Drug Delivery and Translational Research

Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: Design, kinetics and pharmacological study

Drug delivery and translational research

Joshi Poorvashreea, Dhaneshwar Suneelaa*

a Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune-411 038, Maharashtra, India.

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Physico-chemical and spectral characterization of synthesized prodrugs

Prodrug / IR (anhydrous KBr; cm-1) / 1H-NMR (CDCl3; 400MHz) / 13C-NMR (400MHz) / MS (m/z ratio) / Elemental analysis
HBA
M.P.: 40-43°C Rf: 0.60* Aq. Sol. : 0.20 mg/mL Log Poct: 4.00 / 3062 (-NH), 3029 (C-H, Ar), 2925 (C-H, alkane, str.), 1743 (C=O), 1340 (C-N str.), 1224 (C-O str.), 780 (C-Cl) / HCQ backbone δ 1.20-1.23 [t; 3H] –CH3, 1.2-1.3 [t; 3H] –CH3, 2.3-2.6 [m, 4H] -(CH2)2, 2.4-3.0 [t; 2H] –N(CH2)3, 3.0-3.6 [m, 1H] -CH-NH, 4.0-4.1 [t, 2H] -O-CH2, 5.82 [s, 1H] –NH (sec. amine) 6.4-8.8 [m, 5H] Ar- H, NSAID backbone δ 2.65 [s; 2H] OC-CH2-, 7.5-7.2 [m, 7H] Ar- H / 11.62, 11.64, 19.44, 24.6, 30.60, 41.3, 47.81, 51.35, 53.83, 55.19, 61.05, 98.7, 117.5, 120.68, 126.5, 127.00, 127.03, 127.07, 127.51, 128.87, 128.92, 129.44, 129.47, 130.98, 132.83, 140.32, 142.68, 147.26, 149.39, 171.38 / 531.29 (C32H36ClN3O2, predicted: 530.10) / Calculated C, 70.12; H, 6.99; N, 7.67
Found C, 70.24; H, 6.86; N, 7.75
HIN
M.P.: 40-420C (uncorrected) Rf:0.73* Aq. Sol. : 0.18 mg/mL Log Poct: 4.56 / 3377 (-NH), 3010(-C-H, aromatic) 2928 (-C-H, aliphatic, str.), 1719 (-C=O), 1591 (-N-C=O str.), 1310 (-C-N str.), 1228 (-C-O str.) / δ 1.275 [t; 3H] –CH3, 1.4-1.6 [m, 4H] -(CH2)2, 2.79 [m, 1H] -CH-NH, 2.35 [t; 3H] –CH3, 2.4-2.7 [t; 6H] –N(CH2)3, 4.15-4.19 [t, 2H] -O-CH2, 7.3-8.2 [m, 5H] Ar- H, 5.29 [s, 1H] –NH (sec. amine) NSAID backbone δ 2.35 [s, 3H], 3.4-3.6 [s; 2H] –CH2CO, 4.76 [s, 3H] –OCH3 6.9-7.2 [m, 7H] Ar- H / 13.32, 19.78, 22.57, 31.89, 33.15, 50.83, 53.07, 55.78, 60.86, 97.88, 101.61, 101.88, 111.39, 114.82, 115.90, 124.02, 126.43, 129.05, 129.11, 129. 20, 130.51, 131.19, 131.31, 133.63, 135.34, 136.03, 139.05, 139.51, 153.31, 155.94, 168.26, 170.47 / 674.49 (C36H38Cl2N4O4, predicted: 674.24), / Calculated C, 65.77; H, 5.97; N, 8.29
Found C, 65.61; H, 5.50; N, 8.12
HA
M.P.: 64-660C (uncorrected) Rf: 0.70* Aq. Sol. : 0.18 mg/mL Log Poct: 4.56 / 3325.64 (-NH- str., sec. amine); 2814.6 (-CH2), 1742.37 (-C=O str. ester); 1728(-C=O str. Ester); 1491 (-C=C- aromatic); 1363 (-C-N- str.); 1613 (-C=N- aromatic); 1198 (-C-O str.); 787 (-C-Cl str.) / HCQ backboneδ 0.99-1.00 [t; 3H] –CH3, 1.2-1.3 [t; 3H] –CH3, 1.9-2.2 [m, 4H] -(CH2)2,2.4-2.5 [t; 2H] -NCH2,3.5-3.6, [t; 2H] -NCH2,2.7-2.9 [q; 2H] -NCH2,4.1-4.2 [t, 2H] -O-CH2, 2.9-3.0 [m, 1H] -CH-NH, 7.3-8.2 [m, 5H] Ar- H, 5.3-5.4 [s, 1H] –NH (sec amine) NSAID backboneδ 5.1-5.2, [s; 2H], 3.4-3.6 O-CH2-CO, [s, 2H] –CH2-O, 6.9-7.2 [m, 7H] Ar- H, 6.1-6.2 [s, 1H] –NH (sec. amine) / 11.62, 19.44, 24.6, 30.66, 39.36, 47.81, 51.35, 53.83, 55.19, 61.48, 61.65, 98.7, 121.80, 117.67, 117.5, 126.68, 126.51, 127.51, 127.71, 129.80, 129.85, 129.87, 131.60, 131.62, 132.83, 135.2, 131.54, 149.39, 147.26, 151.8, 168.35, 171.38 / 672.31 (C34H37Cl3N4O4, Predicted:670.19) / Calculated C, 60.77; H, 5.55; N, 8.33
Found: C, 60.69; H, 5.58; N, 8.37
HD
M.P.: 100-104 0C (uncorrected) Rf: 0.80* Aq. Sol. : 0.21 mg/mL Log Poct: 3.99 / 3370 (-NH- str. sec amine); 3017.09 (-CH-, aromatic); 2628.5(-CH2-); 1745.26 ( -C=O str. ester); 1247(-C-N- str.); 1448 (-C=C- aromatic); 1106.94 (-C-O str.); 732 (-C-Cl str.) / HCQ backbone δ 0.96-0.97 [t; 3H] –CH3, 1.16-1.19 [t; 3H] –CH3, 1.9-2.1 [m, 1H] -CH-NH,1.9-2.2 [m, 4H] -(CH2)2,2.2-3.2 [t; 6H] -NCH2, 4.0-4.1 [t, 2H] -O-CH2, 6.8-8.8 [m, 5H] Ar- H, 5.8 [s, 1H] –NH (sec. amine) NSAID backbone δ 3.5 [s; 2H] -CH2-CO, 6.8-7.2 [m, 7H] Ar- H, 6.61 [s, 1H] –NH (sec. amine) / 11.4, 11.9, 19.10, 24.10, 34.15, 45.05, 42.50, 41.3, 51.5, 53.4, 53.9, 62.9, 99.15, 115.10, 115.30, 112.13, 121.20, 123.90, 125.10, 127.40, 127.7, 130.20, 130. 08, 135.30, 141.25, 141.75, 151.45, 160.8, 170.8 / 613.39 (C32H35Cl3N4O2, predicted: 612.18) / CalculatedC, 62.60; H, 5.74; N, 9.12
FoundC, 62.04; H, 5.48; N, 9.02
HL
M.P.:98-1040C, (uncorrected) Rf:0.66* Aq. Sol. : 0.17 mg/mL Log Poct: 4.90 / 3334.32 (-NH), 2973.2 (-CH2 str.), 1737 (-C=O), 1613.16, 1575.56 (HC=CH str.), 1373 (C-O str.), 1079.94 (C-N str.), 766 (-C-Cl) / HCQ backboneδ 1.0-1.5 [m;6H] –CH3, 1.5-1.9 [m, 4H] -(CH2)2, 4.9-5.0[m, 1H] -CH-NH, 2.5-3.0 [t; 6H] -NCH2, 4.6-4.2 [t, 2H] -O-CH2, 7.5-9.1 [m, 5H] Ar- H, 6.1-6.3 [s, 1H] –NH (sec. amine) NSAID backboneδ 1.0-1.5 [ s, 6H] -CH3,4.2-4.3 [s; 2H] -CH2-CO, 3.8-4.2 [s, 4H] –CH2 (cyclic aliphatic), 8.1-8.5 [m, 9H] Ar- H / 11.62, 11.64, 19.44, 24.6, 30.60, 41.3, 47.81, 51.35, 53.83, 55.19, 61.05, 98.7, 117.5, 120.68, 126.5, 127.00, 127.03, 127.07, 127.51, 128.87, 128.92, 129.44, 129.47, 130.98, 132.83, 140.32, 142.68, 147.26, 149.39, 171.38 / 696.19 (C42H47Cl2N3O2), predicted:696.30 / CalculatedC, 62.60; H, 5.74; N, 9.12
FoundC, 62.04; H, 5.48; N, 9.02