Computational details
Numerous physicochemical parameters for absorption, distribution, metabolism and excretion (ADME) were evaluated for all the designed R, RI and RII frameworks employing Molinspiration Property Calculation Service126 and DruLiTo software.127 The computed parameters were employed to confirm if the designed derivatives satisfy the Lipinski’s rule of five, the Ghose’s rule, and the Veber criteria.128-131 Compounds violating more than one of Lipinski’s rules might have difficulties with bioavailability. Those violating Ghose’s rules could show absorption problems or low permeation; and those following Veber criteria may have better chances of suitable oral bioavailability.
Since all these conditions are general rules and not rigorous regulations, viable drugs have also to fulfill other vital requirements, such as synthetic accessibility (SA) and safety.132-135 The SA of the designed compounds was determined with the SYLVIA-XT 1.4 program (Molecular Networks, Erlangen, Germany).136 It delivers a value between 1 and 10. The smaller the value the easier to synthesize is the compound. The SYLVIA program has been certified for ranking virtual compounds during drug discovery processes137. Additionally, LD50 and Ames mutagenicity (M) were employed in this work to assess the toxicity of R, RI and RII and its derivatives. The Toxicity Estimation Software Tool (T.E.S.T.), version 4.1, was employed to obtain these parameters.138 This software constructs predictions based on quantitative structure-activity relationships (QSAR), which are envisioned for screening new compounds. The LD50 and M descriptors were determined with the consensus method, which makes predictions as the average of the toxicities obtained with several QSAR methodologies.139 There is a general understanding that the consensus method commonly offers higher accuracy and coverage than other protocols. Selection and elimination scores, expressed in terms of toxicity, manufacturability and ADME properties were used to make the first selection of derivatives.140-142
Gaussian 09 package was employed for electronic structure calculations143. Geometry optimizations and frequency calculations were carried out using the Density Functional Theory (DFT). The M05-2X approach was used in conjunction with 6-311+G(d,p) basis set and the solvation model density (SMD) using water to mimic a polar environment.144 Local minima were identified by the absence of imaginary frequencies. Unrestricted calculations were used for open shell systems. M05-2X is a global hybrid exchange-correlation general gradient approximations functional designed for noncovalent interactions, kinetics and thermochemistry.145 It has also been recommended for calculating reaction energies involving free radicals146. Furthermore, the M05-2X functional has been widely used for estimating pKa values, bonding dissociation energies, and the free radical scavenging activity of numerous antioxidant molecules147-151.
Ionization energies (IE) and electron affinities (EA) were calculated in the framework of the electron propagator theory (EPT),152, 153 which usually delivers values closer to those derived from experimental results than other methodologies. The partial third‐order quasiparticle theory (P3)154 was chosen since it has been reported to have lower mean errors, compared to other methods.155 However, for the EPT approximations (including P3) to be valid, pole strength (PS) values are needed to be larger than 0.80-0.85 156 Electrophilicity, ω, was also estimated for electron transfer reactions157-159to analyze the chemical behavior of the designed R, RIand RII derivatives. In a chemical reaction, involving two molecules, that with the higher ω is expected to act as the electrophile, while the other will behave as the nucleophile. This index was calculated following the equation: