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Synthesis and HIV Protease Inhibitory Activity of New 4-Hydroxy-2-pyrone Derivatives

2000; Wiley; Volume: 333; Issue: 10 Linguagem: Inglês

10.1002/1521-4184(200010)333

1521-4184

Yong Sup Lee, Sun Nam Kim, Yong Sil Lee, Jae Yeol Lee, Chong-Kyo Lee, Hae Soo Kim, Hokoon Park,

Multicomponent Synthesis of Heterocycles

Archiv der PharmazieVolume 333, Issue 10 p. 319-322 Communication to the Editor Synthesis and HIV Protease Inhibitory Activity of New 4-Hydroxy-2-pyrone Derivatives Yong Sup Lee, Yong Sup Lee Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaSearch for more papers by this authorSun Nam Kim, Sun Nam Kim Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaSearch for more papers by this authorYong Sil Lee, Yong Sil Lee Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaSearch for more papers by this authorJae Yeol Lee, Jae Yeol Lee Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaSearch for more papers by this authorChong-Kyo Lee, Chong-Kyo Lee Pharmaceutical Screening Center, Korea Research Institute of Chemical Technology, P.O. Box 107, Yusong, Taejeon 305-600, KoreaSearch for more papers by this authorHae Soo Kim, Hae Soo Kim Pharmaceutical Screening Center, Korea Research Institute of Chemical Technology, P.O. Box 107, Yusong, Taejeon 305-600, KoreaSearch for more papers by this authorHokoon Park, Hokoon Park Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaSearch for more papers by this author Yong Sup Lee, Yong Sup Lee Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaSearch for more papers by this authorSun Nam Kim, Sun Nam Kim Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaSearch for more papers by this authorYong Sil Lee, Yong Sil Lee Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaSearch for more papers by this authorJae Yeol Lee, Jae Yeol Lee Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaSearch for more papers by this authorChong-Kyo Lee, Chong-Kyo Lee Pharmaceutical Screening Center, Korea Research Institute of Chemical Technology, P.O. Box 107, Yusong, Taejeon 305-600, KoreaSearch for more papers by this authorHae Soo Kim, Hae Soo Kim Pharmaceutical Screening Center, Korea Research Institute of Chemical Technology, P.O. Box 107, Yusong, Taejeon 305-600, KoreaSearch for more papers by this authorHokoon Park, Hokoon Park Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaSearch for more papers by this author First published: 06 October 2000 https://doi.org/10.1002/1521-4184(200010)333:10 3.0.CO;2-ACitations: 16AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES 1 a) T. L.Blundell, R.Lapatto, A, F.Wilderspin, A. M.Hemmings, P. M.Hobart, D. E.Danlay, P. J.Whittle, Trends Biol. Sci., 1990, 15, 425–430, b) C Debouck, B. W. Metcalf, Drug. Dev. Res. 1990, 21, 1-17. 10.1016/0968-0004(90)90280-O CASPubMedWeb of Science®Google Scholar 2 a) J. R.Huff, J. 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Des. 1993, 1, 49-68. 10.1126/science.2686029 CASPubMedWeb of Science®Google Scholar 8 All new compounds are characterized by 300 MHz 1 H NMR spectros-copy. 5: (DMSO-d6) ??7.36 (d, 2H, J = 7.3 Hz, Ph), 7.23 (dd, 2H, J = 7.3, 6.9 Hz, Ph), 7.13 (d, 1H, J = 6.9 Hz, Ph), 6.00 (s, 1H, pyrone), 3.23 (d, 1H, J = 10.4 Hz, PhCH-), 2.13 (s, 3H, CH3), 1.85 (m, 1H, cyclopropyl), 0.63-0.17 (m, 4H, cyclopropyl). 6: (CDCl3) ??7.50 (d, 2H, J = 7.5 Hz, Ph), 7.30 (dd, 2H, J=7.5, 7.2 Hz, Ph), 7.22 (d, 1H, J = 7.2 Hz, Ph), 5.93 (s, 1H, pyrone), 3.62 (d, 1H, J = 9.6 Hz, PhCH-), 2.37 (t, 2H, J = 7.5 Hz, propyl), 1.75-1.59 (m, 3H, propyl & cyclo-propyl), 0.95 (t, 3H, J = 7.4 Hz, propyl), 0.71-0.28 (m, 4H, cyclo-propyl). 7: (CDCl3) ??8.10 (m, 1H, Ph), 7.96 (s, 1H, Ph), 7.49-7.27 (m, 7H), 6.87 (br, 1H, OH), 5.62 (s, 1H, pyrone), 3.81 (m, 1H, PhCH-), 3.07-2.98 (m, 2H, m-NO2-Ph-CH2), 2.55 (m, 1H, CH-pyrone), 1.70 (m, 2H, propyl), 1.29 (m, 1H, cyclopropyl), 0.92 (t, 3H, J = 7.4 Hz, CH3), 0.75 (m, 1H, cyclopropyl), 0.66 (m, 1H, cyclopropyl), 0.47 (m, 1H, cyclopropyl), 0.28 (m, 1H, cyclopropyl). 8: (CDCl3) ??7.43-7.21 (m, 6H, Ph and OH), 6.95 (t, 1H, J = 7.7 Hz, Ph), 6.43 (m, 2H, Ph), 6.33 (s, 1H, Ph), 5.52 (s, 1H, pyrone), 3.81 (m, 1H, PhCH), 2.78 (m, 1H, CH-pyrone), 2.65 (m, 1H, m-NH2Ph-CH), 2.43 (m, 1H, m-NH2Ph-CH), 1.65-1.50 (m, 4H, NH2 and propyl), 1.19 (m, 1H, cyclopropyl), 0.79 (t, 3H, J = 7.4 Hz, CH3), 0.67-0.65 (m, 1H, cyclopropyl), 0.54-0.43 (m, 2H, cyclopropyl), 0.23-0.18 (m, 1H, cyclopropyl). 3a: (CDCl3+CD3OD) ??7.68-6.79 (m, 14H, Ph), 5.66 (1s, 1H, pyrone), 3.39 (d, 1H, J = 9.8 Hz, PhCH), 2.80 (m, 2H, PhCH2), 2.48 (m, 1H, CH-pyrone), 1.85-1.54 (m, 3H, propyl and cyclopropyl), 0.86 (t, 3H, J = 7.3 Hz, CH3), 0.67 (m, 1H, cyclopropyl), 0.49-0.47 (m, 1H, cyclopropyl), 0.24 (m, 2H, cyclopropyl). 3b: (CDCl3+CD3OD) ??7.51-6.78 (m, 13H, Ph), 5.68 (1s, 1H, pyrone), 3.37 (d, 1H, J = 10.1 Hz, PhCH), 2.80 (m, 2H, PhCH2), 2.45 (m, 1H, CH-pyrone), 2.35 (s, 3H, CH3-Ph), 1.91-1.51 (m, 3H, propyl and cy-clopropyl), 0.86 (t, 3H, J = 7.3 Hz, CH3), 0.68 (m, 1H, cyclopropyl), 0.49 (m, 1H, cycl opropyl), 0.24 (m, 2H, cyclopropyl). 3c: (CDCl3+CD3OD) ??7.61-6.79 (m, 13H, Ph), 5.67 (s, 1H, pyrone), 3.79 (s, 3H, OCH3), 3.39 (d, 1H, J = 10.3 Hz, CH-Ph), 2.80 (m, 2H, PhCH2), 2.48 (m, 1H, CH-pyrone), 1.89-1.54 (m, 3H, propyl and cyclopropyl), 0.86 (t, 3H, J = 7.4 Hz, 3H), 0.68 (m, 1H, cyclopropyl), 0.49 (m, 1H, cyclopropyl), 0.24 (m, 2H, cyclopropyl). 3d: (CDCl3) ??7.78-6.83 (m, 13H, Ph), 5.66 (s, 1H, pyrone), 3.67 (d, 1H, J = 9.1 Hz, PhCH), 2.79 (m, 2H, PhCH2), 2.46 (m, 1H, CH-pyrone), 1.67-1.53 (m, 3H, propyl and cyclopropyl), 0.85 (t, 3H, J = 7.3 Hz, CH3), 0.71 (m, 1H, cyclopropyl), 0.55 (m, 1H, cyclopropyl), 0.39 (m, 1H, cyclo-propyl), 0.25 (m, 1H, cyclopropyl). 3e: (CDCl3+CD3OD) ??8.21-6.78 (m, 13H, Ph), 5.65 (s, 1H, pyrone), 3.39 (d, 1H, J = 9.8 Hz, PhCH), 2.83 (m, 2H, PhCH2), 2.50 (m, 1H, CH-pyrone), 1.87-1.53 (m, 3H, propyl and cyclopropyl), 0.87 (t, 3H, J = 7.3 Hz, CH3), 0.69 (m, 1H, cyclopropyl), 0.48 (m, 1H, cyclopropyl), 0.24 (m, 2H, cyclopropyl). 3f: (CDCl3+CD3OD) ??7.59-6.73 (m, 13H, Ph), 5.70 (s, 1H, pyrone), 3.38 (d, 1H, J = 9.6 Hz, PhCH), 2.80- 2.71 (m, 2H, PhCH2), 2.34 (m, 1H, CH-pyrone), 2.13 (s, 3H, CH3CO), 1.92-1.49 (m, 3H, propyl and cyclopropyl), 0.83 (t, 3H, J = 7.3 Hz, CH3), 0.68 (m, 1H, cyclopropyl), 0.48 (m, 1H, cyclopropyl), 0.25 (m, 2H, cyclopropyl). 3g: (CDCl3+CD3OD) ??8.07-6.80 (m, 13H, Ph), 5.63 (s, 1H, pyrone), 3.40 (m, 1H, PhCH), 2.89-2.77 (m, 2H, PhCH2), 2.50 (m, 1H, CH-pyrone), 1.89-1.54 (m, 3H, propyl and cyclopropyl), 0.85 (t, 3H, J = 7.3 Hz, CH3), 0.68 (m, 1H, cyclopropyl), 0.49 (m, 1H, cyclopropyl), 0.25 (m, 2H, cyclopropyl). 3h: (CDCl3) ??8.64 (d, 1H, J = 5.4 Hz, pyridine), 7.82-6.79 (m, 12H, pyridine and Ph) 5.66 (s, 1H, pyrone), 3.66 (d, 1H, J = 9.4 Hz, PhCH), 2.77 (m, 2H, PhCH2), 2.42 (m, 1H, CH-pyrone), 1.69-1.62 (m, 3H, propyl and cyclopropyl), 0.83 (m, 3H, CH3), 0.73 (m, 1H, cyclopropyl), 0.55 (m, 1H, cyclopropyl), 0.39 (m, 1H, cyclopropyl), 0.24 (m, 1H, cyclopropyl). 3i: (CD3OD) ??8.72 (s, 1H, pyridine), 7.94-6.62 (m, 11H, pyridine and Ph), 5.59 (1s, 1H, pyrone), 3.12 (1H, overlapped with solvent, PhCH), 2.62 (m, 2H, PhCH2), 2.36 (m, 1H, CH-pyrone), 1.69-1.43 (m, 3H, propyl and cy-clopropyl), 0.69 (t, 3H, J = 7.4 Hz, CH3), 0.49 (m, 1H, cyclopropyl), 0.26 (m, 1H, cyclopropyl), 0.04-0.01 (m, 2H, cyclopropyl). 3j: (CDCl3) ??8.91 (s, 1H, pyridine), 8.03-6.83 (m, 11H, pyridine and Ph), 5.64 (s, 1H, pyrone), 3.67 (d, 1H, J = 9.2 Hz, PhCH), 2.80 (m, 2H, PhCH2), 2.45 (m, 1H, CH-pyrone), 1.69-1.47 (m, 3H, propyl and cy-clopropyl), 0.83 (t, 3H, J = 7.4 Hz, CH3), 0.69 (m, 1H, cyclopropyl), 0.54 (m, 1H, cyclopropyl), 0.37 (m, 1H, cyclopropyl), 0.24 (m, 1H, cyclopropyl). 3k: (CDCl3+CD3OD) ??9.37 (m, 1H, pyridine), 8.49- 6.78 (m, 11H, pyridine and Ph), 5.64 (s, 1H, pyrone), 3.37 (d, 1H, J =10.0 Hz, PhCH), 2.83-2.75 (m, 2H, PhCH2), 2.43 (m, 1H, CH-py-rone), 1.88-1.50 (m, 3H, propyl and cyclopropyl), 0.84 (t, 3H, J = 7.3 Hz, CH3), 0.68 (m, 1H, cyclopropyl), 0.45 (m, 1H, cyclopropyl), 0.25- 0.15 (m, 2H, cyclopropyl). 3l: (CD3OD) ??7.92 (s, 1H, pyridine), 7.52- 6.73 (m, 11H, J = 9.0 Hz), 5.74 (s, 1H, pyrone), 3.32 (1H, overlapped with solvent, PhCH), 2.81-2.73 (m, 2H, PhCH2), 2.46 (m, 1H, CH-py-rone), 1.95-1.48 (m, 3H, propyl and cyclopropyl), 0.86 (m, 3H, CH3), 0.69 (m, 1H, cyclopropyl), 0.44 (m, 1H, cyclopropyl), 0.19-0.18 (m, 2H, cyclopropyl). 9: (CDCl3) ??7.50-7.07 (m, 10H, Ph), 6.51 (br, 1H, OH), 5.58 (s, 1H, pyrone), 3.86 (d, 1H, J = 8.9 Hz, PhCH), 2.96-2.83 (m, 2H, PhCH2), 2.52 (m, 1H, CH-pyrone), 1.72-1.40 (m, 3H, propyl and cyclopropyl), 0.88 (m, 3H, CH3), 0.75-0.68 (m, 1H, cyclopropyl), 0.62-0.49 (m, 2H, cyclopropyl), 0.31-0.25 (m, 1H, cyclopropyl). Google Scholar 9 HIV protease inhibitory activity was measured as follows: HIV pro-tease and the fluorogenic substrate, Abz-Thr-Ile-Nle-p-nitro-Phe-Gln-Arg- NH2 were purchased from Bachem Bioscience. The compounds were serially diluted by 10 fold with assay buffer (50 mM sodium acetate, pH 5.2, 200 mM NaCl, 5 mM dithiothreitol, 10% glycerol). Reaction mixture consisted of 9 ?l of 10??concentrated compounds, 6.5 ?l of 1 mg/ml substrate dissolved in 100% DMSO, 72.5 ?l assay buffer and 2 ?l of HIV protease. The reaction was initiated by addition of 2 ?l of HIV protease (0.7 ?g/?l) and incubated at room temperature. The activity was measured by monitoring the increase in fluorescence intensity at the emission maximum of 460 nm (excitation wavelength was 345 nm) using fluorescence microplate reader (Fluoroskan Ascent, Labsystems). Google Scholar 10 Evaluation of Antiviral activity was measured as follows: Standard virus-induced CPE (cytopathic effect) inhibition assay which employed 3-(4,5-dimethyl thiazoly-2)-2,5-diphenyl tetrazolium bromide (MTT) to measure inhibition of virus-mediated cell death was used with slight modification. MT-4 cells on log phase were pelleted and infected with HIV-1IIIB virus at an M.O.I. (multiplicity of infection) of 100 CCID50 (50% cell culture inhibitory dose) per well. The cells were immediately resuspended with RPMI 1640/10% FBS at the concentration of 1.2 ??10 5 cells/ml. 100 ?l of the resuspended cells were dropped to the wells of 96 well plate containing 100 ?l of 2 ??concentrated compounds in duplicate. After 5 days incubation at 37 ?C, the cells were observed microscopically and quantified by MTT assay. The liquid was aspirated until 50 ?l of liquid and all cells remained, and 20 ?l of 7.5 mg/ml MTT solution was added. The plate were further incubated for 1 h, and 100 ?l of acidified isopropanol was added and shaken on a microplate shaker until the formazan form completely dissolved. The absorbance at 540 nm by using 690 nm as reference wavelength was measured with microplate reader (Vmax, Molecular Devices). The antiviral effective concentration was expressed as the EC50 or concentration of the com-pound required to inhibit virus-induced CPE by 50%. To measure the effect of compounds on the host cell growth, mock-infected cells were applied to the compound containing wells of the same plates in dupli-cate. The cytotoxic concentration was expressed as the CC50 or concen-tration of the compound required to inhibit cell growth by 50%. Google Scholar Citing Literature Volume333, Issue10October 2000Pages 319-322 ReferencesRelatedInformation