Juan Carlos Jiménez-Cruz

GABA is the principal inhibitory neurotransmitter in the central nervous system and exerts its agonistic activity by binding to the extracellular Venus flytrap (VFT) domain of the GABA_B receptor. Due to the limitations associated with baclofen, including the development of tolerance and its limited ability to cross the blood–brain barrier, the search for novel GABA_B receptor agonists is of particular interest. In this study, the baclofen analogue rac-4-amino-4-(4-methoxyphenyl)butanoic acid exhibited a higher binding affinity (−9.05 kcal/mol) than baclofen (−8.64 kcal/mol). Moreover, it formed hydrogen-bond interactions with key residues and maintained complex stability throughout 100 ns of molecular dynamics simulations, suggesting its potential as a GABA_B receptor agonist.

La presente investigación se centra en la extracción natural de medicarpina a partir de fuentes vegetales, considerándola como la molécula parental para la generación de derivados. En particular, se sintetizó un derivado p-nitrobenzoato mediante funcionalización selectiva del grupo hidroxilo, complementada con su elucidación estructural por RMN en estado líquido. Posteriormente, se realizaron estudios cristalográficos para caracterizar la estructura en el estado sólido, incluyendo el análisis de superficies de Hirshfeld y cálculos de contribuciones energéticas mediante DFT, permitiendo evaluar la estabilidad y disposición energética de la red cristalina. Este enfoque integrado combina extracción natural, síntesis selectiva, cristalografía y modelado computacional, proporcionando un análisis detallado del comportamiento supramolecular del compuesto derivado y ofreciendo evidencia química, física y matemática que respalda su potencial aplicación en el desarrollo de futuros candidatos farmacológicos o materiales tecnológicos. Los resultados muestran que la modificación del grupo hidroxilo conserva la integridad estructural de la molécula parental e introduce nuevas propiedades estructurales y energéticas, ampliando las posibilidades de diseño molecular y funcionalización de los alcaloides isoflavonoides, en conjunto, este estudio establece un modelo riguroso para futuras investigaciones en la química de productos naturales.

The present study describes the synthesis of an analog of the anti‐inflammatory drug fenbufen, a compound which has recently attracted of renewed interest in the treatment of chronic degenerative diseases such as cancer and rheumatoid arthritis. The molecule under consideration, 4‐(4‐methoxyphenyl)‐4‐oxobutanoic acid, is distinguished from fenbufen by the absence of the biphenyl moiety. This characteristic results in the generation of nontoxic metabolites during biotransformation. The incorporation of aromatic amino acid residues (phenylalanine and tyrosine) led to the modulation of the hybrid NSAID–amino acid and NSAID–peptide derivatives, thereby altering their biological activity and safety profile. The inhibitory activity against the dual cyclooxygenase‐2/5‐lipoxygenase system was evaluated using molecular docking, free energy calculations, and per‐residue decomposition analysis based on molecular dynamics simulations. Compounds containing a tyrosine residue or the Tyr‐Phe dipeptide exhibited strong drug–receptor binding affinities and long‐term stability during our simulations, in some cases outperforming the reference drugs celecoxib and zileuton. The values of the free energy (Δ G ) obtained through the Boltzmann equation demonstrated a strong correlation with the energy decomposition data, particularly for the lead compounds, which exhibited stabilizing interactions with the heme prosthetic group and the Fe ²⁺ ion. These findings provide substantial support for the identification of these molecules as promising candidates for further preclinical development.

The induction of chirality to obtain enantiopure products of high synthetic value is of great importance across various scientific fields, particularly in the medical area, as it has been demonstrated that the different enantiomers of drugs interact differently with biological receptors. In this context, asymmetric catalysis focuses on the design of catalysts that are easy to synthesize, capable of efficiently and enantioselectively forming C–C bonds, and suitable for reuse in multiple catalytic processes. This work describes the application of a Pd(II) complex coordinated with the R and S forms of proline in direct Aldol, Morita–Baylis–Hillman, and Heck coupling reactions. The catalytic system efficiently promoted the aldol reaction, achieving yields of 80–95%, excellent diastereoselectivities (1:69 syn/anti), and enantiomeric excesses greater than 99%. From a mechanistic perspective, the formation of a transition state is proposed in which a proline molecule generates an enamine that, upon coordination with the metal center, is stabilized through interaction with the intermediate’s double bond. Moreover, the study of the Morita–Baylis–Hillman and Heck coupling reactions highlights the versatility of this type of catalyst.

Parkinson’s disease is the second most common neurodegenerative disease in the world. Natural products can offer a possible option of neuroprotective agents for preventing neurodegenerative diseases. D-Pinitol is a cyclic polyol with anxiolytic and antidepressant effects in acute assays. This work aimed to evaluate the effects of D-Pinitol (10, 50, and 100 mg/kg p.o.) in a chronic reserpine-induced depression model (19 days), using the forced swimming and tail suspension tests in female Balb/c mice, and the neuroprotective effects in an MPTP-induced Parkinsonism model (30 days) in male C57bL/6 mice, using behavioral tests such as wire grip, rotarod, catalepsy, and others. D-Pinitol showed low antidepressant-like effects in the reserpine-induced chronic depression model, compared to amitriptyline (25 mg/kg p.o.). D-Pinitol protected MPTP-treated mice from motor impairment with similar effects to those shown by L-Dopa (25 mg/kg p.o.) as evaluated in different behavioral tests. The inhibition of oxidative stress markers, increase in dopamine levels, and avoidance of apoptosis in neuronal cells were the mechanisms by which D-Pinitol protects MPTP-treated mice from motor impairment.

The mixture of enantiomers in pharmaceuticals can lead to adverse effects, as demonstrated by thalidomide, where one enantiomer exhibited therapeutic properties while the other was teratogenic. Currently, efforts are focused on developing efficient catalysts capable of selectively producing a single stereoisomer, particularly in the synthesis of neuropharmaceuticals and NSAIDs. In this context, a new chiral catalyst was synthesized, featuring a palladium core and the dipeptide L-lysine-glycine as a ligand. The catalyst was characterized using various spectroscopic techniques and exhibited enantiomeric excesses of up to 40% in aldol reactions. Additionally, it efficiently promoted Heck cross-coupling reactions, indicating its potential catalytic versatility.

In this paper, the synthesis of compounds based on a hybrid structure combining a fenbufen analog (a nonsteroidal anti-inflammatory drug, NSAID) with amino acids or peptides is described. Additionally, a detailed molecular docking analysis was performed to investigate their drug–receptor interactions with inflammation-related enzymes COX-2 and 5-LOX. The hybrid compound that demonstrated the best interaction was further evaluated through molecular dynamics simulations, and its binding free energy (ΔG) was calculated using the Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) method.

Background/Objectives: The antinociceptive and anti-inflammatory effects of a patent-pending ointment containing plant extracts from Eucalyptus globulus, Curcuma longa, Hamamelis virginiana, Echinacea purpurea, and Zingiber officinale were evaluated. Methods: Plant extracts were chemically characterized by gas chromatography–mass spectroscopy. The antinociceptive activity of the ointment was assessed using the hot plate, tail flick, and formalin tests, whereas the anti-inflammatory activity was measured using the acute and chronic TPA-induced ear edema tests. Mechanisms of action were evaluated using inhibitors from signaling pathways related to pain response and by using histological analysis and assessing the expression and activity of pro-inflammatory mediators. Results: The ointment showed antinociceptive and anti-inflammatory effects like those observed with diclofenac gel (1.16% v/v) and ketoprofen gel (2.5% v/v). The antinociceptive actions of the ointment are mediated by the possible participation of the opiodergic system and the nitric oxide pathway. The anti-inflammatory response was characterized by a decrease in myeloperoxidase (MPO) activity and by a reduction in ear swelling and monocyte infiltration in the acute inflammation model. In the chronic model, the mechanism of action relied on a decrease in pro-inflammatory mediators such as COX-2, IL-1β, TNF-α, and MPO. An in-silico study with myristic acid, one of the compounds identified in the ointment’s plant mixture, corroborated the in vivo results. Conclusions: The ointment showed antinociceptive activities mediated by the decrease in COX-2 and NO levels, and anti-inflammatory activity due to the reduction in IL-1β and TNFα levels, a reduction in MPO activity, and a decrease in NF-κB and COX-2 expression.