Experimental and computational approach to study physico-chemical and biological properties of five-membered benzo fused heterocyclic compounds

Abstract

The carcinogenic kinase PAK1 (p21-activated kinase 1) is associated with the progression of many disorders, including Alzheimer's disease and various cancers. Although few synthetic PAK1 inhibitors and herbal therapeutics, such as propolis and curcumin, are available, a comprehensive remedy for PAK1-related ailments is still not studied in detail. Several phthalimide-metal complexes (viz. Λ-FL172, Λ-FL411) disclosed marked inhibition potency towards PAK1. However, a complete understanding of the inhibition of PAK1 by phthalimide analogs, it is crucial to explore their quantum chemical properties, molecular docking study, pharmacokinetic properties, and their synthesis. Therefore, in the first part of the study, a theoretical investigation of the coupling reaction between isoindoline-1, 3-dione (phthalimide) and aroyl chloride has been performed. Firstly, density functional theory (DFT) was employed to explore the structural insights of the coupled product 5, 6-diaryl isoindoline-1, 3-dione. Then, the dispersion corrected functional ꞷB97X-D was applied to determine the transition states of the coupling reaction in the gas phase and the solution phase by the SMD solvation model. In the two-step mechanism, the calculated results indicate that the energy barrier of the C-C bond formation between benzoyl cation and phthalimide is the rate-determining step of the reaction, and the activation energy was found at 53.3 kcal/mol in1,4-dioxane. Moreover, thermodynamic calculation shows that the arylation reactions are either spontaneous or nonspontaneous depending on the aroyl halide used, although all these reactions are exothermic. However, B3LYP/6-311+G (d, p) functional was applied to compute equilibrium geometry, HOMO-LUMO energy gap, dipole moments, polarizability, and first-order hyper polarizability, and mapped electrostatic potential (MEP) to understand the structural features of the products. Moreover, the phthalimide derivatives were subjected to molecular docking studies, and binding affinities ranging from -7.3 to -7.7 kcal/mol against PAK1 kinase were determined. The docked ligands demonstrated stronger hydrogen bonding, electrostatic interactions, and hydrophobic interactions with PAK1 kinase. The derivatives with an elevated docking score were chosen against ADMET in silico, and most of them have excellent oral bioavailability without carcinogenesis or mutagenicity effect. Moreover, the synthesis of phthalimide derivatives was also described. Finally, experimental and computed FT-IR analysis of the phthalimide derivatives showed well correlation.

In the second part of the study, however, a computational approach has been applied to investigate 2-arylbenzofuran-based molecules which act as effective Alzheimer's disease-modifying agents. For this, a rhodium-catalyzed cycloaddition reaction between diazo-compound and phenylacetylene (PhA) yielding two constitutional isomer-dihydro benzofuran-4-one (DBF) and spiro [2.5] oct-1-ene (SOE) derivatives. This reaction is found regioselectivity towards DBF. To explore why one constitutional isomer is a preferred yield in this reaction and the mechanism of the reaction, thermochemistry, conformational stability, spectroscopic properties, and density functional theory (DFT) calculations were performed at B3LYP and M06-2X level theory. For mechanistic studies, the calculation employing B3LYP/GenECP/LanL2DZ/6-311++G (d, p) level of theory demonstrated that a [3+2] cycloaddition reaction between diazo-compound and PhA proceeds through a two-step mechanism through a barrierless and highly exergonic process with relative free energy 73.61 kcal/mol to yield the kinetically-favored DBF derivatives In contrast, the assemble of SOE derivatives follows [1+2] cycloaddition between in situ generated cyclohexane-1, 3-dione carbene-2, and PhA, with the potential energy barrier 4.41 kcal/mol. Thermochemistry calculation disclosed that the cycloaddition reactions are spontaneous, and DBF (6a) is thermodynamically more stable than its constitutional isomer SOE (7a) by 42.59 kcal/mol. However, NBO, HOMO-LUMO energy gaps (4.62-4.89eV), dipole moments, polarizability, first-order hyperpolarizability and global reactivity descriptors were calculated to understand products' structural features. Additionally, Merck Molecular Force Field (MMFF94), followed by the B3LYP level of theory, was applied to predict the relative stability for the various conformations of 6b and 7b. The Boltzmann weighted average 1H chemical shift computed by GIAO-B3LYP/6-311+(2d, p) method, vibrational frequency analysis and UV-vis absorption calculated using time-dependent density functional theory (TD-DFT) demonstrated their spectrochemical properties. In conclusion, this research successfully illustrated the physico-chemical and biological properties of five-membered benzo-fused heterocyclic compoundsthrough experimental and computational approach.