verlapped), 1.34 (t, J = 7.0 Hz), 1.431.48 (m, 2H), 1.74.81 (m, 4H), 3.91.95 (m, 4H), four.03 (q, J = 7.0 Hz, 2H), five.51.41 (brs, imidamide NHs), 6.51 (dd, J = eight.5, two.five Hz, 1H), 6.56 (d, J = 2.5 Hz, 1H), 6.90 (s, 1H), 6.98 (brs, 1H), 7.05 (s, 1H), 7.39 (ddd, J = 0.9, 4.eight, 7.4 Hz, 1H), 7.45 (s, 1H), 7.81 (td, J = 7.eight, 1.six Hz, 1H), eight.47 (d, J = 7.eight Hz, 1H), eight.57 (d, J = 4.six Hz, 1H);13C NMR (176 MHz, CDCl3) 15.0, 26.1, 26.six, 29.1, 29.three, 29.5, 31.two, 47.1, 64.five, 68.three, 102.2, 106.1, 118.9, 122.0, 123.five, 125.two, 129.six, 137.0, 137.two, 148.0, 151.2, 151.5, 153.5, 156.5; HRMS (ESI) m/z (M +H)+ calcd for C25H34N5O2, 436.27070; discovered, 436.27139; Anal. Calcd for C25H33N5O2: C, 68.94; H, 7.64; N, 16.08. Found: C, 68.66; H, 7.65; N, 15.86. N-(4-((8-(1H-imidazol-1-yl)octyl)oxy)-2-isopropoxyphenyl) picolinimidamide (24c). Yellow powder, 92 mg, yield 34 starting from 210 mg 23c (0.60 mmol); mp 825 ; 1H NMR (700 MHz, CDCl ) 1.25 (brd, J = 5.9 Hz, 6H), 1.28.38 (m, 6H), 1.42.48 three (m, 2H), 1.74.80 (m, 4H), 3.92 (t (apparent), J = 6.9 Hz, 4H), 4.44 (sep, J = 5.9 Hz, 1H), 5.38.16 (brs, imidamide NHs), 6.55 (dd, J = eight.5, two.five Hz, 1H), 6.57 (d, J = 2.five Hz, 1H), 6.80.98 (brs, 2H total, overlapped), 6.90 (s), 7.05 (s, 1H), 7.36.39 (m, 1H), 7.46 (s, 1H), 7.78.82 (m, 1H), eight.43 (brs, 1H), eight.57 (d, J = 3.9 Hz, 1H); 13C NMR (176 MHz, CDCl3) 22.4, 26.1, 26.6, 29.two, 29.3, 29.five, 31.two, 47.2, 68.3, 72.1, 105.9, 107.7, 118.9, 121.8, 123.7,ACS Infect Dis. Author manuscript; available in PMC 2022 July 09.Abdelhameed et al.Page125.0, 129.6, 133.eight, 136.8, 137.2, 147.9, 149.8, 152.0, 152.six, 156.1; HRMS (ESI) m/z (M +H)+ calcd for C26H36N5O2, 450.28635; identified, 450.28778; Anal. Calcd for C26H35N5O2: C, 69.46; H, 7.85; N, 15.58. Found: C, 69.40; H, 7.90; N, 15.37.Author Manuscript Author Manuscript Author Manuscript Author Manuscript2-(8-bromooctyl) HDAC5 site isoindoline-1, 3-dione (26). To a remedy of 1,8-dibromooctane (eight.eight g, 32.four mmol) in dry DMF (30 mL) was added phthalimide potassium salt (two.0 g, 10.eight mmol) plus the mixture was stirred at 90 for 24h. The reaction mixture was extracted with CH2Cl2 (two 30 mL) and washed with 0.1N NaOH (50 mL). The combined organic layer was dried more than anhydrous Na2SO4, filtered and evaporated below reduced stress. The crude solution was purified by column chromatography making use of hexanes/ethyl acetate 15:1 as eluent to afford the pure solution as a white powder, two.2 g, yield 60 ; 1H NMR (400 MHz, CDCl3) 1.25.46 (m, 8H), 1.621.72 (m, 2H), 1.79.87 (m, 2H), three.38 (t, J = six.9 Hz, 2H), three.67 (t, J = 7.three Hz, 2H), 7.67.73 (m, 2H), 7.81.86 (m, 2H); 13C NMR (one hundred MHz, CDCl3) 26.eight, 28.2, 28.6, 28.7, 29.1, 32.9, 34.1, 38.1, 123.three, 132.3, 134.0, 168.6.8-(1H-imidazol-1-yl)octan-1-amine (27). Compound 27 was prepared more than two measures with slight modification to a previously published CCR4 supplier process.31 To a resolution of 26 (2.0 g, 5.91 mmol) in dry DMF (20 mL) wasACS Infect Dis. Author manuscript; accessible in PMC 2022 July 09.Abdelhameed et al.Pageadded 1.five equivalents K2CO3 (1.22 g, eight.86 mmol) and two equivalents of imidazole (0.80g, 11.82 mmol) and the mixture was stirred at 80 for 12h. Soon after the reaction was completed, the suspension was filtered along with the filtrate was concentrated beneath lowered stress. The crude solution was subjected to silica gel chromatography utilizing DCM/MeOH 10:0.three because the eluent to afford the pure product as a white powder, 1.20 g, yield 62 . The 2-(8-(1H imidazol-1-yl)octyl)isoindoline-1,3-dione solution (1.1. g, 3.38 mmol) was heated to reflux with six equivale