María-Luisa Jimeno

Novel tacrine-grafted Ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic acid hybrids

Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA‐blood–brain barrier (BBB) analysis of new tacrine–ferulic acid hybrids (TFAHs). We identified (E)‐3‐(hydroxy‐3‐methoxyphenyl)‐N‐{8[(7‐methoxy‐1,2,3,4‐tetrahydroacridin‐9‐yl)amino]octyl}‐N‐[2‐(naphthalen‐2‐ylamino)2‐oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50=68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β‐amyloid (Aβ) anti‐aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA‐BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM), affording good neuroprotection against toxic insults such as Aβ1–40, Aβ1–42, H2O2, and oligomycin A/rotenone on SH‐SY5Y cells, at 1 μM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer′s disease.

9-Arylpurines as a Novel Class of Enterovirus Inhibitors

Here we report on a novel class of enterovirus inhibitors that can be structurally described as 9-arylpurines. These compounds elicit activity against a variety of enteroviruses in the low microM range including Coxsackie virus A16, A21, A24, Coxsackie virus B3, and echovirus 9. Structure-activity relationship (SAR) studies indicate that a chlorine or bromine atom is required at position 6 of the purine ring for antiviral activity. The most selective compounds in this series inhibited Coxsackie virus B3 replication in a dose-dependent manner with EC(50) values around 5-8 microM. No toxicity on different cell lines was observed at concentrations up to 250 microM. Moreover, no cross-resistance to TBZE-029 and TTP-8307 CVB3 resistant strains was detected.

Ceramides from the fungus Phellinus pini

Abstract Two new ceramides were identified among the chemical constituents of the fungus Phellinus pini. The structures of these compounds, N- (2′-hydroxynonacosanoyl)- d -erythro-1,3,4- trihydroxy-2-amino-octadecane and N- (2′-hydroxytriacontanoyl)- d -erythro-1,3,4- trihydroxy-2-amino-octadecane , were established by spectroscopic and chemical means. In addition, the lignan (+)-pinoresinol and the steroids episterol and ergosterol peroxide have been isolated from the same source.

Synthesis and pharmacological assessment of diversely substituted pyrazolo(3,4-b)quinoline, and benzo(b)pyrazolo(4,3-g)(1,8)naphthyridine derivatives

The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1-6, by Friedländer-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1-6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H-benzo[b]pyrazolo[4,3-g][1,8]naphthyridin-3-yl)acetamide (5) [IC(50) (EeAChE) = 0.069 ± 0.006 μM; IC(50) (eqBuChE) = 6.3 ± 0.6 μM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K(i) = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.

A neo-clerodane diterpenoid from Scutellaria baicalensis

An acetone extract of the aerial parts of Scutellaria baicalensis provided a new neo-clerodane, scutebaicalin, the structure of which was established as 6α,7β-dibenzoyloxy-8β-hydroxy-neo-cleroda-4(18),13-dien-15,16-olide by spectroscopic means.

Carbocycles from carbohydrates: a free radical route to aminocyclitol derivatives

Abstract Some derivatives of (1R,2R,3R,4S,5R) and 1R,2R,3R,4R,5S)-5-amino-1,2,3,4-cyclohexanetetrol have been synthesized from acyclic carbohydrate intermediates via 6-exo free radical cyclization.

Novel 3'-spiro nucleoside analogues of TSAO-T. Part II. A comparative study based on NMR conformational analysis in solution and theoretical calculations.

The structures of two novel 3′-spiro nucleosides analogues of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-m3T, in solution, as derived from NMR spectroscopy are described. In these TSAO analogues the spiro amino oxathioledioxide moiety has been replaced by spiro amino oxazolone or spiro amino oxathiazoledioxide moieties. A comparative study based on theoretical calculations of the hydrophobicity, the solvation free energies and molecular electrostatic potentials (MEP) of the three compounds is also described. No significant conformational differences were detected in solution between TSAO-m3T and its analogues that might account for the differencesobserved in their inhibitory activity against HIV-1 RT. The calculated hydrophobicity (log P) values, dipole moments and the electrostatic contributions to the solvation free energies of the three spiro ring systems were also similar. However, the differences found in the calculated MEPs of the spiro systems between TSAO-m3T and its analogues suggest that the different electrostatic surroundings of the 4″-amino group of the spiro moiety in the analogues may be responsible for a detrimental electrostatic interaction of the spiro rings with the Glu-B138 of RT.

Synthesis of [1-[3′,5′-Bis-O-(tert-butyldimethylsilyl)-β-d-arabino- and β-d-ribofuranosyl]cytosine]-2′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide). Analogues of the highly specific anti-HIV-1 agent TSAO-T

Abstract Reaction of O -mesylcyanodrins of furanos-2′-ulosyl cytosine with bases afforded β- d -arabino- and ribo-2′-spiro substituted nucleosides. Two of them exist, in solution, as mixtures of rotationally restricted “ syn-anti ” isomers.

A new synthetic route to chiral, multiply functionalized cyclopentane rings

The tributyltin hydride mediated free radical cyclization of sugar derivatives 4–6 gives the annulated furanoses 9–11 in good yield and high diastereoselectivity. This protocol is a new synthetic route for the preparation of complex cyclopentanoid molecules.

Difluorobenzenes revisited: an experimental and theoretical study of spin-spin coupling constants for 1,2-, 1,3-, and 1,4-difluorobenzene

The experimental spin–spin coupling constants (SSCCs) for 1,3‐ and 1,4‐difluorobenzene have been determined anew, and found to be consistent with previously determined values. SSCCs for 1,2‐, 1,3‐, and 1,4‐difluorobenzene have been analyzed by comparing them with the coupling constants computed using the second‐order polarization propagator approximation (SOPPA) and the equation‐of‐motion coupled cluster singles and doubles method (EOM‐CCSD). Eighty experimental values have been analyzed using SOPPA calculations, and a subset of 40 values using both SOPPA and EOM‐CCSD approaches. One‐bond coupling constants 1J(CC) and 1J(CF) are better described by EOM‐CCSD, whereas one‐bond 1J(CH) values are better described by SOPPA. An empirical equation is presented which allows for the prediction of unknown coupling constants from computed SOPPA values. A similar approach may prove useful for predicting coupling constants in larger systems. Copyright