Synthesis, structural and X-ray analysis evaluations and computational studies of newly tetrahydroisoquinoline...

Tetrahydroisoquinolines (THIQs) are a significant class within the broad range of natural compounds known as isoquinoline alkaloids. Natural and manmade drugs based on THIQ have a variety of biological effects that protect against different infectious pathogens and neurological diseases. In this study, two new THIQ derivatives were synthesized and characterized using by X-ray crystallographic analysis. The performed Hirshfeld analysis shows the intermolecular interactions and reactive sites of compounds. The 2D fingerprints reveal dominants H···C interactions up to 8.8% in 3a while 43% H···H elemental interactions are observed in compound 3b. In studied compound 3a, the repulsion energies (k_-rep) dominate the other energies where the highest amount of 63.8 kJ/mol is obtained whereas 3b has a significant contribution from E_-dis to the total energy of the molecule from the energy framework study. Moreover, the density functional theory study reveals better thermodynamic and electronic stabilities. These compounds have reduced HOMO-LUMO gaps (E_H-L) ranging from 3.66 to 3.60 eV, indicating their remarkable conductive and electronic properties. The significant reduction in E_H-L also guarantees our synthesized compounds' soft nature and reactivity. Our studied compound's NBO charges and MEPs analysis show electron-rich sites and donor-acceptor mechanism. Our synthesized compounds have remarkable polarizability (α_o) and hyperpolarizability (β_o) values (446.23 - 1312.73 au), which indicates their optical and nonlinear optical properties. The density of states spectra further illustrates their notable structural-electronic properties and reduced band gaps. Based on structural activity relationship studies, we found that these tetrahydro-isoquinolines derivatives are potent against microsomal prostaglandin E synthase 1(MPGES1), the docking analysis shows that studied compounds have a good binding affinity with MPGES1, and further ADME/T analysis was carried out for both compounds. In addtion to this molecular dynamics, studies were performed to understand the binding stability of both compounds in protien complex system during 100 ns simulation.Communicated by Ramaswamy H. Sarma.