Anti-AIDS agents 82: Synthesis of seco-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives as novel anti-HIV agents

Abstract

Thirteen novel seco-DCK analogs (4–16) with several new skeletons were designed, synthesized and screened for in vitro anti-HIV-1 activity. Among them, three compounds (5, 13, and 16) showed moderate activity, and compound 9 exhibited the best activity with an EC50 value of 0.058 μM and a therapeutic index (TI) of 1000. The activity of 9 was better than that of 4-methyl DCK (2, EC50: 0.126 μM, TI: 301.2) in the same assay. Additionally, 9 also showed antiviral activity against a multi-RT inhibitor-resistant strain (RTMDR), which is insensitive to most DCK analogs. Compared with 2, compound 9 has a less complex structure, fewer hydrogen-bond acceptors, and a reduced log P value. Therefore, it is likely to exhibit better ADME, and appears to be a promising new lead for further development as an anti-HIV candidate.

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

“…While ring-A opened DCK analogues did not exhibit antiviral activity, ring-C opened DCK analogues (seco-DCKs) were active. In fact, compared with 2 , seco-DCK analogue 7 showed better anti-HIV activity and increased sensitivity against RTMDR in anti-HIV replication assays using HIV-1 IIIB in MT-2 cell lines, as well as HIV-1 NL4-3 and RTMDR in MT-4 lymphocytes [13]. The seco-DCKs have a simplified skeleton, fewer hydrogen-bond acceptors and lower log P values, resulting in increased water solubility and better pharmacokinetic properties compared with DCKs.…”

Therapeutic potential of coumarins as antiviral agents

“…Therefore, in furtherance to the development of DCK-related clinical drug candidates (49e51) they identified hydroxymethyl derivative of DCK (49) as first moderate orally bioavailable drug (water soluble, F ¼ 15%) which acts inhibiting the production of double-stranded viral DNA from the single-stranded DNA intermediate [49]. Moreover, ring opened DCK analogues or seco-DCK (52) which contains lesser hydrogen bond acceptor also showed improvement in ADME properties and found to be effective against RTMDR strains [50]. Isomeric replacement of coumarin with chromone resulted in DCP analogues (53) which are potent anti-HIV agents against the resistant strains RTMDR [51].…”

Synthesis and Anti-human Immunodeficiency Virus Activity of the Skeleton Isomers of 3',4'-Di-(O)-(-)-camphanoyl-(+)-khellactone

“…Lee and his coworkers reported the structure-activity relationship (SAR) of the analogue of DCK (1a); in particular, they discussed the optimization of substituents on the angular benzo[2,1-b:4,3-bЈ]dipyran skeleton. [1][2][3][4][5][6] We believe that one of the most important studies on the SAR of DCK must involve the arrangement of an angular benzodipyran skeleton. In this paper, we describe the synthesis and anti-HIV activity of the optically active structural isomers (1b-f and dst-1b-f) of DCK (Fig.…”