(M1330-04-22) In Silico Evaluation of Coumarin Derivatives as Potential Antioxidant Agents on Psoriasis Treatment

Purpose: Oxidative stress is an imbalance where the levels of reactive oxygen and nitrogen species increase.¹ These species have cellular functions such as signaling, immunological protection, cellular respiration, and gene expression, among others. In a healthy person, the body regulates oxidation processes through antioxidant enzymes and free radical scavengers.² However, in patients with psoriasis, an overproduction of nitric oxide (NO), hydrogen peroxide (H₂O₂), and superoxide anion (O₂^-●) increasing in the skin of psoriatic patients is observed. They are involved as markers in signaling inflammation in the skin, generating the characteristic scaly plaques.^3,4 Therefore, interest in natural derivatives with potential antioxidant properties, such as coumarin derivatives, becomes relevant. This investigation aims to evaluate the antioxidant activity of coumarin derivatives in terms of the charge transfer process. Terms of density functional approximation calculations were used to obtain vertical ionization energy (IE), electron affinity (EA), electrondonating power (w-), and electroaccepting power (w+). Then electron acceptance (Ra) and electron donation (Rd) indexes were calculated, and fluor and sodium were used as models of reference to construct the donator acceptor map (DAM).⁵ According to the results four derivatives are good donors and one derivative is the best antiradical of the series.

Methods: The antioxidant capacity of five derivatives was evaluated with the calculation of vertical ionization potential (IP) and electron affinity (EA) according with 1 and 2 equations (Figure 1). The electronic descriptors of donor (w-) and acceptor () charge transfer capacities were calculated with the equations 3 and 4, and are related with the IP and EA. As well the donor (Ra, equation 5) and acceptor (Rd, equation 6) indexes were calculated, we used as references sodium (Na) and fluorine (F) as Martinez described.⁵BHT (Butylhydroxytoluene) was chose to his good antioxidant capacity to contrast. All the calculation were carried out using the density functional theory (DFT) calculations, at B3LYP, 6-31G++ (d, p level of theory), implemented in the Gaussian 09 software.

Results: The vertical IP shows the relative antioxidant efficiency, compounds with low values are the most oxidized molecules an as a result, they represent the most efficient antiradicals based on their good electron donating capacity. The result indicates that 13 (7.98 eV), is the best structure with antioxidant capacity. In contrast, the vertical EA is a good indicator of the electron attraction, molecules with high and positive values have a greater capacity for accepting electrons and represent the most efficient antiradicals; the data indicated <07 (1.93 eV) behave as an antiradical agent (Table 1). A better assessment of the antiradical and antioxidant capacity was carried out with a charge-transfer model the electrodonating power (w-) and electroaccepting power (w+) values. On electrodonating power, lower values imply a greater capacity for donating charge, <16 (4.66 eV) has the highest donating capacity of the series. In the case of electroaccepting power, higher values imply a greater capacity for accepting charge, 07 (1.93 eV) shows the best capacity accepting a charge which means it’s the best derivative which behaves as the best antiradical agent. It is important to note that IP and EA refer to donating or accepting a single electron, while w- and w+ refer to fractional charges. Finally, the DAM construction from the Ra and Rd indexes showed a distribution in two quadrants (Figure 2). Quadrant IV correspond to good antiradical and good antioxidant agents: 13, 16, 20 and 25 are good charge donator; they show a good tendency to be able to stabilize a cation or a radical charge as BHT which indicates the tendency to behave as antioxidants. Quadrant III correspond to the best antiradicals agents: 07 shows the capacity to accept and donate charge, this capacity confers it’s the best antiradical potential of the series.

Conclusion: The potential use of coumarin derivatives as antipsoriatic agents was evaluating in silico through their antioxidant capacity, considering this is one of the conditions for the development of its pathology. The results show derivatives 13, 16, 20 and 25 have good profiles as antioxidant agents and 07 as antiradical agent. Both mechanisms are involved in the regulation of oxidative stress, as a result the derivatives data generating a promising horizon as a therapeutic agent with a good potential in the medical area.

References: 1. Pleńkowska, J., Gabig-Cimińska, M., & Mozolewski, P. (2020). Oxidative stress as an important contributor to the pathogenesis of psoriasis. International Journal of Molecular Sciences, 21(17), 6206. https://doi.org/10.3390/ijms21176206
2. Escarza, J. M. O. & López, M. E. M. (2020). Estrés oxidativo ¿un asesino silencioso?. Educación química, 31(1), 1-11. https://dx.doi.org/10.22201/fq.18708404e.2020.1.69709
3. Zhou, Q., Mrowietz, U., & Rostami-Yazdi, M. (2009). Oxidative stress in the pathogenesis of psoriasis. Free Radical Biology and Medicine, 47(7), 891-905. https://doi.org/10.1016/j.freeradbiomed.2009.06.033
4. Nickoloff, B. J. & Nestle, F. O. (2004). Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. The Journal of Clinical Investigation, 113(12), 1664-1675. https://doi.org/10.1172%2FJCI22147
5. Martinez, A. (2009). Donator acceptor map of psittacofulvins and anthocyanins: are they good antioxidant substances? The Journal of Physical Chemistry B, 113(14), 4915-4921. https://doi.org/10.1021/jp8102436

Acknowledgements: Thanks to CONAHCyT for a scholarship, grant number 1000620. Thanks to Laboratorio de Síntesis Asimétrica y Bioquimioinformática of Ingenieria Quimica, Universidad Autónoma de Zacatecas. Thanks to Laboratorio 4 of Facultad de Farmacia, Universidad Autónoma del Estado de Morelos.

Figure 1. Equations used to obtain electronic descriptors.


Table 1. Vertical ionization energies (IE), vertical electron affinities (EA), electron donation and acceptance powers (ω- and ω+), and indexes Rd and Ra, energies eV.


Figure 2. Donator Acceptor Map, DAM.