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

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-1NL4-3 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 EC50 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 EC50 values of 0.47 and 0.88 μM, and TI of 96 and 51, respectively, against HIV-1NL4-3 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.

Thirty 1′-O-, 1′-S-, 4′-O- and 4′-substituted-2′,3′-seco-3′-nor DCP and DCK analogues (8–37) were designed, synthesized, and screened against HIV-1NL4-3 and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR) strains. 1′-O-Isopropoxy-2′,3′-seco-3′-nor-DCP (12) showed the greatest potency.Figure optionsDownload as PowerPoint slideHighlights
► Thirty 2′,3′-seco-3′-nor DCP and DCK analogs (8–37) were designed and synthesized.
► Several seco-compounds showed potent anti-HIV activity against HIV-1NL4-3 and RTMDR strains.
► 1′-O-Isopropoxy-2′,3′-seco-3′-nor-DCP (12) showed the greatest potency among the newly synthesized compounds.
► The seco-analogues exhibited better chemical stability in acidic conditions than DCP/DCK compounds.
► Seco-DCP analogues may be favorable for development as novel anti-HIV candidates.