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. 2011 Dec 22;54(24):8582-91.
doi: 10.1021/jm201134m. Epub 2011 Nov 29.

Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents

Mariela Bollini  1 , Robert A Domaoal, Vinay V Thakur, Ricardo Gallardo-Macias, Krasimir A Spasov, Karen S Anderson, William L Jorgensen
Affiliations

Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents

Mariela Bollini et al. J Med Chem. .

Abstract

A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.

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Figures

Figure 1
Figure 1
Computed structures of a catechol diether (31) bound to HIV-RT starting from the 2be2 crystal structure. Two possible conformations of the uracilylethoxy sidechain, gaa (left) and aag (right), are illustrated. Carbon atoms of the inhibitor are colored gold.
Figure 2
Figure 2
Small molecule crystal structure of 20. Details are in the Supplementary Information.
Figure 3
Figure 3
Computed structure of 42 (JLJ0494) bound to HIV-RT illustrating the positioning of the cyanovinyl group between Tyr188 and Phe227. Carbon atoms of 42 are colored gold.
Figure 4
Figure 4
Computed structure of 42 bound to HIV-RT illustrating the possible halogen bond between the oxygen of Pro95 and the 5-chlorine in the terminal phenyl ring of the inhibitor. The O-Cl distance is 3.4 Å.
Scheme 1
Scheme 1
a. Synthesis of compounds 5-15 aReagents: (a) DIAD, bromoethanol, Ph3P, THF, rt, overnight; (b) 180 °C, 1.5 h.
Scheme 2
Scheme 2
a Synthesis of compounds 20-27, 36 and 44. aReagents: (a) K2CO3, DMSO, 110 °C, 2-5 h; (b) BBr3, CH2Cl2, -78 °C, overnight; (c) DIAD, bromoethanol, Ph3P, THF, rt, overnight; (d) 2,4-bis((trimethylsilyl)oxy)pyrimidine, 180 °C, 1.5 h, or 3-benzoylpyrimidine-2,4(1H,3H)-dione, K2CO3, DMF, overnight, rt then MeOH, NH4OH, 2h, rt; (e) Fe, NH4Cl, EtOH, H2O, 75 °C; (f) NaNO2, conc HCl, KI, 80 °C, 2h; (g) Acrylonitrile, PdCl2(PPh3)2, Et3N, DMF, 140 ° C, 2 h.
Scheme 3
Scheme 3
a Synthesis of compounds 28 – 32 and 40-47 aReagents: (a) K2CO3, DMSO, 110 °C 2-5 h; (b) Fe, NH4Cl, EtOH, H2O, 75 °C; (c) NaNO2, conc HCl, CuCl, 80 °C, 1h; (d) CH3B(OH)2, Cu(OAc)2, pyr, dioxane, reflux; (f) Acrylonitrile, PdCl2(PPh3)2, Et3N, DMF, 140 °C, 2 h; (g) BBr3, CH2Cl2, -78 °C, overnight or LiCl, DMF 160 °C, overnight; (h) DIAD, bromoethanol, Ph3P, THF, rt, overnight; (i) 3-benzoylpyrimidine-2,4(1H,3H)-dione, K2CO3, DMF, rt, overnight then NH4OH, MeOH, rt.
Scheme 4
Scheme 4
a Synthesis of compounds 33-35. aReagents: (a) DIAD, bromoethanol, Ph3P, THF, rt, overnight; (b) NaBH4, MeOH, 0 °C to rt, 3h; (c) NaH, DMF, rt, 2h.
Scheme 5
Scheme 5
See this image and copyright information in PMC

References

    1. Flexner C. HIV drug development: the next 25 years. Nature Rev Drug Disc. 2007;6:959–966. - PubMed
    2. De Clerq E. The design of drugs for HIV and HCV. Nature Rev Drug Disc. 2007;6:1001–1018. - PubMed
    3. Jochmans D. Novel HIV-1 reverse transcriptase inhibitors. Virus Res. 2008;134:171–185. - PubMed

    1. Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA. Crystal Structure at 3.5 Å Resolution of HIV-1 Reverse Transcriptase Complexed with an Inhibitor. Science. 1992;256:1783–1790.. For a review, see: Prajapati DG, Ramajayam R, Yadav MR, Giridhar R. The search for potent, small molecule NNRTIs: A review. Bioorg Med Chem. 2009;17:5744–5762.

    1. Adams J, Patel N, Mankaryous N, Tadros M, Miller CD. HIV/AIDS: Nonnucleoside Reverse Transcriptase Inhibitor Resistance and the Role of the Second-Generation Agents. Ann Pharmacotherapy. 2010;44:157–165. - PubMed
    2. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. The Challenge of Finding a Cure for HIV Infection. Science. 2009;323:1304–1307. - PubMed

    1. For a review, see: Jorgensen WL. Efficient Drug Lead Discovery and Optimization. Acc Chem Res. 2009;42:724–733.

    1. Zeevaart JG, Wang L, Thakur VV, Leung CS, Tirado-Rives J, Bailey CM, Domaoal RA, Anderson KS, Jorgensen WL. Optimization of Azoles as Anti-HIV Agents Guided by Free-Energy Calculations. J Am Chem Soc. 2008;130:9492–9499. - PMC - PubMed
    2. Leung CS, Zeevaart JG, Domaoal RA, Bollini M, Thakur VV, Spasov K, Anderson KS, Jorgensen WL. Eastern extension of azoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternatives. Bioorg Med Chem Lett. 2010;20:2485–2488. - PMC - PubMed

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