Exploration of the effects of linker chain modifications on anti-HIV activities in a series of cosalane analogues

doi:10.1016/0968-0896(96)00159-9

Bioorganic & Medicinal Chemistry

Volume 4, Issue 10, October 1996, Pages 1637-1648

https://doi.org/10.1016/0968-0896(96)00159-9 Get rights and content

Abstract

The effects of linker chain modifications were investigated in a series of cosalane analogues. The modifications investigated included: (1) shortening the three-carbon linker chain between the dichlorodisalicylmethane and the cholestane moiety by one carbon atom; (2) lengthening the linker chain by one carbon; (3) hydrogenation of the double bond in the linker chain; (4) changing the point of attachment of the linker chain from C-3 to C-6; (5) insertion of a phosphate between the steroid and the linker chain. With the exception of the phosphate modification, which abolished anti-HIV activity and increased cytotoxicity, the linker chain modifications produced relatively minor changes in anti-HIV potency. The steroid and attached linker chain of cosalane therefore appear only to provide a general lipophilic appendage for the dichlorodisalicylmethane pharmacophore.

The effects of linker chain modifications on anti-HIV activity were investigated in a series of cosalane (1) analogues. The modifications included shortening and lengthening the linker chain between the steroid and the dichlorodisalicylmethane pharmacophore, as well as changing the point of attachment of the linker chain to the steroid. The results indicate that the linker chain and attached steroid provide a general lipophilic appendage for the pharmacophore.

References (20)

C. Pidgeon et al.
J. Biol. Cnem.
(1993)
M. Cushman et al.
J. Med. Chem.
(1994)
R.F. Keyes et al.
J. Med. Chem.
(1996)
M. Cushman et al.
J. Med. Chem.
(1991)
M. Cushman et al.
J. Med. Chem.
(1995)
L.S. Kucera et al.
AIDS Res. Human Retroviruses
(1990)
C. McGuigan et al.
AIDS
(1991)
K.L. Meyer et al.
J. Med. Chem.
(1991)
D.L. Cooper et al.
J. Am. Chem. Soc.
(1993)
L. Krugner-Higby et al.
AIDS Res. Human Retroviruses
(1995)

There are more references available in the full text version of this article.

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Derivatives 22 and 26 which were coupled with the four methylene units exhibited the highest activities with MBC values of 128 and 64 μM, respectively. In addition, there are several investigators demonstrated that the bioactivities were influenced by the carbon linker, such as antibacterial, anti-HIV and anti-parasites [30–32]. Indeed, the length of carbon chain was crucial to the antibacterial activities.
Emergence of multidrug-resistant bacteria causes an urgent need for new generation of antibiotics, which may have a different mechanism of inhibition or killing action from the existing. Here, we report on the design, synthesis, and biological evaluation of thirty-nine coumarin derivatives in order to solve the antibacterial resistance by targeting at the inhibition of biosynthesis pathway of fatty acids. Their antibacterial activities against Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, and Flavobacterium cloumnare are tested and action mechanism against the key enzyme in bacterial fatty acid synthesis pathway are studied. The results show that compounds 13 and 18 have potent and broad spectrum antimicrobial activity. In addition, 9, 14 and 19 show eminent antimicrobial efficacy toward S. aureus, S. agalactiae, and F. cloumnare. Mechanistically, coumarin derivatives display the antibacterial activity via the control of FabI and FabK function. The structure-activity relationship analysis indicate that the length of linker and imidazole substitute group could significantly influence the antimicrobial activity, as well as the inhibitory activity against FabI and FabK. The structural optimization analysis of coumarin suggest that derivatives 9, 13, 14, 18 and 19 could be a viable way of preventing and controlling bacteria and considered as promising lead compounds for the development of commercial drugs.
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This rule was also observed in the other four groups. What’s more, there are several investigators demonstrated that the bioactivities were influenced by the carbon linker, such as antibacterial,31 anti-HIV.32 By contrast, the linker consisting of four carbon atoms was confirmed to be the optimal length to link the arctigenin and heterocyclic nitrogen compounds in our test.
To control the parasitic disease of Dactylogyrus intermedius, a series of new arctigenin derivatives were designed, synthesized and tested in our study. The anthelmintic activity of most of the derivatives ranged from 1 to 10 mg/L. Compared to traditional drug praziquantel (EC₅₀ = 2.69 mg/L), ether derivatives 2g and 2h exhibited slightly higher anti-parasitic activity, with the EC₅₀ values of 2.48 and 1.52 mg/L, respectively. Furthermore, the arctigenin-imidazole hybrids 4a and 4b also removed D. intermedius effectively, with the EC₅₀ values of 2.13 and 2.07 mg/L, respectively. The structure-activity relationship analysis indicated that four carbon atoms length of linker and imidazole substitute group could significantly increase the anthelmintic activity, and reduced the toxicity. Through the scanning electron microscope observation, compounds 4a and 4b caused the D. intermedius tegumental damage such as intensive wrinkles, holes and nodular structures. Overall, the structural optimization analysis of arctigenin suggested that 4a and 4b can be used for preventing and controlling Dactylogyrus infections and considered as promising lead compounds for the development of commercial drugs.
Enhanced transport of a novel anti-HIV agent - Cosalane and its congeners across human intestinal epithelial (Caco-2) cell monolayers
2003, International Journal of Pharmaceutics
Purpose: Cosalane is a potent inhibitor of HIV replication with activity against a broad range of viral targets. However, oral bioavailability of this highly lipophilic compound is extremely poor (<1%). The purpose of this study is to screen a variety of permeation enhancers (cyclodextrin derivatives, cremophor EL, bile salts and mixed micelles) for their ability to enhance the transport of cosalane and its analogs/prodrugs across Caco-2 cell monolayers. Methods: Cosalane and its different analogs/prodrugs were synthesized and their physicochemical properties were determined. Caco-2 cells were cultured at a density of 66 000 cells/cm² either on collagen coated clear polyester membranes or Transwell^® inserts. Side-bi-side diffusion cells and Transwell^® inserts were employed to study for the transport of cosalane and its analogs/prodrugs with various permeation enhancers across Caco-2 cell monolayers. Results: Permeabilities of EH-3-39, EH-3-55 and EH-3-57 significantly improved compared to that of cosalane in the presence of bile salt, sodium desoxycholate. Among the various cyclodextrins studied, hydroxypropyl beta cyclodextrin (HP-β-CD) and dimethyl beta cyclodextrin (DM-β-CD) exhibited 22.3-fold and 19-fold permeability enhancement of cosalane respectively across Caco-2 cell monolayers. Sodium desoxycholate (10 mM) also showed a remarkable (105-fold) enhancement on the permeability of cosalane (P_app 11.72±3.31×10⁻⁶ cm/s) without causing any measurable cellular damage. Cremophor EL resulted in higher transport of ¹⁴C mannitol. The mechanism of enhancement effect can be mainly attributed to the alteration of membrane fluidity by cyclodextrin and opening of tight junctions by cremophor EL. Conclusions: Among the enhancers tested, 10 mM sodium desoxycholate and HP-β-CD appear to be viable candidates for further development of an oral formulation of cosalane and its congeners.
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Substituted diarylmethylenepiperidines (DAMPs) were synthesized as conformationally restricted analogues of the alkenyldiarylmethane (ADAM) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Although, like the ADAMs, the DAMPs were found to inhibit the cytopathic effect of HIV-1_RF in CEM-SS cells, they were completely inactive as inhibitors of HIV-1 reverse transcriptase. The DAMPs were assessed for inhibition of HIV attachment and fusion. DAMP Scheme 1, Scheme 4 was active in both assays with IC₅₀ values of 26.5 μM (TI 3.8) and 12.1 μM (TI: >8), respectively. DAMP Scheme 1, Scheme 4 also inhibited HIV fusion with an IC₅₀ 12.8 μM (TI: >6), but not virus attachment. However, attempts to verify inhibition of virus attachment and fusion as antiviral targets using time-of-addition experiments failed to confirm these observations, and instead identified an antiviral target occurring after completion of reverse transcription. DAMPs Scheme 1, Scheme 3, Scheme 1, Scheme 3, Scheme 1, Scheme 4, and Scheme 1, Scheme 4 were found to inhibit virus replication if added 8 h post virus exposure, and DAMP Scheme 1, Scheme 3 was equipotent at inhibition of virus replication if added 24 h after virus addition. DAMPs Scheme 1, Scheme 3, Scheme 1, Scheme 3, and Scheme 1, Scheme 4 did not inhibit virus replication in TNF-α induced latently infected U1 cells, a model for post-integrative antiviral targets. When tested in both 3′ end-processing and strand-transfer assays in the presence of HIV-1 integrase, none of the DAMPs showed any inhibitory activity, indicating that HIV-1 integrase is not involved in the mechanism of the antiviral action. Thus, the DAMPs are novel conformationally restricted analogues of the previously published ADAM series with an unidentified antiviral target bounded by the completion of reverse transcription and virus integration.
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Cosalane is a novel anti-HIV agent that inhibits the attachment of gp120 to CD4. The therapeutic potential of cosalane is limited by poor oral absorption. In an attempt to target the ileal bile acid transporter and thus facilitate oral bioavailability, a cosalane analog was synthesized in which the disalicylmethane pharmacophore is attached to a bile acid through a linker chain appended to C-17 of the steroid nucleus. The resulting bile acid analog of cosalane retained antiviral activity vs. HIV-1_IIIB and HIV-2_ROD in MT-4 cells, but was less potent than cosalane.

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Exploration of the effects of linker chain modifications on anti-HIV activities in a series of cosalane analogues

Abstract

J. Biol. Cnem.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

AIDS Res. Human Retroviruses

AIDS

J. Med. Chem.

J. Am. Chem. Soc.

AIDS Res. Human Retroviruses