Anti-AIDS agents 86. Synthesis and anti-HIV evaluation of 2′,3′-seco-3′-nor DCP and DCK analogues

Abstract

In a continuing study of novel anti-HIV agents with drug-like structures and properties, 30 1′- O-, 1′- S-, 4′- O- and 4′-substituted-2′,3′-seco-3′-nor DCP and DCK analogues ( 8-37) were designed and synthesized. All newly synthesized seco-compounds were screened against HIV-1 NL4-3 and a multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR) strain in the TZM-bl cell line, using seco-DCK ( 7) and 2-ethyl-DCP ( 4) as controls. Several compounds ( 14, 18, 19, 22–24, and 32) exhibited potent anti-HIV activity with EC 50 values ranging from 0.93 to 1.93 μM and therapeutic index (TI) values ranging from 20 to 39. 1′- O-Isopropoxy-2′,3′-seco-3′-nor-DCP ( 12) showed the greatest potency among the newly synthesized compounds with EC 50 values of 0.47 and 0.88 μM, and TI of 96 and 51, respectively, against HIV-1 NL4-3 and RTMDR strains. The seco-compounds exhibited better chemical stability in acidic conditions compared with DCP and DCK compounds. Overall, the results suggested that seco-DCP analogues with simplified structures may be more favorable for development as novel anti-HIV candidates.