Anti-AIDS agents. Part 56: Synthesis and anti-HIV activity of 7-thia-di-O-(−)-camphanoyl-(+)-cis-khellactone (7-thia-DCK) analogs

Chen, Ying; Zhang, Qian; Zhang, Beina; Xia, Peng; Yi, Xin; Yang, Zheng; Kilgore, Nicole; Wild, Carl; Morris‐Natschke, Susan L.; Lee, Kuo‐Hsiung

doi:10.1016/j.bmc.2004.09.038

Cited by 54 publications

(31 citation statements)

References 7 publications

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“…In addition, previous bioisosteric replacement study demonstrated that 1-thia, 1′-thia, and 1-aza DCKs maintained potent antiviral activity or had better activity against HIV compared with 2 4,5,7. These results motivated us to synthesize compounds 13 – 16 with sulfur or nitrogen rather than oxygen linked to the camphanoyl group of the seco-DCKs…”

Section: Resultsmentioning

confidence: 99%

“…(a) A 4-methyl is favorable for enhancing anti-HIV activity and decreasing toxicity 2. (b) Certain bioisosteric DCK analogs, including 1-thia, 1-aza, 1′-thia and 1′-carbon DCKs, show comparable anti-HIV activity with 1 4–7. (c) Two bulky cis -( S )-(−)-camphanoyl groups at the 3′- and 4′-positions are preferred to other substituents; however, both of them are not essential.…”

Section: Introductionmentioning

confidence: 99%

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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

Tang

Qian

Zhang

et al. 2010

Bioorganic & Medicinal Chemistry

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Tang

Qian

Zhang

et al. 2010

Bioorganic & Medicinal Chemistry

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“…A preliminary mechanistic study showed that DCK and its analogs did not inhibit HIV-RT, integrase, or protease and might inhibit HIV-1 replication by a novel mechanism. Currently, their mechanism of action is still under investigation [20,117]. Fig.…”

Section: Dck Analoguesmentioning

confidence: 99%

Coumarins as Inhibitors of HIV Reverse Transcriptase

Kostova

2006

CHR

148

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Acquired immunodeficiency syndrome (AIDS), a degenerative disease of the immune and central nervous systems, is an enormous world-wide health threat. No cure has been found, and research is aimed at developing chemotherapy against the causative agent, human immunodeficiency virus (HIV). Chemotherapy for AIDS has progressed steadily in the past decade. However, new, effective, and less toxic chemotherapeutic agents are still needed. Plants, particularly anti-infective or immunomodulating herbal medicines, can serve as sources of new active leads to be further developed as anti-AIDS drug candidates. A lot of structurally different natural coumarins were found to display potent anti-HIV activity and continued progress is anticipated in the discovery of new leads and in the development of these agents as potential anti-AIDS drug candidates. Recent studies based on the account of various coumarins from plant sources and their analogs--synthetic coumarins, indicate that some of them serve as potent nonnucleoside RT-inhibitors, another as inhibitors of HIV-integrase or HIV-protease. The current review demonstrates the variety of coumarins of natural plant origin and synthetic coumarins having unique mechanism of action to one of the most important stage of HIV replication (RT-inhibition). The merits of selecting potential anti-HIV agents to be used in rational combination drugs design and structure-activity relationships are discussed. The scientific community is looking actively for new drugs and combinations for treatment of HIV infection effective for first-line treatment, as well as against drug-resistant mutants.

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“…In a continuing effort to identify the pharmacophores of the 2′-position, 2′-monomethyl substituted 4-methyl DCK analogs were designed to further explore SAR at this position. We also extended our new design to 1′-thia derivatives, because bioisosteric replacement of sulfur for oxygen has also resulted in potent inhibitory effects on HIV-1 replication 9. The structures of the newly designed compounds ( 5 – 12 ) are shown in Figure 2.…”

Section: Introductionmentioning

confidence: 99%

Anti-AIDS agents 84. Synthesis and anti-human immunodeficiency virus (HIV) activity of 2′-monomethyl-4-methyl- and 1′-thia-4-methyl-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs☆

Xu¹,

Yan²,

Chen³

et al. 2010

Bioorganic & Medicinal Chemistry

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In a continuing investigation into the pharmacophores and structure-activity relationship (SAR) of (3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) as a potent anti-HIV agent, 2′-monomethyl substituted 1′-oxa, 1′-thia, 1′-sulfoxide and 1′-sulfone analogs were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Among them, 2′S-monomethyl-4-methyl DCK (5a) and 2′S-monomethyl-1′-thia-4-methyl DCK (7a) exhibited potent anti-HIV activity with EC 50 values of 40.2 and 39.1 nM and remarkable therapeutic indexes of 705 and 1000, respectively, which were better than those of the lead compound DCK in the same assay. In contrast, the corresponding isomeric 2′R-monomethyl-4-methyl DCK (6) and 2′R-monomethyl-1′-thia-4-methyl DCK (8) showed much weaker inhibitory activity against HIV-1 replication. Therefore, the bioassay results suggest that the spatial orientation of the 2′-methyl group in DCK analogs can have important effects on anti-HIV activity of this compound class. † Anti-AIDS Agents 84. For part 83, see T. Zhou, Q. Shi, and K.H. Lee. Anti-AIDS agents 83. Efficient microwave-assisted one-pot preparation of angular 2,2-dimethyl-2H-chromone containing compounds. Supporting Information Available Additional information on compound purity including elemental analysis, high-resolution mass spectral data, and HPLC analysis results of the target compounds.

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Anti-AIDS agents. Part 56: Synthesis and anti-HIV activity of 7-thia-di-O-(−)-camphanoyl-(+)-cis-khellactone (7-thia-DCK) analogs

Cited by 54 publications

References 7 publications

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

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

Coumarins as Inhibitors of HIV Reverse Transcriptase

Anti-AIDS agents 84. Synthesis and anti-human immunodeficiency virus (HIV) activity of 2′-monomethyl-4-methyl- and 1′-thia-4-methyl-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs☆

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