Contributions of nonconventional intramolecular hydrogen bond on the bioactivity of a series of substituted 6-amino, 4-phenyl, tetrahydroquinoline derivatives

Although intramolecular hydrogen bond formation/disruption is a critical tool in the drug absorption process, it is difficult to be determined due to its group-atom nature. We proposed a proper descriptor to reasonably correlate pIC50 of a series of 19 substituted 6-amino, 4-phenyl, tetrahydroquinoline (6A4PTHQ) derivatives with their non-conventional intramolecular hydrogen bond (nCIHB) using quantum chemical calculations at B3LYP/ 6-31++G (d,p) level of theory. Effects of the protic and aprotic solvents and water on the nCIHB were studied. Solvents, especially protic solvents, weaken nCIHB in all 6A4PTHQ derivatives. It was found that the nCIHB is preserved within the 6A4PTHQ derivatives when docked in the human follicle-stimulating hormone (FSH) re-ceptor. However, Molecular dynamic simulations showed that nCIHB disruption occurs in the aqueous compartment of the two-layered membrane, which enhances the absorption process via entropy increasing mechanism. Our approach may lead to the clarification of the complex role of nCIHB in drug transport and absorption processes in further research.

Automated summary

A proper descriptor was proposed to correlate pIC50 of a series of 19 substituted 6-amino, 4-phenyl, tetrahydroquinoline (6A4PTHQ) derivatives with their non-conventional intramolecular hydrogen bond (nCIHB). Solvents, especially protic solvents, were found to weaken nCIHB in all 6A4PTHQ derivatives. The study provides a way to clarify the complex role of nCIHB in drug transport and absorption processes.