In the search to cover the urgent need to combat infectious diseases, natural products have gained attention in recent years. The caespitate molecule, isolated from the plant Helichrysum caespititium of the Asteraceae family, is used in traditional African medicine. Caespitate is an acylphloroglucinol with biological activity. Acylphloroglucinols have attracted attention for treating tuberculosis due to their structural characteristics, highlighting the stabilizing effect of their intramolecular hydrogen bonds (IHBs). In this work, a conformational search for the caespitate was performed using the MM method. Posteriorly, DFT calculations with the APFD functional were used for full optimization and vibrational frequencies, obtaining stable structures. A population analysis was performed to predict the distribution of the most probable conformers. The calculations were performed in the gas phase and solution using the implicit SMD model for water, chloroform, acetonitrile, and DMSO solvents. Additionally, the multiscale ONIOM QM1/QM2 model was used to simulate the explicit solvent. The implicit and explicit solvent effects were evaluated on the global reactivity indexes using the conceptual-DFT approach. In addition, the QTAIM approach was applied to analyze the properties of the IHBs of the most energetically and populated conformers. The obtained results indicated that the most stable and populated conformer is in the gas phase, and chloroform has an extended conformation. However, water, acetonitrile, and DMSO have a hairpin shape. The optimized structures are well preserved in explicit solvent and the interaction energies for the IHBs were lower in explicit than implicit solvents due to non-covalent interactions formed between the solvent molecules. Finally, both methodologies, with implicit and explicit solvents, were validated with ¹H and ¹³C NMR experimental data. In both cases, the results agreed with the experimental data reported in the CDCl₃ solvent.

La enfermedad de Alzheimer (EA) es la forma más común de demencia y consiste en un deterioro cognitivo y conductual que afecta principalmente a los adultos mayores. Se estima que, en los próximos 30 años, 115 millones de personas en todo el mundo estarán afectadas por esta enfermedad. Ante el aumento previsto de casos, los investigadores están buscando alternativas para controlar la EA. Un enfoque importante es el estudio de la proteína γ-secretasa, relacionada con la neurotoxicidad de los péptidos involucrados en la cascada amiloide, una vía bioquímica fundamental en el desarrollo de la EA. En este trabajo se realizaron estudios in silico con los fármacos JNJ-40418677, GSM-1, bexaroteno y trodusquemina para evaluar su eficacia como moduladores del sitio activo de la subunidad catalítica presenilina 1 (PSEN-1), que forma parte del complejo γ-secretasa. Según los valores de energía de afinidad obtenidos en el acoplamiento molecular, JNJ-40418677 fue identificado como el compuesto con mayor potencial de unión a PSEN-1, seguido de trodusquemina, bexaroteno y GSM-1. Los resultados obtenidos aportan información relevante sobre las características químicas y físicas básicas que deberán ser consideradas en el diseño de moléculas con potencial inhibitorio sobre la γ-secretasa que, como consecuencia, tendrían implicaciones en el tratamiento de la EA.

Tuberculosis is a highly lethal bacterial disease worldwide caused by Mycobacterium tuberculosis (Mtb). Caespitate is a phytochemical isolated from Helichrysum caespititium, a plant used in African traditional medicine that shows anti-tubercular activity, but its mode of action remains unknown. It is suggested that there are four potential targets in Mtb, specifically in the H37Rv strain: InhA, MabA, and UGM, enzymes involved in the formation of Mtb’s cell wall, and PanK, which plays a role in cell growth. Two caespitate conformational structures from DFT conformational analysis in the gas phase (GC) and in solution with DMSO (CS) were selected. Molecular docking calculations, MM/GBSA analysis, and ADME parameter evaluations were performed. The docking results suggest that CS is the preferred caespitate conformation when interacting with PanK and UGM. In both cases, the two intramolecular hydrogen bonds characteristic of caespitate’s molecular structure were maintained to achieve the most stable complexes. The MM/GBSA study confirmed that PanK/caespitate and UGM/caespitate were the most stable complexes. Caespitate showed favorable pharmacokinetic characteristics, suggesting rapid absorption, permeability, and high bioavailability. Additionally, it is proposed that caespitate may exhibit antibacterial and antimonial activity. This research lays the foundation for the design of anti-tuberculosis drugs from natural sources, especially by identifying potential drug targets in Mtb.