Synthesis and Molecular Docking Study of Novel Chromeno-chromenones as Anti-HIV-1 NNRT Inhibitors

Abstract

l-Proline has been employed efficiently for the synthesis of chromeno-chromenone derivatives via a one-pot, three component condensation reaction of salicylaldehydes, 4-hydroxy coumarin, and indole or barbituric acid. The simple procedure and good to excellent yields (78–90%) are notable features of the method. The obtained derivatives were studied for their molecular docking as an anti-HIV-1 RT.

Keywords

chromeno-chromenone - salicylaldehyde - 4-hydroxycoumarin - l-proline - anti-HIV activity - molecular docking

• References and Notes

• 1 Fujioka H, Murai K, Kubo O, Ohba Y, Kita Y. Org. Lett. 2007; 9: 1687
• 2 Dömling A. Chem. Rev. 2006; 106: 17
• 3 Frankel AD, Young JA. T. Annu. Rev. Biochem. 1998; 67: 1
• 4 Davey RT. Jr, Dewar RL, Reed GF, Vasudevachari MB, Polis MA, Kovacs JA, Falloon J, Walker RE, Masur H, Haneiwich SE, O’Neill DG, Decker MR, Metcalf JA, Deloria MA, Laskin OL, Salzmant N, Lane HC. Proc. Natl. Acad. Sci. U.S.A. 1993; 90: 5608
• 5 Ragno R, Frasca S, Manetti F, Brizzi A, Massa S. J. Med. Chem. 2005; 48: 200
• 6 Kostova I, Raleva S, Genova P, Argirova R. Bioinorg. Chem. Appl. 2006; 68274: 1
• 7 Spino C, Dodier M, Sotheeswaran S. Bioorg. Med. Chem. Lett. 1998; 8: 3475
• 8 Murakami A, Gao G, Omura M, Yano M, Ito C, Furukawa H, Takahashi D, Koshimizu K, Ohigashi H. Bioorg. Med. Chem. Lett. 2000; 10: 59
• 9 Xia Y, Yang Z.-Y, Xia P, Hackl T, Hamel E, Mauger A, Wu J.-H, Lee K.-H. J. Med. Chem. 2001; 44: 3932
• 10 Itoigawa M, Ito C, Tan HT.-W, Kuchide M, Tokuda H, Nishino H, Furukawa H. Cancer Lett. 2001; 169: 15
• 11 Yamaguchi T, Fukuda T, Ishibashi F, Iwao M. Tetrahedron Lett. 2006; 47: 3755
• 12 Yamamoto Y, Kurazono M. Bioorg. Med. Chem. Lett. 2007; 17: 1626
• 13 Rashamuse TJ, Musa MA, Klein R, Kaye PT. J. Chem. Res. 2009; 5: 302
• 14 Bourinbaiar AS, Tan X, Nagorny R. AIDS 1993; 7: 129
• 15 Tummino PJ, Ferguson D, Hupe L, Hupe D. Biochem. Biophys. Res. Commun. 1994; 200: 1658
• 16 Tummino PJ, Ferguson D, Hupe D. Biochem. Biophys. Res. Commun. 1994; 201: 290
• 17 Vara Prasad JV. N, Para KS, Lunney EA, Ortwine DF, Dunbar JB. Jr, Ferguson D, Tummino PJ, Hupe D, Tait BD, Domagala JM, Humblet C, Bhat TN, Liu B, Guerin DM. A, Baldwin ET, Erickson JW, Sawyer TK. J. Am. Chem. Soc. 1994; 116: 6989
• 18 Lunney EA, Hagen SE, Domagala JM, Humblet C, Kosinski J, Tait BD, Warmus JS, Wilson M, Ferguson D, Hupe D, Tummino PJ, Baldwin ET, Bhat TN, Liu B, Erickson JW. J. Med. Chem. 1994; 37: 2664
• 19 Zhou T, Shi Q, Chen CH, Huang L, Ho P, Morris-Natschke SL, Lee KH. Eur. J. Med. Chem. 2012; 47: 86
• 20 Zhou T, Shi Q, Chen CH, Zhu H, Huang L, Ho P, Lee KH. Bioorg. Med. Chem. 2010; 18: 6678
• 21 Gong K, Wang H, Luo J, Liu Z. J. Heterocycl. Chem. 2009; 46: 1145
• 22a Heravi MM, Jani BA, Derikvand F. Catal. Commun. 2008; 10: 272
• 22b Heravi MM, Sadjadi S, Haj NM, Oskooie HA. Catal. Commun. 2009; 10: 1643
• 23 Shaabani A, Samadi S, Badri Z, Rahmati A. Catal. Lett. 2005; 104: 39
• 24 Seifi M, Sheibani H. Catal. Lett. 2008; 126: 275
• 25 Abdolmohammadi S, Balalaie S. Tetrahedron Lett. 2007; 48: 3299
• 26 Khurana JM, Kumar S. Tetrahedron Lett. 2009; 50: 4125
• 27 Khurana JM, Nand B, Saluja P. Tetrahedron Lett. 2010; 66: 5637
• 28 Karimi AR, Sedaghatpour F. Synthesis 2010; 1731
• 29 Chen Z, Zhu Q, Su W. Tetrahedron Lett. 2011; 52: 2601
• 30 Yua T, Yang S, Zhao Y, Zhang H, Han X, Fan D, Qiu Y, Chen L. J. Photochem. Photobiol., A 2010; 214: 92
• 31 Rao P, Konda S, Iqbal J, Oruganti S. Tetrahedron Lett. 2012; 53: 5314
• 32 General Procedure for the Synthesis of Chromeno-chromenone Derivatives A mixture of salicylaldehyde (1 mmol), 4-hydroxycoumarin (1 mmol), and l-proline (0.1 mmol) in EtOH (5 mL) was heated to reflux for 6 h. Indole or barbituric acid (1 mmol) was then added to the reaction mixture and reflux continued with stirring for a further 6–8 h (monitoring by TLC). The solid formed was filtered washed with EtOH then with H₂O to afford analytically pure product.
• 33 Representative Analytical Data 9,11-Dibromo-7-(1H-indol-3-yl)-6H,7H-chromeno[4,3-b]chromen-6-one (4c) Brownish solid; yield 90%; mp (280 °C). IR: 3410, 2900, 2350, 2300, 1700, 1600, 1550, 1450, 1400, 1300, 1210, 1150,900, 750, 700 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 10.29 (s 1 H, NH), 8.23 (d, 1 H), 8.03 (d, 1 H), 7.67 (t, 2 H), 7.48 (m, 3 H), 7.32 (t, 1 H), 7.21 (d, 2 H), 5.31 (s, 1 H). ¹³C NMR (300 MHz, CDCl₃): δ = 164.53, 158.62, 151.25, 149.00, 147.63, 141.00, 140.87, 135.00, 133.39, 132.52, 130.43, 25.55, 125.06, 124.62, 124.25, 123.87, 117.93, 117.13, 116.57, 111.82, 105.03, 104.00, 103.80, 30.47 cm^–1. GC–MS: m/z = 523 [M⁺]. 9-Bromo-11-iodo-7-(1H-indol-3-yl)-6H,7H-chromeno[4,3-b]chromen-6-one (4g) Brownish solid; yield 85%; mp (282 °C). IR: 3300, 2910, 2870, 1700, 1610, 1490, 1395, 1210, 1050, 850, 820, 710, 600 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 10.38 (s, 1 H, NH), 8.14 (dd, 1 H), 8.02 (dd, 1 H), 7.65 (m, 1 H), 7.55 (m, 1 H), 7.52 (m, 1 H), 7.49 (m, 1 H), 7.41 (m, 2 H), 7.34 (d, 1 H), 7.24 (s, 1 H), 7.12 (s, 1 H). ¹³C NMR (300 MHz, CDCl₃): δ = 166.00, 157.12, 153.00, 149.00, 146.00, 143.50, 136.00, 135.39, 134.42, 130.52, 126.85, 125.06, 124.32, 124.25, 124.00, 117.91, 117.12, 116.51, 111.00, 106.00, 101.52, 100.00, 31.00. GC–MS: m/z = 570 [M⁺]. 5-{9-Chloro-6-oxo-6H,7H-chromeno[4,3-b]chromen-7-yl}-6-hydroxypyrimidine-2,4-(1H,3H)-dione (4m) Brownish solid; yield 89%; mp (89 °C). IR: 3600, 3420, 3380, 2996, 2817, 1702, 1663, 1611, 1566, 1452, 1400, 1215, 1168, 786, 530 cm^–1. ¹H NMR (400 MHz, DMSO): δ = 12.87 (s, 1 H, OH), 9.89 (s, 1 H, NH), 8.04 (d, 1 H), 7.85 (s, 1 H), 7.60 (s, 1 H), 7.49 (t, 1 H), 7.29 (t, 2 H), 7.18 (d, 1 H), 6.81 (s, 1 H, NH), 5.73 (s, 1 H). ¹³C NMR (300 MHz, CDCl₃): δ = 167.08, 165.76, 163.80, 161.00, 154.29, 152.42, 150.80, 132.36, 131.10, 129.00, 127.63, 127.23, 125.72, 125.12, 120.00, 117.49, 117.12, 115.12, 110.00, 81.50, 29.24. GC–MS: m/z = 410 [M⁺].