The compound in question utilises an indole scaffold, substituted at the 2-, 3- and 5- positions to optimise interactions within the allosteric pocket of HIV RT. Key features of the compound include a double hydrogen bonding interaction to Lys101, facilitated by the indole NH and the substituent at the 2-position. The substituent at the 3-position fulfils two important roles: The first of these is a - stacking interaction with Tys181, as well as a - interaction with the conserved residue, Trp229. The second interaction is occupation of a small hydrophobic pocket located in the vicinity of Val179. This particular substituent on the indole scaffold was designed to be somewhat flexible in comparison to our previous generation inhibitors. The result was a 100X improvement in potency. At the 5-position of the scaffold a halogen substituent effectively occupies another small hydrophobic pocket.
Very potent novel NNRTI
Short synthetic sequence potentially simple to scale up.
Highly potent indole based NNRTI, with very low toxicity
Interactions optimised for - stacking interaction with Tys181, as well as a - interaction with the conserved residue, Trp229.
Dr SC Pelly, Senior lecturer Synthetic and Medicinal Chemistry; Dept. of Chemistry and Polymer Science, Stellenbosch University.
Prof WAL van Otterlo, Professor of synthetic chemistry; Dept. of chemistry and polymer science, Stellenbosch University.
Dr A Basson, Senior Medical Scientist; HIV Virology, National Institute for Communicable Diseases (NICD).
Ms Ronel Mϋller, MSc student; Dept. of chemistry and polymer science, Stellenbosch University.