STRUCTURE-ACTIVITY DEPENDENCE OF NEW NON-NUCLEOSIDE HIV-1 REVERSE TRANSCRIPTASE INHIBITORS BASED ON LINKER MODIFICATION
The review presents modern scientific work on the design and construction of new non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs). In particular, modifications of panel linkers of new derivatives DAPY, HEPT and DABO are considered, most of which showed high activity against wild-type HIV-1 and against the HIV-1 double mutant K103N/Y181C. In this work, the dependence «structure-activity» for the leaders of a number of NNRTIs was studied. It has been proven that the influence of the linker plays a significant role in the interaction between inhibitors and RT (including through the formation of new hydrogen bonds with amino acids of the hydrophobic pocket), so further modifications can lead to even more potent anti-HIV compounds. In the lines of these NNRTIs, linkers consisting of an oxygen atom, sulfur, an amino group, a methylene fragment, a naphthalene ring, a keto group, and a peptide bond were considered. Compounds with a piperidine linker, effective derivatives of dihydro[3,4-d]pyrimidine, have shown potent antiviral activity as NNRTIs. As well as diatomic linkers containing a methylene fragment with a nitrogen, oxygen or sulfur atom and combinations: amide bond, methylene fragment, oxygen/sulfur; carbonyl group, methylene fragment, sulfur. The data confirming the high inhibitory activity are given. When comparing the anti-HIV-1 activity of previously published compounds with a methylene or carbonyl linker, it was found that their activity is highly dependent on the position of the substituents in the adjacent aromatic ring.