Zuleyma Martínez-Campos

Currently, ( R )‐baclofen is the only FDA‐approved agonist of the GABA _B receptor for the treatment of muscle spasticity and spinal cord injuries. However, its efficacy is limited by its low cerebral uptake and short duration, necessitating high concentrations that can lead to toxic effects. In this study, we designed new ( R )‐baclofen derivatives as potential GABA _B agonists, employing three different drug design strategies. We modified the three structural elements of ( R )‐baclofen: 1) replacing the para ‐chlorophenyl with an isoxazole ring, 2) changing the carboxylic acid with a tetrazole ring, and 3) altering the amino group to increase its lipophilicity. Electronic and steric effects resulting from the isosteric replacements (isoxazole and tetrazole rings) were analyzed using natural bond orbital (NBO) and molecular electrostatic potential (MEP) surfaces analysis. A robust molecular docking technique was used to study the molecular interaction of our candidates with the GABA _B receptor. To achieve this, we employed molecular dynamics simulations to generate a substantial number of conformers of the GABA _B1 receptor. Our final candidates, ( R )‐ 9s , ( R )‐ 12f , ( R )‐ 13f , ( R )‐ 14a , and ( R )‐ 14b , exhibited higher lipophilicity (ClogP) and interaction energies (kcal/mol) than ( R )‐baclofen and other known GABA _B receptor agonists, thereby enhancing their ADME properties, including permeability across the blood–brain barrier.

γ-amino butyric acid (GABA) is an inhibitory neurotransmitter whose deficiency has been associated with various neurological disorders. However, its low liposolubility limits its use as a supplement. Thus, multiple investigations have focused on searching for lipophilic GABA analogs that can modulate the activity of the GABA_B receptor, which could be associated with the etiology of some central nervous system disorders. The GABA analogs available on the market are Vigabatrin, Gabapentin as well as Pregabalin and Baclofen. In this work, we report on the synthesis of GABA analogs, taking the scaffold of GABA, Pregabalin, and Baclofen as a starting point. The analogs include structural features that could favor the affinity of the molecules for the GABA_B receptor, such as heterocyclic rings in the γ-position and alkyl or p-Cl-phenyl substituents (in analogy to Pregabalin and Baclofen, respectively). These analogs were synthesized by a sequence of reactions involving an N-alkylation, a 1,4-conjugated addition of dialkyl and diarylcuprates and a basic hydrolysis. Furthermore, a computational molecular docking over the GABA_B receptor was performed to evaluate the interaction of each compound in the Baclofen binding site. With this information, we evaluated our compounds as GABA_B agonists through a QSAR analysis. Finally, by means of molecular similarity analysis, and in silico ADME prediction, we support our three best compounds (8a–b, 8d) as potential GABA_B receptor agonists.

Lomentospora prolificans is a pathogenic and multidrug-resistant fungus that can infect both immunocompetent and immunocompromised patients, with mortality rates up to 87%. The World Health Organization (WHO) included this fungal species in its first list of 19 priority fungal pathogens, which focused on fungal pathogens that can cause invasive acute and subacute systemic fungal infections. Therefore, there is a growing interest in finding new therapeutic alternatives. In this work, the synthesis of twelve α-aminophosphonates by the microwave-assisted Kabachnik–Fields reaction and twelve α-aminophosphonic acids by a monohydrolysis reaction is reported. All compounds were evaluated by the agar diffusion method as a preliminary screening in comparison with voriconazole, showing inhibition halos for compounds 7, 11, 13, 22 and 27. The five active compounds in the preliminary tests were evaluated against five strains of L. prolificans following protocol M38-A2 from CLSI. The results showed that these compounds exhibit antifungal activity in the concentration range of 900->900 μg/mL. Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay, and it was shown that compound 22 was the least cytotoxic, with a viability of 67.91%, comparable to the viability exhibited by voriconazole (68.55%). Docking studies showed that the possible mechanism of action of the active compounds could be through the inhibition of the enzyme lanosterol-14-alpha-demethylase in an allosteric hydrophobic cavity.

La propagación de los Agaves spp. en México es muy extensa y el país cuenta con 151 especies endémicas. Sin embargo, prácticas como la construcción, el desarrollo de fibras, la elaboración de alimentos y bebidas alcohólicas, así como la elaboración de productos ornamentales han ocasionado una considerable disminución entre las poblaciones silvestres. En este sentido, el presente trabajo tiene como objetivo realizar la caracterización morfométrica por el método de I.S.T.A de las semillas de Agave spp. colectadas en los diferentes municipios del estado de Guerrero (Agave cupreata Trel. & A. Berger y Agave angustifolia Haw.). Los resultados obtenidos se sometieron a análisis de varianza y pruebas de medias (Tukey, p ≤ 0.05), tomándose el largo, ancho, grosor de las semillas y su volumen. El sitio de muestreo que presentó el mayor número de semillas por kilogramo (233,590) fue Lamazintla. Por otra parte, las semillas de mayor longitud, anchura y grosor se encontraron en el municipio de Alpoyeca (8.6; 6.4; 0.62 mm, respectivamente). Además el análisis de pureza demostró que la muestra obtenida en Amojileca cuenta con el mayor número de semillas maduras con un promedio del 57%.

The study of γ‐aminobutyric acid B receptor (GABA_B) activation is of great interest for several brain disorders. The search of new GABA_B receptor agonists has been carried out by many research groups. As a result, Baclofen has become the prototypical GABA_B receptor agonist. However, several attempts have been made to modify its structure to generate derivatives with improved activity. In this work, we carried out a theoretical and computational study for a wide range of GABA_B receptor agonists reported in the literature. Molecular docking and QSAR techniques were combined by using the interaction energies of the agonists with the key residues of GABA_B receptor, as molecular descriptors for the QSAR construction. The resulting mathematical model suggests that the activity of GABA_B receptor agonists is influenced by three factors: their shape and molecular size (PW5 and PJI2), their constitutional features (E_LUMO and T(N…O)) and the energy interaction with GABA_B receptor (E_TRP278). This model was validated by the QUIK, REDUNDANCY and OVERFITTING rules, and its predicted ability was tasted by the Q_LOO, Q_ASYM, and rules. Finally, six new compounds are proposed (35–40) with high potential to be used as GABA_B receptor agonists.