Functionalized p-cymene and pyrazine derivatives: Physicochemical, ADMT, drug-likeness, and DFT studies

Abstract

The p-cymene and pyrazine derivatives functionalized with the hydroxy and methoxy group(s) were under the focus to explore the electronic structural properties, which would play a critical role in the biochemical reactivity features via performing systematic computational analyses. The DFT computations of the data set were performed by B3LYP/6–311 G* * level to predict the structural and electronic properties as well as the physicochemical values. The physicochemical properties such as lipophilicity and water solubility features were determined because these values should be in balance with each other in early-stage-drug-design research. The averaged lipophilicity of the p-cymene and pyrazine derivatives were calculated as CYM3 (2.39)< CYM1 (2.82)< CYM4 (3.11)< CYM2 (3.21)< CYM (3.50) and PYZ3 (1.22)< PYZ (1.28)< PYZ1 (1.40)< PYZ2 (1.79)< PYZ4 (2.00), respectively. According to the ESOL approach, the water solubility (mg/mL)x10⁻² values of the p-cymene and pyrazine compounds were changed in the following orders of CYM3 (15.6)> CYM4 (10.2)> CYM1 (7.40)>CYM2 (5.16)> CYM (3.12) and PYZ (512)> PYZ1 (170)> PYZ3 (166)> PYZ2 (118)> PYZ4 (77.3), respectively. The ADMT properties of the data set were dealt with in detail to estimate the structural advantage or disadvantage because the possible side effects on human-health and the environment have to be considered in designing the novel agent in addition to the possible potencies. All compounds would be promising agents in terms of the Caco-2 and MDCK penetration and Pgp-inhibition potencies. According to the IGC₅₀, LC₅₀FM, and LC₅₀DM results, the p-cymene compounds could have lower (or no) risk than the glyphosate and pyrazine derivatives like being for BCF scores. The FMO analyses were performed to estimate the possible reactive region for nucleophilic or electrophilic attacks.