Can (S)‐Stereoisomers of Perezone and Its Derivatives Show Similar Activity to Its (R)‐Stereoisomers? A Computational Characterization and Docking Study

Abstract

Asymmetric synthesis, in particular enantioselectivity, has permitted the assembly of complex molecules; consequently, many clinical trials are going on to compare the efficacy and safety of each pair of enantiomers. In this sense, to envisage the suitability to synthesize the (S)-stereoisomers (hypothetical) of (R)-perezone, (R)-isoperezone and their corresponding sulfurderivatives, in this work, their molecular properties (geometrical, electronic, and spectroscopic) and chemical reactivity descriptors at the theoretical level were compared with the results of the previously studied (R)-stereoisomers, using DFT/ B3LYP/6-311 + + G(d,p), in agreement between both (S/R)enantiomers. Concerning the electronic properties, the 6isopropylsulfanyl-(8S)-perezone (1 a) and 6-benzylsulfanyl-(8R)-perezone (2 c) are hard molecules, in addition (8R)-isoperezone (4), 3-benzylsulfanyl-(8S)-isoperezone (3 c), and 6-benzylsulfanyl-(8S)-perezone (1 c) displayed comparable features to 6benzylsulfanyl-(8R)-perezone (2 c). The docking studies showed that (S)-derivatives exhibited a lower affinity to COX-2 due to steric hindrance. Thus, 2 c showed the highest affinity to COX-2 (ΔG = À 9.53 kcal/mol). The highest differences in ΔG values were shown between 1 c and 2 c, while the lowest differences in ΔG values were displayed by 3 a and 4 a. Finally, the biological activity prediction for the hypothetic (S)-compounds revealed anti-neoplasic activity, consequently their synthesis is recommended.

Synthesis, Cytotoxic Activity and In Silico Study of Novel Dihydropyridine Carboxylic Acids Derivatives

“…The geometries found by theoretical calculations were considered as true energy minima only when all calculated frequencies (PES) were positive. Theoretical vibrational analysis of 3a and 3b were executed with the same theory approach, and computed frequencies were assigned to respective modes of vibrations using a scale factor of 0.9679 [27,30,81,82]. Optimized geometries were also used to reproduce 1 H and 13 C NMR chemical shifts obtained using the Gauge-Independent Atomic Orbital (GIAO) approach [83,84] with a global scaling factor of 31.9699 and 184.1279 for 1 H and 13 C, respectively, with respect to TMS in gas phase.…”

“…On the other hand, DFT calculations are favored nowadays for replications of experimental facts such as molecular geometry, vibrational frequencies, and chemical shifts, including other properties of organic molecules [27]. In this sense, calculated frequencies and chemical shifts are scaled to compensate for the estimated handling of electron correlation, basis set deficiencies, and anharmonicity [28,29], creating good approximations for organic molecules [27,30].…”