Discovery synthesis and optimization of an N-alkoxy indolylacetamide against HIV-1 carrying NNRTI-resistant mutations from the Isatis indigotica root

摘要

From an aqueous decoction of the traditional Chinese medicine “ban lan gen” (the root), an antiviral natural product was isolated as an NNRTI (non-nucleoside reverse transcriptase inhibitor) (EC  = 3.40  M). Its novel structure was determined as methyl (1-methoxy-1 -indol-3-yl)acetamidobenzoate by spectroscopic data and confirmed by single crystal X-ray diffraction. Through synthesis and structure-activity relationship (SAR) investigation of and 57 new derivatives (24 with EC values of 0.06–8.55  M), two optimized derivatives and (EC : 0.06  M and 0.06  M) having activity comparable to that of NVP (EC  = 0.03  M) were obtained. Further evaluation verified that and were RT DNA polymerase inhibitors and exhibited better activities and drug resistance folds compared to NVP against seven NNRTI-resistant strains carrying different mutations. Especially, (EC  = 0.43  M) was more active to the L100I/K103N double-mutant strain as compared to both NVP (EC  = 0.76  M) and EFV (EC  = 1.08  M). The molecular docking demonstrated a possible binding pattern between and RT and revealed activity mechanism of against the NNRTI-resistant strains.