1,2,3,4‐Tetrahydroisoquinolines as inhibitors of HIV‐1 integrase and human LEDGF/p75 interaction

Abstract

Alkaloids are a class of organic compounds with a wide range of biological properties, including anti-HIV activity. The 1,2,3,4-tetrahydroisoquinoline is a ubiquitous structural motif of many alkaloids. Using a short and an efficient route for synthesis, a series of 1,2,3,4-tetrahydroisoquinolines/isoquinolines was developed. These compounds have been analysed for their ability to inhibit an important interaction between HIV-1 integrase enzyme (IN) and human LEDGF/p75 protein (p75) which assists in the viral integration into the active genes. A lead compound 6d is found to inhibit the LEDGF/p75-IN interaction in vitro with an IC of ~10 μm. Molecular docking analysis of the isoquinoline 6d reveals its interactions with the LEDGF/p75-binding residues of IN. Based on an order of addition experiment, the binding of 6d or LEDGF/p75 to IN is shown to be mutually exclusive. Also, the activity of 6d in vitro is found to be unaffected by the presence of a non-specific DNA. As reported earlier for the inhibitors of LEDGF/p75-IN interaction, 6d exhibits a potent inhibition of both the early and late stages of HIV-1 replication. Compound 6d differing from the known inhibitors in the chemical moieties and interactions with CCD could potentially be explored further for developing small molecule inhibitors of LEDGF/p75-IN interaction having a higher potency.

Succinct Syntheses of Methopholine, (±)‐Homolaudanosine, and (±)‐Dysoxyline via Metal‐free One‐Pot Double Alkylation on 1‐Methyl‐3,4‐dihydroisoquinolines

“…Through solvent screening processes, DCE and CH 3 CN turned out to be better than other solvents for the formation of double alkylating product 3a (entries [2][3][4][5][6]. As alkylation at the C1-methyl of iminium salt was known to be enabled by converting iminium salt to enamine with the help of bases, 31,32 addition of bases, such as Na 2 CO 3 , DIPEA, Et 3 N, DBU, and NMP, was performed in DCE and CH 3 CN (entries [7][8][9][10][11][12][13][14][15][16]. Apparently addition of the base was beneficial to increase the yield of 3a.…”

“…Yield: 90% (224 mg, 0.513 mmol), slightly yellow solid. 1 13 2-Benzyl-4-methyl-1-phenethyl-3,4-dihydroisoquinolin-2-ium bromide (3p): 1e (100 mg, 0.629 mmol) and benzyl bromide (538 mg, 3.14 mmol) were used. Yield: 82% (216 mg, 0.514 mmol), slightly yellow solid.…”

“…[1][2][3][4][5][6] Numerous methodologies have been reported for the syntheses of THIQ analogs. 1,3,6 In particular, THIQs substituted at the C1 and N positions display various biological activities, such as antitumor, 7-10 anti-HIV, [11][12][13] antibacterial, 1,14 and neuroprotective. 15,16 For instance, solifenacin is an approved drug as a selective muscarinic M3 receptor antagonist for the treatment of overactive bladder ( Figure 1).…”

“…Yield: 68% (129 mg, 0.389 mmol), yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.35-7.31 (m, 2H), 7.23 (dd, J = 7.5, 2.4 Hz, 1H), 7.23 (t, J = 7.6 Hz, 2H), 4.05 (s, 3H), 3.89 (s, 3H), 3.36-3.27 (m, 4H), 1.44 (t, J = 7.5 Hz, 3H);13 C NMR (125 MHz, CDCl 3 ) δ 179.9, 159.3, 129.8, 129.2, 128.9, 126.7, 122.1, 115.3 56.1, 54.2, 46.8, 25.9, 25.2, 12.2; LC/MS m/z 204.2 [M -I − ]; HRMS (FAB+) m/z calcd for C 13 H 18 NO + [M -I − ] 204.1383, found 204.1390. 2-Allyl-1-(but-3-en-1-yl)-7-methoxy-3,4-dihydroisoquinolin-2-ium bromide (3c): 1a (100 mg, 0.571 mmol) and allyl bromide (345 mg, 2.85 mmol) were used.…”

“…Yield: 80% (230 mg, 0.456 mmol), yellow solid. 1 H NMR (300 MHz, CDCl 3 ) δ 7.36-7.34 (m, 6H), 7.30-7.06 (m, 5H), 5.71 (s, 2H), 4.09 (t, J = 7.2 Hz, 2H), 3.85-3.80 (m, 5H), 3.18-3.09 (m, 4H);13 C NMR (125 MHz, CDCl 3 ) δ 179.4, 159.4, 139.9, 135.5, 134.6, 133.6, 131.1, 130.4, 129.7, 129.6, 129.4, 128.4, 128.0, 127.5, 127.2, 126.8, 126.6, 123.2, 115.7, 60.8, 56.1, 51.9, 34.0, 33.9, 25.5; LC/MS m/z 424.1 [M -Br − ]; HRMS (FAB+) m/z calcd for C 25 H 24 Cl 2 NO + [M -Br − ] 424.1229, found 424.1222. 7-Methoxy-2-(3-methoxybenzyl)-1-(3-methoxyphenethyl)-3,4-dihydroisoquinolin-2-ium bromide (3l): 1a (100 mg, 0.571 mmol) and 3-methoxybenzyl bromide (573 mg, 2.85 mmol) were used.…”