of new drugs. This review summarizes detailed and updated information, described in recent non-patent literature, about the most relevant pharmacological properties of phthalazinone derivatives, highlighting the application of this potent pharmacophore in drug discovery.

New platelet aggregation inhibitors based on pyridazinone moiety.

New series of pyridazinone derivatives (4, 5 and 6) were synthesized in good yields following a synthetic strategy based on singlet oxygen oxidation of alkyl furans, in which a suitable β(α)-substituted γ-hydroxybutenolide (10 or 11) or a bicyclic lactone (12 or 13) was the key intermediate. The synthesized compounds were tested in vitro as antiplatelet agents and some of them (compounds 4b, 4d and 5b) exhibited potent inhibitory effects on collagen-induced platelet aggregation with IC50 values in the low μM range. Studies performed with the most active compound of these series (4b) demonstrated its lack of activity as inhibitor of platelet aggregation induced by other agonists as thrombin, ionomycin or U-46619 suggesting a selective action on the biochemical mechanisms triggered by collagen in the platelets.

Synthesis and structure-activity relationship study of novel 3-heteroarylcoumarins based on pyridazine scaffold as selective MAO-B inhibitors

Compounds of hybrid structure pyridazine-coumarin were discovered as potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B). These compounds were synthesized in good yield following a multistep approach based on Knoevenagel reaction and using as key intermediate pyridazinone 16, which was obtained from maleic anhydride and furan. Compounds 9b and 9d are the most active compounds of these series, with IC50 values in the sub-micromolar range, and lack of cytotoxic effects. Theoretical calculation of ADME properties also suggested a good pharmacokinetic profile for both compounds. Docking simulations provided insights into enzyme inhibitor interactions and allowed us to rationalize the observed structure-activity relationships (SARs).

Synthesis and cytostatic activity of purine nucleosides derivatives of allofuranose

Several new purine nucleosides derivatives of allofuranose were prepared according to Vorbrüggen method, starting from 1,2,5,6-di-O-isopropylidene-α-D-allofuranose and using 1,2,3,5,6-pentaacetoxy-β-D-allofuranose as key intermediate. The synthesized allofuranosyl nucleosides, as well as some acetyl derivatives, were evaluated for their cytotoxicity in vitro in three human cancer cell lines (MCF-7, Hela-229 and HL-60). Among the studied compounds the 9-(2,3,5,6-tetra-O-acetyl-β-D-allofuranosyl)-2,6-dichloropurine (9) was the most potent one on the three cell lines evaluated, being its activity against HL-60 cells similar to cisplatin.

Nucleoside Analogues of Purine with a 1,2-Disubstituted Cyclopentene Ring

Abstract One, two-disubstituted carbonucleoside analogues of purine with unsaturated carbocyclic were synthesized by construction of the heterocyclic base about the primary amino group of the amino alcohol 4 intermediate, which was also synthesized in good yield starting from cyclopentadiene.

Synthesis, biological evaluation and molecular modeling studies of phthalazin-1(2H)-one derivatives as novel cholinesterase inhibitors

A new series of donepezil analogues based on the phthalazin-1(2H)-one scaffold was designed and synthesized with the aim of exploring its potential as human ChEIs. Biological results revealed that the structural modifications proposed significantly affected ChE inhibitory potency as well as selectivity for AChE/BuChE. Compound 1d showed promising in vitro inhibition of both enzymes in the μM range. However, most target compounds were significantly more active against AChE than BuChE, specifically 1f, 1h and 1j, with IC50 values in the low micromolar or submicromolar range, the most active compounds in the series. Docking simulations suggested that the most active compounds can recognize the donepezil binding site using a similar interactions network. These results allowed us to rationalize the observed structure–activity relationships. Moreover, the predicted physicochemical and ADME properties were also comparable to those of donepezil.

Synthesis and complete assignment of the 1H and 13C NMR spectra of 6-substituted and 2,6-disubstituted pyridazin-3(2H)-ones.

Several pyridazin‐3(2H)‐one derivatives were synthesized starting from alkyl furans using oxidation with singlet oxygen to give 4‐methoxy or 4‐hydroxybutenolides, key intermediates of the synthetic strategy followed. For all pyridazinones reported, a complete assignment of the 1H and 13C NMR spectra using one‐ and two‐dimensional NMR spectroscopic methods, which included NOE, DEPT, COSY, HSQC and HMBC experiments, was accomplished. Correlations between the chemical shifts of the heterocyclic ring atoms and substituents at N‐2 and C‐6 were analyzed. Copyright

Complete assignment of the 1H and 13C NMR spectra of cis and trans isonucleoside derivatives of purine with a tetrahydropyran ring

1H and 13C NMR chemical shifts of cis and trans isonucleoside analogues of purine in which the furanose moiety is substituted by a tetrahydropyran ring were completely assigned using one‐ and two‐dimensional NMR experiments that include NOE, DEPT, COSY and HSQC. The significant 1H and 13C NMR signals differentiating between the cis and trans stereoisomers were compared. Copyright

Synthesis of carbocyclic analogues of MECA and NECA 1,2-disubstituted as potential adenosine receptor agonists.

Abstract A new class of 1,2-disubstituted carbocyclic nucleosides of MECA and NECA analogues was synthesized in gool yield starting from (±) 6-azabicyclo[3.2.0]heptan-7-one.