Synthesis, QSAR and anti-HIV activity of new 5-benzylthio-1,3,4-oxadiazoles derived from α-amino acids

Abstract

2-(1-[(4-Chloro/methylphenylsulfonylamino)alkyl]-5-thioxo-4,5-dihydro-1,3,4-oxadiazoles (4a–e) were synthesized, in four steps, via the sulfonyl derivatives of l-amino acids (l-alanine, l-methionine and l-phenylalanine) 1a–e, the esters 2a–e, the hydrazides 3a–e and finally the cyclization to 4a–e. Alkylation of 4a–e with 1.0 mole eq. of substituted benzyl halides furnished S-benzyl derivatives 5a–t, while 1.1 mole eq. yielded major 5a–t and minor amount of 6a–d. Alternatively, treatment of 4a–e with 2.0 mole eq. of substituted benzyl halides furnished 6a–d only. The structures of 5b and 5l were further confirmed by single crystal X-ray analysis. Compounds 5a–t and 6a–d showed no selective inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 5f and 5j–5q exhibited some inhibitory activity against both types with EC₅₀ values (>11.50 − >13.00 µg/mL). These results suggest that the structural modifications of these compounds might lead to the development of new antiviral agents. The quantum structure-activity relationship of these novel structural congeners is discussed.

Keywords::

• Anti-HIV activity
• α-amino acids
• 5-benzylthio-1
• 3,4-oxadiazoles
• QSAR

Introduction

Among the various viral human ailments, acquired immunodeficiency syndrome is perhaps the most complicated disease, and as yet no effective drugs or methods of control are available owing to the mutational changes in HIV virus¹. In spite of the beneficial effects of the drugs in use, the side effects are intensified with the combination therapy². Therefore, synthesis or design of novel potent, selective, and less toxic drugs remains one of the most challenging tasks that chemists are facing. 1,3,4-oxadiazole is a versatile molecule^3–6 for designing potential antiviral agents. The safety and efficacy of Raltegravir⁷, a new anti-HIV drug containing the 1,3,4-oxadiazole moiety, has recently been described. On the other hand, sulphonamides attract significant attention because of their chemotherapeutic importance^8–11. Cyclotriazadisulphonamide compounds are new effective HIV entry inhibitors¹². We selected in the present work, two backbones: 1,3,4-oxadiazole and a sulphonamide since both having potential anti-HIV activity, which might lead to a remarkable potent anti-HIV agent with high therapeutic index. In continuation of our interest in the synthesis of biologically active azoles^13–17, we report here the synthesis of chiral sulphonamides bearing 1,3,4-oxadiazole derivatives and evaluation of their anti-HIV activity.

Experimental section

General

Melting points were measured on a Gallenkamp melting point apparatus (MP-D) and are uncorrected. The R_f values were determined using pre-coated silica gel aluminium packed plates, Kieselgel 60 HF₂₅₄ from Merck (Germany). Infrared (IR) spectra were recorded on a FTS 3000 MX, Bio-RAD Merlin spectrophotometer (Excalibur Model, USA). Nuclear magnetic resonance (NMR) spectra were recorded on a 300 (¹H) and 75 MHz (¹³C) NMR spectrometer (Bruker Avance, Switzerland) with tetramethylsilane as internal standard on a δ scale in ppm, multiplicities are abbreviated as s = singlet, d = doublet, t = triplet, q = quartet, ad = apparent doublet, aq = apparent quartet, qn = quintet and m = multiplet. Electron impact (EI) mass spectra were recorded on a Agilent technologies 6890N (GC) mass spectrometer and an inert selective detector 5973 (Agilent Technologies, USA). Elemental analyses were recorded on CHNS-932 Leco (Leco Corporation, USA).

General procedure for synthesis of the hydrazides (3a–e)

The hydrazides 3a–e were synthesized from the appropriate amino acids via three steps of sulfonylation furnishing 1a–e, followed by esterfication with acidic MeOH to give 2a–e and finally treatment with the hydrazine hydrate. The hydrazides were characterized by comparison of their physical data with the literature values^3,17.

General procedure for the synthesis of N-[1-(5-mercapto-1,3,4-oxadiazol-2-yl)alkyl]-4-chloro/methylbenzenesulphonamides (4a-e)

A mixture of 2-(4-chloro/methylphenylsulfonylamino)alkane hydrazide (5.40 mmol), CS₂ (10.80 mmol) and KOH (10.80 mmol) in MeOH (25 mL) was heated under reflux for 18–20 h. The solvent was evaporated to 5 mL, poured into ice-cooled water, and acidified with HOAc to pH 5. The resulting precipitate was collected, dried and recrystallized from aq. EtOH, except 4d, which was purified by column chromatography using n-hexane and ethyl acetate (8:2) as an eluent.

N-[1-(5-Mercapto-1,3,4-oxadiazol-2-yl)ethyl]-4-methylbenzenesulphonamide (4a)

Yield: 0.93 g (58%); m.p. 190–192°C; R_f: 0.39 (n-hexane: ethyl acetate 3:2); IR (υ_max, cm⁻¹): 3278, 2925, 2936, 1474, 1327, 1261, 1160; ¹H-NMR (300 MHz, acetone-d₆): δ 12.86 (1H, s, N-H), 7.73 (2H, d, J = 8.4 Hz, Ar-H), 7.37 (2H, d, J = 7.8 Hz, Ar-H), 7.31 (1H, d, J = 8.4 Hz, N-H), 4.65 (1H, q, J = 7.2 Hz, CH), 2.41 (3H, s, CH₃), 1.49 (3H, d, J = 7.2Hz, CH₃). ¹³C-NMR (75 MHz, acetone-d₆): δ 178.6, 162.8, 143.5, 137.8, 129.6, 126.8, 45.5, 20.6, 18.2. Anal. calcd. for C₁₁H₁₃N₃O₃S₂ (299.37): C, 44.13; H, 4.38; N, 14.04%. Found: C, 44.24; H, 4.33; N, 13.57%. EI-MS [m/z (%)]: 299 [M⁺].

4-Chloro-N-[1-(5-mercapto-1,3,4-oxadiazol-2-yl)ethyl]benzenesulphonamide (4b)

Yield: 0.94 g (52%); m.p. 191–193°C; R_f:0.39 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3297, 2939, 1496, 1333, 1261, 1168. ¹H-NMR (300 MHz, acetone-d₆): δ 9.30 (1H, s, N-H), 7.85 (2H, d, J = 8.7 Hz, Ar-H), 7.61 (2H, d, J = 8.7 Hz, Ar-H), 7.54 (1H, d, J = 8.1 Hz, N-H), 4.71 (1H, aq, J = 7.2 Hz, CH), 1.52 (3H, d, J = 6.9 Hz, CH₃). ¹³C-NMR (75 MHz, acetone-d₆): δ 178.6, 162.6, 139.7, 138.5, 129.3, 128.6, 45.5, 18.2. EI-MS [m/z (%)] 286 (55), 218 (100), 175 (75), 111 (70), 75 (20). Anal. calcd. for C₁₀H₁₀N₃O₄S₂Cl (335.79): C, 37.56; H, 3.15; N, 13.1%4. Found: C, 38.06; H, 3.37; N, 12.60%.

N-[1-(5-Mercapto-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]-4-methylbenzenesulphonamide (4c)

Yield: 1.24 g (64%); m.p. 144–146°C; R_f: 0.41 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3261, 2910, 1472, 1331, 1291, 1160, 1086. ¹H-NMR (300 MHz, acetone-d₆): δ 14.35 (1H, s, N-H), 8.65 (1H, d, J = 8.4 Hz, N-H), 7.60 (2H, d, J = 8.4 Hz, Ar-H), 7.33 (2H, d, J = 8.1 Hz, Ar-H), 4.50 (1H, aq, J = 7.8 Hz, CH), 2.50 (2H, m, -CH₂), 2.36 (3H, s, CH₃), 2.03–1.93 (2H, m, CH₂), 1.93 (3H, s, CH₃). ¹³C-NMR (75 MHz, acetone-d₆): δ 178.1, 170.5, 143.6, 137.8, 130.0, 126.9, 48.3, 31.6, 29.2, 21.5, 14.7. Anal. calcd. for C₁₃H₁₇N₃O₃S₃ (359.49): C, 45.52; H, 3.80; N, 8.33%. Found: C, 46.02; H, 3.87; N, 8.35%. EI-MS [m/z (%)]: 258 (52), 171 (5), 155 (32), 91 (100), 73 (86), 61 (83).

4-Chloro-N-[1-(5-mercapto-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]benzenesulphonamide (4d)

Yield: 1.37 g (67%); m.p. 148–150°C; R_f: 0.40 (n-hexane: ethyl acetate 3:2); IR (υ_max, cm⁻¹): 3256, 1467, 1336, 1278, 1161, 1090. ¹H-NMR (300 MHz, DMSO-d₆): δ 14.38 (1H, s, N-H) 8.67 (1H, d, J = 8.4 Hz, N-H), 7.72 (2H, d, J = 8.7 Hz, Ar-H), 7.61 (2H, d, J = 8.7 Hz, Ar-H), 4.55 (1H, q, J = 8.1 Hz, CH), 2.50–2.35 (2H, m, -CH₂), 2.01–1.91 (2H, m, CH₂), 1.95 (3H, s, CH₃). ¹³C-NMR (75 MHz, DMSO-d₆): δ 178.0, 161.9, 139.5, 138.2, 129.7, 128.7, 48.3, 31.5, 29.2, 14.8. EI-MS [m/z (%)]: 191 (33), 175 (30), 144 (8), 128 (28), 111 (100), 75 (82), 61 (5). Anal. calcd. for C₁₂H₁₄N₃O₃S₃Cl (379.91): C, 37.94; H, 3.71; N, 11.06%. Found: C, 37.55; H, 3.61; N, 11.03%.

N-[1-(5-Mercapto-1,3,4-oxadiazol-2-yl)-2-phenylethyl]-4-methylbenzenesulphonamide (4e)

Yield: 1.45 g (72%); m.p. 150–152°C; R_f: 0.42 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3279, 2950, 1462, 1334, 1270, 1156, 1085. ¹H-NMR (300 MHz, DMSO-d₆): δ 13.80 (1H, s, N-H), 8.67 (1H, d, J = 8.4 Hz, N-H), 7.72 (2H, d, J = 8.7 Hz, Ar-H), 7.61 (2H, d, J = 8.7 Hz, Ar-H), 7.21–7.11 (5H, m, Ar-H), 4.55 (1H, aq, J = 8.1 Hz, CH), 2.50–2.35 (2H, m, CH₂), 2.01–1.91 (2H, m, CH₂), 1.95 (3H, s, CH₃). ¹³C-NMR (75 MHz, DMSO-d₆): δ 178.0, 161.6, 143.4, 137.6, 136.0, 129.8, 129.6, 128.8, 128.4, 127.4, 126.6, 51.1, 38.2, 21.5. EI-MS [m/z (%)]: 274 (82), 155 (72), 91 (100), 77 (5), 65 (25). Anal. calcd. for C₁₇H₁₇N₃O₃S₂ (375.47): C, 54.38; H, 4.56; N, 11.19%. Found: C, 54.56; H, 4.61; N, 11.03%.

N-[1-(5-benzylthio/4-halobenzylthio)-1,3,4-oxadiazol-2-yl)alkyl]-4-methyl/4-halobenzenesulphonamides (5a-t)

A mixture of 4a–e (0.92 mmol), 4-halobenzyl halide (0.92 mmol) and K₂CO₃ (2.76 mmol) was stirred in acetone (30 mL) at room temperature for 3–4 h. The reaction mixture was filtered, the filtrate concentrated and poured into ice-cold water. The resulting solid was filtered and recrystallized from acetone - water or purified by column chromatography using n-hexane and ethyl acetate (4: 1) as eluent.

N-[1-(5-Benzylthio-1,3,4-oxadiazol-2-yl)ethyl]-4-methylbenzenesulphonamide (5a)

Yield: 0.308 g (86%); m.p. 98–100°C; R_f: 0.57 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3275, 1596, 1570, 1328, 1153, 1087. ¹H-NMR (300 MHz, CDCl₃): δ 7.70 (2H, d, J = 8.4 Hz, Ar-H), 7.41–7.31 (5H, m, Ar-H), 7.24 (2H, d, J = 7.8 Hz, Ar-H), 4.75 (1H, q, J = 7.2 Hz, CH), 4.36 (3H, s, NH, CH₂), 2.39 (3H, s, CH₃), 1.54 (3H, d, J = 7.2 Hz, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.8, 164.6, 143.9, 136.6, 135.6, 129.7, 129.1, 128.8, 128.2, 127.1, 45.5, 36.7, 21.6, 20.4. EI-MS [m/z (%)]: 389 [M⁺], 234 (2), 198 (10), 155 (18), 91 (100), 77 (4), 65 (20). Anal. calcd. for C₁₈H₁₉N₃O₃S₂ (389.49): C, 55.51; H, 4.92; N, 10.79%. Found: C, 55.70; H, 4.99; N, 10.52%.

N-[1-(5-(4-Bromobenzylthio)-1,3,4-oxadiazol-2-yl)ethyl]-4-methylbenzenesulphonamide (5b)

Yield: 0.335 g (80%); m.p. 135–137°C; R_f: 0.56 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3142, 1593, 1578, 1334, 1167, 1093, 1032. ¹H-NMR (300 MHz, CDCl₃): δ 7.70 (2H, d, J = 8.1 Hz, Ar-H), 7.46 (2H, d, J = 8.4 Hz, Ar-H), 7.24–7.30 (4H, m, Ar-H), 4.74 (1H, q, J = 6.9 Hz, CH), 4.50 (1H, s, NH), 4.31 (2H, s, CH₂), 2.39 (3H, s, CH₃), 1.53 (3H, d, J = 6.9 Hz, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 167.0, 164.3, 143.9, 136.6, 134.5, 131.9, 130.8, 129.7, 127.1, 122.2, 45.5, 35.9, 21.6, 20.3; EI-MS [m/z (%)]: 467 /469 [M⁺], 314/312 (3), 298 (1), 198 (41), 171 /169 (90), 155 (53), 91 (100), 65 (27). Anal. calcd. for C₁₈H₁₈BrN₃O₃S₂ (456.38): C, 46.16; H, 3.87; N, 8.97%. Found: C, 45.47; H, 3.96; N, 8.76%.

N-[1-(5-(4-Fluorobenzylthio)-1,3,4-oxadiazol-2-yl)ethyl]-4-methylbenzenesulphonamide (5c)

Yield: 0.36 g (96%); m.p. 106–108°C; R_f: 0.57 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3283, 1597, 1575, 1336, 1223, 1150, 1086. ¹H-NMR (300 MHz, CDCl₃): δ 7.71 (2H, d, J = 8.4 Hz, Ar-H), 7.36–7.40 (2H, m, Ar-H), 7.25 (2H, d, J = 8. Hz, Ar-H), 7.05 (2H, at, J = 8.4 Hz, Ar-H), 4.74 (1H, q, J = 6. Hz, CH), 4.41 (2H, s, CH₂), 4.35 (1H, s, NH), 2.39 (3H, s, CH₃), 1.54 (3H, d, J = 6.9 Hz, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 167.0, 164.5, 162.0 (J = 246.0 Hz), 144.0, 136.6, 131.2 (J = 3.7 Hz), 130.9 (J = 8.2 Hz), 129.0, 127.0, 115.7 (²J = 21.7 Hz), 45.5, 35.8, 21.6, 20.4. EI-MS [m/z (%)]: 407 (1), 392 (1), 252 (2), 198 (20), 155 (25), 109 (100), 91 (32), 65 (15). Anal. calcd. for C₁₈H₁₉FN₃O₃S₂ (408.49): C, 53.06; H, 4.45; N, 10.31%. Found: C, 52.48; H, 4.53; N, 10.09%.

N-[1-(5-(4-Chlorobenzylthio)-1,3,4-oxadiazol-2-yl)ethyl]-4-methylbenzenesulphonamide (5d)

Yield: 0.319 g (82%); m.p. 103–105°C; R_f: 0.57 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3134, 1597, 1578, 1334, 1167, 1129, 1092, 1032. ¹H-NMR (300 MHz, CDCl₃): δ 7.71 (2H, d, J = 8.4 Hz, Ar-H), 7.35 (2H, d, J = 8.7 Hz Ar-H), 7.30 (2H, d, J = 8.7 Hz, Ar-H), 7.25 (2H, d, J = 8.1 Hz, Ar-H), 4.75 (1H, q, J = 6.9 Hz, CH), 4.61 (1H, s, NH), 4.33 (2H, s, CH₂), 2.39 (3H, s, CH₃), 1.53 (3H, d, J = 7.2 Hz, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.9, 164.4, 143.9, 136.6, 134.1, 134.0, 130.5, 129.7, 128.9, 127.1, 45.5, 35.8, 21.6, 20.3. EI-MS (m/z %) 423/425 [M⁺], 268 (1), 198 (19), 155 (32), 125/127 (100), 113/111 (2), 91 (60), 65 (17). Anal. calcd. for C₁₈H₁₈ClN₃O₃S₂ (423.94): C, 51.00; H, 4.28; N, 9.91%. Found: C, 51.00; H, 4.31; N, 9.83%.

N-[1-(5-Benzylthio-1,3,4-oxadiazol-2-yl)ethyl]-4-chlorobenzenesulphonamide (5e)

Yield: 0.233 g (62%); m.p. 98–100°C; R_f: 0.49 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3243, 1580, 1568, 1330, 1165, 1083. ¹H-NMR (300 MHz, CDCl₃): δ 7.75 (2H, d, J = 8.7 Hz, Ar-H), 7.44 (2H, d, J = 8.7 Hz, Ar-H), 7.31–7.40 (5H, m, Ar-H), 4.81 (1H, s, NH), 4.75 (1H, q, J = 7.2 Hz, CH), 4.39 (2H, s, CH₂), 1.58 (3H, d, J = 7.2 Hz, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.5, 164.9, 139.5, 138.2, 135.1, 129.4, 129.1, 128.8, 128.6, 128.2, 45.6, 36.7, 20.3. EI-MS [m/z (%)]: 409 [M⁺], 332 (1), 218 (10), 177/175 (16), 113/111 (25), 91 (100), 77 (6), 65 (16). Anal. calcd. for C₁₇H₁₆ClN₃O₃S₂ (409.91): C, 49.81; H, 3.93; N, 10.25%. Found: C, 49.67; H, 4.00; N, 10.00%.

N-[1-(5-(4-Bromobenzylthio)-1,3,4-oxadiazol-2-yl)ethyl]-4-chlorobenzenesulphonamide (5f)

Yield: 0.292 g (65%); m.p. 114–116°C; R_f: 0.50 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3225, 1585, 1510, 1342, 1171, 1083, 1032. ¹H-NMR (300 MHz, CDCl₃): δ 7.75 (2H, d, J = 8.4 Hz, Ar-H), 7.44 (4H, d, J = 9.0 Hz, Ar-H), 7.29 (2H, d, J = 8.1 Hz, Ar-H), 5.83 (1H, d, J = 8.7 Hz, NH), 4.78 (1H, aq, J = 6.9 Hz, CH), 4.33 (2H, s, CH₂), 1.57 (3H, d, J = 7.2 Hz, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.6, 164.6, 139.5, 138.1, 134.3, 131.9, 130.8, 129.4, 128.6, 122.3, 45.6, 35.9, 20.2. EI-MS [m/z (%)]: 489 /487 [M⁺], 288 /286 (2), 218 (13), 175 (22), 171 /169 (100), 111 (48), 75 (20), 28 (17). Anal. calcd. for C₁₇H₁₅BrClN₃O₃S₂ (488.81): C, 41.77; H, 3.09; N, 8.60%. Found: C, 42.01; H, 3.15; N, 8.80%.

N-[1-(5-(4-Fluorobenzylthio)-1,3,4-oxadiazol-2-yl)ethyl]-4-chlorobenzenesulphonamide (5g)

Yield: 0.232 g (59%); m.p. 92–94°C; R_f: 0.48 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3274, 1599, 1569, 1331, 1158, 1229, 1089. ¹H-NMR (300 MHz, CDCl₃): δ 7.75 (2H, d, J = 8. Hz, Ar-H), 7.43 (2H, d, J = 8.7 Hz, Ar-H), 7.36–7.39 (2H, m, Ar-H), 7.03 (2H, at, J = 8.4 Hz, Ar-H), 6.05 (1H, d, J = 8.1 Hz, NH), 4.79 (1H, at, J = 7.2 Hz, CH), 4.35 (2H, s, CH₂), 1.57 (3H, d, J = 6.9 Hz, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.6, 164.7, 162 (¹J = 246 Hz), 139.5, 138.2, 131.0 (overlapped), 130.9 (³J = 8.2 Hz), 129.4, 128.6, 115.8 (²J = 21.7 Hz), 45.5, 35.9, 20.1. EI-MS [m/z (%)]: 427 [M⁺], 332 (1), 252 (2), 218 (8), 175 (12), 109 (100); Anal. calcd. for C₁₇H₁₅ClFN₃O₃S₂ (427.9): C, 47.72; H, 3.53; N, 9.82%. Found: C, 48.08; H, 3.79; N, 9.65%.

N-[1-(5-(4-Chlorobenzylthio)-1,3,4-oxadiazol-2-yl)ethyl]-4-chlorobenzenesulphonamide (5h)

Yield: 0.236 g (63%); m.p. 87–89°C; R_f: 0.47 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): δ3129, 1577, 1332, 1170, 1083, 1032. ¹H-NMR (300 MHz, CDCl₃): δ 7.74 (2H, d, J = 8.7 Hz, Ar-H), 7.44 (2H, d J = 8.7 Hz Ar-H), 7.31 (2H, d, J = 8.7 Hz, Ar-H);7.36 (2H, d, J = 8.7 Hz, Ar-H), 5.58 (1H, s, NH), 4.75 (1H, q, J = 6.9 Hz, CH); 4.35 (2H, s, CH₂), 1.58 (3H, d, J = 7.2 Hz, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.5, 164.6, 139.6, 138.1, 134.2, 133.7, 130.6, 129.4, 129.0, 128.6, 45.5, 35.9, 20.3. EI-MS [m/z (%)]: 218 (12), 175 (24), 159/157 (4), 127/125 (100), 113/111 (39). Anal. calcd. for C₁₇H₁₅ClN₃O₃S₂ (408.9): C, 45.95; H, 3.40; N, 9.46%. Found: C, 46.29; H, 3.65; N, 8.94%.

N-[1-(5-Benzylthio-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]-4-methylbenzenesulphonamide (5i)

Yield: 0.256 g (62%); m.p. 120–122°C; R_f: 0.52 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3280, 1596, 1327, 1153, 1083. ¹H-NMR (300 MHz, CDCl₃): δ 7.68 (2H, d, J = 8.4 Hz, Ar-H), 7.31–7.41 (5H, m, Ar-H), 7.23 (2H, d, J = 8.1 Hz, Ar-H), 5.70 (1H, d, J = 9.3 Hz, NH), 4.83 (1H, m, CH), 4.36 (2H, s, CH₂), 2.55 (2H, m, CH₂), 2.38 (3H, s, CH₃), 2.16–2.08 (2H, m, CH₂), 2.05 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.0, 164.6, 143.9, 136.5, 135.0, 129.7, 129.1, 128.8, 128.2, 127.1, 48.6, 36.7, 33.2, 29.6, 21.6, 15.3. EI-MS [m/z (%)]: 358 (4), 326 (3), 312 (25), 171 (2), 155 (11), 109 (100), 91 (40), 75 (10), 61 (38). Anal. calcd. for C₂₀H₂₃N₃O₃S₃ (449.61): C, 53.43; H, 5.16; N, 9.35%. Found: C, 53.45; H, 5.15; N, 9.10%.

N-[1-(5-(4-Bromobenzylthio)-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]-4-methylbenzenesulphonamide (5j)

Yield: 0.33 g (68%); m.p. 119–121°C; R_f: 0.55 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3264, 1597, 1327, 1153, 1080, 1069. ¹H-NMR (300 MHz, CDCl₃): δ 7.70 (2H, d, J = 8.4 Hz, Ar-H), 7.47 (2H, d, J = 8.4 Hz, Ar-H), 7.22–7.29 (4H, m, Ar-H), 5.70 (1H, d, J = 9.3 Hz, NH), 4.83 (1H, m, CH), 4.31 (2H, s, CH₂), 2.53 (2H, t, J = 6.9 Hz, CH₂), 2.38 (3H, s, CH₃), 2.16–2.08 (2H, m, CH₂), 2.04 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.3, 164.3, 143.9, 136.5, 134.5, 131.9, 130.8, 129.7, 127.1, 122.2, 48.5, 35.9, 33.1, 29.6, 21.6, 15.3. EI-MS [m/z (%)]: 372 /370 (27), 300 /298 (36), 258 (5), 169 /171 (85), 91 (100), 75 (18), 65 (21), 61 (82), 28 (95). Anal. calcd. for C₂₀H₂₂BrN₃O₃S₃ (528.51): C, 45.45; H, 4.20; N, 7.95%. Found: C, 45.32; H, 4.24; N, 7.60%.

N-[1-(5-(4-Fluorobenzylthio)-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]-4-methylbenzenesulphonamide (5k)

Yield: 0.342 g (78%); m.p. 108–110°C; R_f: 0.45 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3262, 1597, 1569, 1326, 1154, 1142, 1089. ¹H-NMR (300 MHz, CDCl₃): δ 7.70 (2H, d, J = 8.4 Hz, Ar-H), 7.35–7.40 (2H, m, Ar-H), 7.24 (2H, d, J = 8.1 Hz, Ar-H), 7.03 (2H, at, J = 8.7 Hz, Ar-H), 5.42 (1H, s, NH), 4.83 (1H, at, J = 7.2 Hz, CH), 4.34 (2H, s, CH₂), 2.54 (2H, t, J = 6.7 Hz, CH₂), 2.39 (3H, s, CH₃), 2.16–2.06 (2H, m, CH₂), 2.04 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.2, 164.5, 162.0 (J = 246 Hz), 149.3, 136.5, 131.1 (J = 3.0 Hz), 130.9 (J = 8.2 Hz), 129.7, 127.1, 115.7 (J = 21.7 Hz), 48.6, 35.9, 33.1, 29.6, 21.6, 15.3. EI-MS [m/z (%)]: 358 (4), 326 (3), 312 (25), 171 (2), 155 (11), 109 (100), 91 (40), 75 (10), 61 (38). Anal. calcd. for C₂₀H₂₂FN₃O₃S₃ (467.6): C, 51.37; H, 4.74; N, 8.99%. Found: C, 51.39; H, 4.91; N, 8.77%.

N-[1-(5-(4-Chlorobenzylthio)-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]-4-methylbenzenesulphonamide (5l)

Yield: 0.338 g (76%); m.p. 114–116°C; R_f: 0.45 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3261, 1596, 1567, 1325, 1153, 1089, 1039. ¹H-NMR (300 MHz, CDCl₃): δ 7.71 (2H, d, J = 8.4Hz, Ar-H), 7.35 (2H, d, J = 8.1 Hz, Ar-H), 7.31 (2H, d, J = 9.0 Hz, Ar-H), 7.24 (2H, d, J = 8.1 Hz, Ar-H), 4.83 (1H, at, J = 6.9 Hz, CH), 4.81 (1H, s, NH), 4.33 (2H, s, CH₂), 2.53 (2H, t, J = 6.9 Hz, CH₂), 2.39 (3H, s, CH₃), 2.16–2.06 (2H, m, CH₂), 2.04 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.2, 164.4, 143.9, 136.5, 134.1, 133.9, 130.5, 129.7, 129.1, 127.1, 48.6, 35.9, 33.1, 29.6, 21.6, 15.3; EI-MS [m/z (%)]: 358 (2), 328 (28), 313 (2), 155 (15), 125 (100), 91 (72), 65 (12), 61 (65). Anal. calcd. for C₂₀H₂₂ClN₃O₃S₃ (484.05): C, 49.63; H, 4.58; N, 8.68%. Found: C, 50.00; H, 4.73; N, 8.73%.

N-[1-(5-Benzylthio)-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]-4-chlorobenzenesulphonamide (5m)

Yield: 0.25 g (58%); m.p. 102–104°C; R_f: 0.48 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3132, 1579, 1338, 1167, 1083. ¹H-NMR (300 MHz, CDCl₃): δ 7.74 (2H, d, J = 8.7 Hz, Ar-H), 7.44 (2H, d, J = 8.7Hz, Ar-H), 7.33–7.38 (5H, m, Ar-H), 5.71 (1H, d, J = 9.3 Hz, NH), 4.88 (1H, m, CH), 4.39 (2H, s, CH₂), 2.58 (2H, t, J = 7.2 Hz, CH₂), 2.10–2.18 (2H, m, CH₂), 2.08 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 165.5, 165.0, 139.6, 137.9, 134.9, 129.4, 129.1, 128.8, 128.6, 128.2, 48.6, 36.8, 33.0, 29.6, 15.4. EI-MS [m/z (%)]: 294 (52), 111 (5), 91 (100), 65 (20), 28 (51). Anal. calcd. for C₁₉H₂₀ClN₃O₃S₃ (470.03): C, 48.55; H, 4.29; N, 8.94%. Found: C, 47.98; H, 4.38; N, 8.52%.

N-[1-(5-(4-Bromobenzylthio)-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]-4-chlorobenzenesulphonamide (5n)

Yield: 0.308 g (61%); m.p. 98–100°C; R_f: 0.48 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3150, 1575, 1330, 1163, 1084, 1070. ¹H-NMR (300 MHz, CDCl₃): δ 7.74 (2H, d, J = 8.7 Hz, Ar-H), 7.48 (2H, d, J = 8.4 Hz, Ar-H), 7.43 (2H, d, J = 8.4 Hz, Ar-H), 7.29 (2H, d, J = 8.4 Hz, Ar-H), 4.86 (1H, at, J = 6.9 Hz, CH), 4.45 (1H, s, NH), 4.33 (2H, s, CH₂), 2.54 (2H, t, J = 6.6 Hz, CH₂), 2.09–2.16 (2H, m, CH₂), 2.05 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.2, 164.6, 139.5, 138.2, 134.2, 132.0, 129.4, 128.9, 128.6, 122.3, 48.7, 36.0, 33.0, 29.6, 15.3; EI-MS [m/z (%)]: 346 (3), 171/169 (100), 111 (10), 75 (16), 28 (62). Anal. calcd. for C₁₉H₁₉BrClN₃O₃S₃ (548.92): C, 41.57; H, 3.49; N, 7.65%. Found: C, 41.60; H, 3.52; N, 7.55%.

N-[1-(5-(4-Fluorobenzylthio)-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]-4-chlorobenzenesulphonamide (5o)

Yield: 0.246 g (55%); m.p. 94–96°C; R_f: 0.48 (n-hexane: ethyl acetate 3: 2); IR (υ_max, cm⁻¹): 3226, 1573, 1326, 1227, 1165, 1084. ¹H-NMR (300 MHz, CDCl₃): δ 7.75 (2H, d, J = 8.7 Hz, Ar-H), 7.43 (2H, d, J = 8.7 Hz, Ar-H), 7.37–7.40 (2H, m, Ar-H), 7.04 (2H, at, J = 8.4 Hz, Ar-H), 4.88 (1H, at, J = 7.2 Hz, CH), 4.37 (3H, s, CH₂, NH), 2.57 (2H, t, J = 6.9 Hz, CH₂), 2.10–2.18 (2H, m, CH₂), 2.07 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 165.8, 164.8, 163.0 (J = 246 Hz), 139.6, 138.0, 130.9 (J = 8.4 Hz), 312 (21), 191 (3), 175 (10), 109 (100), 111 (20), 75 (10), 61 (35). 130.9, 129.4, 128.6, 115.8 (J = 21 Hz), 48.6, 35.9, 32.9, 29.6, 15.4. EI-MS [m/z (%)]: 378 (3), 346 (2). Anal. calcd. for C₁₉H₁₉ClFN₃O₃S₃ (488.02): C, 46.76; H, 3.92; N, 8.61%. Found: C, 46.96; H, 3.90; N, 8.49%.

N-[1-(5-(4-Chlorobenzylthio)-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]-4-chlorobenzenesulphonamide (5p)

Yield: 0.233 g (54%); m.p. 85–87°C; R_f: 0.48 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3241, 1574, 1326, 1190, 1165, 1093; ¹H-NMR (300 MHz, CDCl₃): δ 7.75 (2H, d, J = 8.7 Hz, Ar-H), 7.43 (2H, d, J = 8.7 Hz, Ar-H), 7.35 (2H, d, J = 8.7 Hz, Ar-H), 7.31 (2H, d, J = 8.7 Hz, Ar-H), 4.92 (1H, s, NH), 4.88 (1H, at, J = 7.5 Hz, CH), 4.35 (2H, s, CH₂), 2.65 (2H, t, J = 6.9 Hz, CH₂), 2.10–2.18 (2H, m, CH₂), 2.06 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 165.9, 164.7, 139.6, 137.9, 134.2, 133.7, 130.5, 129.4, 129.0, 128.6, 48.5, 35.9, 32.9, 29.6, 15.4. EI-MS [m/z (%)]: 278 (12), 175 (14), 127/125 (10), 113/111 (45), 73 (91), 61 (100), 28 (35). Anal. calcd. for C₁₉H₂₀ClN₃O₃S₃ (470.03): C, 45.52; H, 3.80; N, 8.33%. Found: C, 46.02; H, 3.87; N, 8.35%.

N-[1-(5-Benzylthio)-1,3,4-oxadiazol-2-yl)-2-phenylethyl]-4-methylbenzenesulphonamide (5q)

Yield: 0.325 g (76%); m.p. 155–157°C; R_f: 0.47 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3210, 1570, 1330, 1163, 1088. ¹H-NMR (300 MHz, CDCl₃): δ 7.56 (2H, d, J = 8.4 Hz, Ar-H), 7.34–7.38 (5H, m, Ar-H), 7.21–7.24 (3H, m, Ar-H), 7.17 (2H, d, J = 8.1 Hz, Ar-H), 6.98–7.01 (2H, m, Ar-H), 5.02 (1H, s, NH), 4.88 (1H, aq, J = 6.9 Hz, CH), 4.33 (2H, s, CH₂), 3.16 (2H, m, CH₂), 2.37 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 165.8, 164.5, 143.9, 136.1, 135.2, 134.1, 129.7, 129.3, 129.1, 128.9, 128.8, 128.3, 127.6, 127.1, 50.7, 40.4, 36.7, 21.6. EI-MS [m/z (%)]: 374 (20), 310 (13), 274 (3), 155 (24), 91 (100), 77 (3), 65 (14). Anal. calcd. for C₂₄H₂₃N₃O₃S₂ (465.59): C, 61.91; H, 4.98; N, 9.03%. Found: C, 62.46; H, 5.37; N, 9.02%.

N-[1-(5-(4-Bromobenzylthio)-1,3,4-oxadiazol-2-yl)-2-phenylethyl]-4-methylbenzenesulphonamide (5r)

Yield: 0.37 g (74%); m.p. 150–152°C; R_f: 0.47 (n-hexane: ethyl acetate; 3: 2); IR (υ_max, cm⁻¹): 3256, 1595, 1567, 1330, 1162, 1091, 1075. ¹H-NMR (300 MHz, CDCl₃): δ 7.56 (2H, d, J = 8.4 Hz, Ar-H), 7.48 (2H, d, J = 8.4 Hz, Ar-H), 7.22–7.25 (3H, m, Ar-H), 7.18 (2H, d, J = 8.1 Hz, Ar-H), 7.05 (2H, d, J = 8.7 Hz, Ar-H), 6.97–7.01 (2H, m, Ar-H), 5.18 (1H, d, J = 8.7 Hz, NH), 4.87 (1H, aq, J = 6.9 Hz, CH), 4.29 (2H, s, CH₂), 3.09–3.22 (2H, m, CH₂), 2.38 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.0, 164.2, 143.9, 136.1, 134.5, 134.1, 132.0, 130.8, 129.7, 129.3, 128.9, 127.6, 127.1, 122.3, 50.7, 40.3, 35.9, 21.6. EI-MS (m/z %) 274 (3), 171/169 (100), 155 (11), 91 (60), 65 (22). Anal. calcd. for C₂₄H₂₂BrN₃O₃S₂ (544.48): C, 52.94; H, 4.07; N, 7.72%. Found: C, 52.94; H, 4.30; N, 7.57%.

N-[1-(5-(4-Fluorobenzylthio)-1,3,4-oxadiazol-2-yl)-2-phenylethyl]-4-methylbenzenesulphonamide (5s)

Yield: 0.355 g (80%); m.p. 140–142°C; R_f: 0.47 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3129, 1599, 1540, 1331, 1226, 1157, 1089. ¹H-NMR (300 MHz, CDCl₃): δ 7.57 (2H, d, J = 8.4 Hz, Ar-H), 7.36 (2H, m, Ar-H), 7.22–7.24 (3H,m, Ar-H), 7.18 (2H, d, J = 8.1 Hz, Ar-H), 7.03 (2H, at, J = 8.7 Hz, Ar-H), 6.97–6.99 (2H, m, Ar-H), 5.18 (1H, d, J = 8.4 Hz, NH), 4.87 (1H, aq, J = 6.9 Hz, CH), 4.32 (2H, s, CH₂), 3.09–3.22 (2H, m, CH₂), 2.38 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 165.9, 164.3, 162.5 (J = 243 Hz), 143.9, 136.1, 134.1, 131.2 (J = 3.7 Hz), 130.9 (J = 7.5 Hz), 129.7, 129.3, 128.9, 127.6, 127.1, 50.7, 40.3, 35.9, 21.6. EI-MS [m/z (%)]: 483 [M⁺], 392 (22), 328 (18), 274 (5), 155 (51), 109 (100), 91 (95), 65 (15). Anal. calcd. for C₂₄H₂₂FN₃O₃S₂ (483.58): C, 59.61; H, 4.59; N, 8.69%. Found: C, 60.03; H, 4.74; N, 8.75%.

N-[1-(5-(4-Chlorobenzylthio)-1,3,4-oxadiazol-2-yl)-2-phenylethyl]-4-methylbenzenesulphonamide (5t)

Yield: 0.345 mg (75%); m.p: 146–148° C; R_f: 0.47 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 3139, 1598, 1568, 1331, 1163, 1090, 1030. ¹H-NMR (300 MHz, CDCl₃): δ 7.57 (2H, d, J = 8.1Hz, Ar-H), 7.30 (4H, m, Ar-H), 7.21–7.23 (3H, m, Ar-H), 7.18 (2H, d, J = 8.4 Hz, Ar-H), 6.97–6.99 (2H, m, Ar-H), 5.18 (1H, d, J = 8.4 Hz, NH), 4.87 (1H, at, J = 6.9 Hz, CH), 4.31 (2H, s, CH₂), 3.08–3.23 (2H, m, CH₂), 2.38 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 166.1, 164.2, 143.9, 136.2, 134.2, 134.1, 133.9, 130.5, 129.7, 129.3, 129.0, 128.9, 127.6, 127.1, 50.7, 40.3, 35.9, 21.6.; EI-MS [m/z (%)]: 499 [M⁺], 410/408 (23), 344 (15), 155 (48), 127/125 (80), 91 (100), 65 (14). Anal. calcd. for C₂₄H₂₂ClN₃O₃S₂ (500.03): C, 57.65; H, 4.43; N, 8.40%. Found: C, 57.03; H, 4.51; N, 8.26%.

Synthesis of 2-{N-[4-halobenzyl]-1-(4-chloro/methyl-phenylsulphonylamino)alkyl}-5-benzylthio-1,3,4-oxadiazoles (6a-d)

Compounds 6a–d were prepared by following the same procedure as for the preparation of 5a–d from treatment of 4a–e with 1.1 mol. eq. of 4-halobenzyl halides to give a mixture of mono- and disubstituted products. Compounds 5 and 6 were separated by SiO₂ column chromatography, using n-hexane and ethyl acetate (4:1) as an eluent.

N-(4-Bromobenzyl)-N-[1-(5-(4-bromobenzylthio)-1,3,4-oxadiazol-2-yl)ethyl]-4-methylbenzenesulphonamide (6a)

Yield: 0.135 g (23%); m.p. 156–158°C; R_f: 0.64 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 2982, 1593, 1565, 1486, 1469, 1327, 1155, 1070. ¹H-NMR (300 MHz, CDCl₃): δ 7.71 (2H, d, J = 8.1 Hz, Ar-H), 7.49 (2H, d, J = 8.4 Hz, Ar-H), 7.30–7.36 (6H, m, Ar-H), 7.10 (2H, d, J = 8.1 Hz, Ar-H), 5.36 (1H, q, J = 6.9 Hz, CH), 4.47 (1H, d, J = 15.9 Hz, CH), 4.30 (1H, d, J = 15.2 Hz, CH), 4.26 (2H, s, CH₂), 2.45 (3H, s, CH₃), 1.46 (3H, d, J = 6.9 Hz, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 165.8, 164.7, 144.1, 136.9, 135.3, 134.5, 131.9, 130.9, 129.9, 129.8, 127.2, 122.2, 121.7, 48.5, 47.3, 35.8, 21.6, 15.7. EI-MS [m/z (%)]: 281 (6), 212/210 (11), 198 (25), 171/169 (65), 155 (145), 133 (27), 91 (100), 73 (10), 65 (18), 28 (85). Anal. calcd. for C₂₅H₂₃Br₂N₃O₃S₂ (639.42): C, 47.11; H, 3.64; N, 6.59%. Found: C, 45.37; H, 3.45; N, 5.94%.

N-(4-Bromobenzyl)-N-[1-(5-(4-bromobenzylthio)-1,3,4-oxadiazol-2-yl)ethyl]-4-chlorobenzenesulphonamide (6b)

Yield: 0.125 g (19%); m.p. 144–146°C; R_f: 0.65 (n-hexane: ethyl acetate; 3:2); IR (υ_max, cm⁻¹): 2990, 1596, 1570, 1480, 1468, 1331, 1156, 1069. ¹H-NMR (300 MHz, CDCl₃): δ 7.75 (2H, d, J = 8.7 Hz, Ar-H), 7.48 (4H, d, J = 8.7 Hz, Ar-H), 7.37 (2H, d, J = 8.4 Hz, Ar-H), 7.31 (2H, d, J = 8.4 Hz, Ar-H), 7.11 (2H, d, J = 8.1 Hz, Ar-H), 5.35 (1H, q, J = 7.2 Hz, CH), 4.32 (1H, d, J = 15.7 Hz, CH), 4.31 (1H, d, J = 17.1 Hz, CH), 4.30 (2H, s, CH₂), 1.49 (3H, d, J = 7.2 Hz, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 165.5, 164.9, 139.7, 138.3, 134.9, 134.4, 131.9, 131.6, 130.9, 129.8, 129.6, 128.6, 122.2, 121.9, 48.8, 47.6, 35.8, 16.2; EI-MS [m/z (%)]: 300/298 (70), 212/210 (30), 183 (5), 171/169 (100), 143 (12), 89 (31), 75 (15), 63 (20). Anal. calcd. for C₂₄H₂₀Br₂ClN₃O₃S₂ (659.84): C, 43.82; H, 3.06; N, 6.39%. Found: C, 44.14; H, 3.47; N, 6.03%.

N-(4-Fluorobenzyl)-N-[1-(5-(4-fluorobenzylthio)-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl]-4-methylbenzenesulphonamide (6c)

Yield: 0.143 g (27%); brownish oil; R_f: 0.65 (n-hexane: ethyl acetate 3:2); IR (υ_max, cm⁻¹): 2950, 1597, 1560, 1486, 1472, 1340, 1158, 1069. ¹H-NMR (300 MHz, CDCl₃): δ 7.72 (2H, d, J = 8.4 Hz, Ar-H), 7.48 (2H, d, J = 8.7 Hz, Ar-H), 7.37–7.42 (2H, m, Ar-H), 7.30 (2H, d, J = 8.1 Hz, Ar-H), 7.05 (2H, at, J = 8.4 Hz, Ar-H), 6.9 (2H, at, J = 8.7 Hz, Ar-H), 5.39 (1H, t, J = 7.5 Hz, CH), 4.38 (1H, d, J = 15.9 Hz, CH), 4.30 (1H, d, J = 15.2 Hz, CH), 4.30 (2H, s, CH₂), 2.30–2.55 (3H, m, CH₂, CH), 2.43 (3H, s, CH₃), 1.90–1.96 (1H, m, CH), 1.96 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 164.4, 164.0, 162.5 (J = 246 Hz), 162.3 (J = 245 Hz), 144.1, 136.8, 131.8 (J = 3.7 Hz), 131.1 (J = 3.7 Hz), 130.5 (J = 8.2 Hz), 130.4 (J = 8.2 Hz), 129.8, 127.3, 115.8 (J = 21.7 Hz), 115.3 (J = 21.7 Hz), 51.7, 48.4, 35.7, 30.2, 29.7, 21.6, 15.2. EI-MS [m/z (%)]: 500 (3), 420 (11), 297 (2), 155 (3), 109 (100), 91 (8), 65 (5), 61 (10).

N-(4-bromobenzyl)-N-[1-(5-(4-bromobenzylthio)-1,3,4-oxadiazol-2-yl)-3-(methylthio)propyl-4-methylbenzenesulphonamide] (6d)

Yield: 0.109 g (17%); brownish oil; R_f: 0.63 (n-hexane: ethyl acetate 3:2); IR (υ_max, cm⁻¹): 2917, 1601, 1562, 1508, 1472, 1340, 1155, 1220. ¹H-NMR (300 MHz, CDCl₃): δ 7.71 (2H, d, J = 8.4 Hz, Ar-H), 7.48 (2H, d, J = 8.4 Hz, Ar-H), 7.37 (2H, d, J = 8.4 Hz, Ar-H), 7.28–7.32 (4H, m, Ar-H), 7.15 (2H, d, J = 8.4 Hz, Ar-H), 5.39 (1H, at, J = 7.5 Hz, CH), 4.30 (1H, d, J = 13.5 Hz, CH), 4.29 (1H, d, J = 13.5 Hz, CH), 4.27 (2H, s, CH₂), 2.52–2.23 (3H, m, CH₂, CH), 2.43 (3H, s, CH₃), 1.89–1.96 (1H, m, CH), 1.95 (3H, s, CH₃). ¹³C-NMR (75 MHz, CDCl₃): δ 164.7, 144.1, 136.7, 135.5, 134.4, 131.9, 131.6, 130.9, 130.1, 129.9, 127.3, 122.3, 121.9, 51.8, 48.4, 35.8, 29.7, 21.6, 15.2. EI-MS [m/z (%)]: 697/695 (2), 276/274 (2), 186/184 (95),157/155 (20), 75 (31), 65 (45), 28 (15).

X-ray structure determinations

Crystal data and refinement details are presented in Table 1. Data collection and reduction: Crystals were mounted in inert oil on glass fibres and transferred to the cold gas stream of an Oxford Diffraction diffractometer (5b: Xcalibur S with monochromated Mo-Kα radiation, λ = 0.71073 Å; 5l: Xcalibur Nova E with mirror-focussed Cu-Kα radiation, λ = 1.54184 Å). Absorption corrections were performed on the basis of multi-scans. Structure refinement: The structures were refined anisotropically against F² (program SHELXL-97¹⁹). Hydrogens of NH groups were refined freely; methyl groups were refined as idealized rigid groups allowed to rotate but not tip; other hydrogen atoms were included with a riding model. For 5b, restraints to displacement parameters were employed to improve stability of refinement. For both structures, the absolute configuration was confirmed by the Flack parameter.

Table 1.  Crystallographic data for compounds 5b and 5l.

Data	5b	5l
Formula	C18H18BrN3O3S2	C20H22ClN3O3S3
Mr	468.38	484.04
Habit	Colourless tablet	Colourless tablet
Crystal size (mm)	0.2 × 0.2 × 0.1	0.2 × 0.2 × 0.1
Crystal system	Orthorhombic	Monoclinic
Space group	P212121	P21
Cell constants
a (Å)	5.5822 (1)	14.8104 (5)
b (Å)	17.8004 (3)	5.1998 (2)
c (Å )	20.1547 (4)	15.9657 (6)
α (°)	90	90
β (°)	90	111.615 (4)
γ (°)	90	90
V (Å^3)	2002.68	1143.08
Z	4	2
Dx (Mg m^−3)	1.553	1.406
μ (mm^−1)	2.29	4.27
Radiation	Mo-Kα	Cu-Kα
Wavelength (Å)	0.71073	1.54184
F (000)	952	504
T (°C)	−173	−173
2θmax	60	152
Completeness (%)	99.7	99.9 (to 2θ 145°)
Reflux measured	102274	24447
Reflux independant	5848	4320
Rint	0.039	0.037
Parameters	250	277901
Restraints	162	1
wR (F^2, all refluxes)	0.040	0.064
R (F, >4σ (F))	0.020	0.024
Flack parameter	−0.006 (3)	0.007 (10)
S	0.97	1.04
maximum Δρ (e Å^−3)	0.50	0.22

Complete crystallographic data (excluding structure factors) have been deposited at the Cambridge Crystallographic Data Centre under the numbers CCDC-762468 (5b) and 762469 (5l). Copies may be requested free of charge from http://www.ccdc.cam.ac.uk/products/csd/request/.

Results and discussion

Three different amino acids: l-alanine, l-methionine and l-phenylalanine (a–c) were selected in our present work to synthesize the desired chiral compounds. The l-amino acids were converted into the corresponding sulphonamides 1a–e by reaction with 4-chlorobenzenesulfonyl chloride and 4-methylbenzenesulfonyl chloride (Scheme 1). Compounds 1a–e were converted into their respective methyl esters 2a–e²⁰, followed by treatment with the hydrazine hydrate to yield the corresponding acid hydrazides 3a–e²¹. The hydrazides 3a–e were cyclized to 1,3,4-oxadiazoles 4a–e²², using CS₂ in the presence of KOH. The 1,3,4-oxadiazoles 4a–e were further derivatized with 4-substituted benzylhalides¹³. Thus, treatment of 4a–e with a slight excess (1.1 equiv.) of 4-substituted benzyl halides resulted in the substitution at S- as well as N-(sulphonamide), giving a mixture of two products: S-substituted and S,N-disubstituted products. However, repetition of the experiment using equimolar ratios of 4-substituted benzylhalide and 1,3,4-oxadiazoles led to the S-substitution only and furnished 5a–t.

The structures of 4a–e were confirmed from the NMR, IR and mass spectra. In the IR spectra, the C=N absorption appeared in the region υ_max 1496–1462 cm⁻¹ at the expense of strong carbonyl absorption of the hydrazides 3a–e (υ_max 1686–1664 cm⁻¹). The weak absorption for C-S in the range of υ_max 1291–1261 cm⁻¹ was a further support for formation of the desired molecules. In the ¹H-NMR spectra, the signals at δ 14.38–9.30 ppm were assigned to the N-H proton. The two signals in the ¹³C-NMR spectra at δ 178.6–178.0 ppm and δ 170.5–161.6 ppm were assigned to the C-2 and C-5 of the oxadiazole ring respectively. The mass spectra demonstrated a common fragment for 4a, 4c and 4e at m/z 155 and for 4b and 4d at m/z 175, resulting by cleavage of the sulphonamide linkage. The base peak observed for compounds 4a–e was attributed to the tropyllium cation at m/z 91 or the chlorotropyllium cation at m/z 127/125. Analogously, the structures of 5a–t were confirmed by the ¹H-, ¹³C-NMR and mass spectra. In the ¹H-NMR spectra of 5a–t, two signals for four aromatic protons in the range δ 7.75–7.03 ppm together with two protons singlet (δ 4.88–4.74 ppm) assigned to the benzylic protons were observed. The ¹³C-NMR spectra showed new signals corresponding to the methylene carbons of the benzyl group resonating in the range δ 48.6–45.5 ppm. In the mass spectra, the most abundant fragments were observed at m/z 91 or 90 + X (X = Cl). The fragments at m/z 155 (R′ = CH₃) and m/z 175 (R′ = Cl) were generated due to the cleavage of the sulphonamide moiety.

The synthesis of compounds 5a–t was further confirmed by the single crystal X-ray structure analysis of compounds 5b and 5l. Compound 5b (Figure 1) is a disc-shaped molecule in which all three rings lie at the periphery of the disc and are approximately perpendicular to the mean molecular plane (interplanar angles 86° to the five-membered ring, 81° to the ring C8–13, 86° to the ring C16–21). Compound 5l is also disc-shaped, the height of the disc being approximately the breadth of a phenyl ring (Figure 2); the rings C10–15 and C18–23 subtend angles of 86° and 84°, respectively, to the mean molecular plane, but the angle from the five-membered ring is 27°. A least-squares fit of both molecules in the region C-5,6,7 and N-tosyl gives a root mean squared (RMS) deviation of 0.13 Å. Figure 3 shows clearly that the molecules differ significantly in the torsion angles involving the rotation of the five-membered ring (N5-C6-C5-O1 = -47.5° for 5b and 65.9° for 5l) and about the short C-S chain (C2-S1-C15-C16 -84.7° for 5b, C2-S3-C17-C18 169.8° for 5l). The crystallographic data for 5b and 5l are listed in Table 1.

Figure 1.  The molecule of compound 5b in the crystal. Ellipsoids represent 50% probability levels.

Figure 2.  The molecule of compound 5l in the crystal. Ellipsoids represent 50% probability levels.

Figure 3.  Least-squares fit of the N-tosyl regions of 5b (numbered) and 5l (dashed bonds).

The structures of the disubstituted 1,3,4-oxadiazole derivatives 6a–d were confirmed by the NMR, IR and mass spectra. The IR spectra demonstrated the disappearance of NH stretchings in the range of υ_max 3256–3297 cm⁻¹ with the appearance of the strong C–X (X = Cl, Br, F) absorptions in the range υ_max 1220–1069 cm⁻¹. The ¹H-NMR spectra of 6a–d demonstrated eight additional aromatic protons in the range of δ 7.75–6.90 ppm, the singlets’ oriented in the region δ 4.51–4.19 ppm corresponding to CH₂ protons of the benzylthio group, and the two doublets (²J couplings) in the region δ 4.47–4.30 ppm attributed to the N-benzyl group. In the ¹³C-NMR spectra, eight new signals corresponding to aromatic portion of halobenzyl groups were observed. Further, two methylene carbons appeared in the range of δ 51.7–47.3 ppm. In the mass spectra, the most abundant fragments were observed at m/z 91 or 90 + X.

In vitro anti-HIV assay

Compounds 5a–t and 6a–d were tested for their anti-HIV-1 and HIV-2 activity, in vitro, using III_B and ROD strain in human T-lymphocyte (MT-4) cells, and the results are summarized in Table 2, in which the data for Nevirapine (BOE/BIRG587²³) and azidothymidine (DDN/AZT²⁴) have been included for comparison purposes. Compound-induced cytotoxicity was also measured in MT-4 cells parallel with the antiviral activity. None of the new 1,3,4-oxadiazole derivatives were found to inhibit HIV-1 or HIV-2 replication, in vitro, at EC₅₀ lower than the CC₅₀ in comparison to the Nevirapine and AZT.

Table 2.  In vitro anti-HIV-1^a and HIV-2^b of some new sulphonamide derivatives.

Compound	Virus strain	EC50 (µg/mL)^c	CC50 (µg/mL)^d	SI^e
5a	IIIB	>59.58	59.58	<1
	ROD	>59.58	59.58	<1
5b	IIIB	>75.33	75.33	<1
	ROD	>75.33	75.33	<1
5c	IIIB	>70.80	70.80	<1
	ROD	>70.80	70.80	<1
5d	IIIB	>27.93	27.93	<1
	ROD	>27.93	27.93	<1
5e	IIIB	>65.63	>65.63	<1
	ROD	>65.63	>65.63	<1
5f	IIIB	>12.33	>12.33	<1
	ROD	>12.33	>12.33	<1
5g	IIIB	>58.75	58.75	<1
	ROD	>58.75	>58.75	<1
5h	IIIB	>14.08	14.08	<1
	ROD	>14.08	14.08	<1
5i	IIIB	>30.48	30.48	<1
	ROD	>30.48	30.48	<1
5j	IIIB	>11.75	11.75	<1
	ROD	>11.75	11.75	<1
5k	IIIB	>11.50	≥11.50	<orX1
	ROD	>11.50	≥11.50	<orX1
5l	IIIB	>13.00	13.00	<1
	ROD	>13.00	13.00	<1
5m	IIIB	>12.67	12.67	<1
	ROD	>12.67	12.67	<1
5n	IIIB	>12.30	12.30	<1
5o	ROD	>12.30	>12.30	<1
	IIIB	>13.65	13.65	<1
	ROD	>13.65	13.65	<1
5p	IIIB	>11.88	11.88	<1
	ROD	>11.88	11.88	<1
5q	IIIB	>11.67	11.67	<1
	ROD	>11.67	11.67	<1
5r	IIIB	>82.10	82.10	<1
	ROD	>82.10	82.10	<1
5s	IIIB	>90.83	90.83	<1
	ROD	>90.83	90.83	<1
5t	IIIB	>99.40	99.40	<1
	ROD	>99.40	99.40	<1
6a	IIIB	>125.00	>125.00	X1
	ROD	>125.00	>125.00	X1
6b	IIIB	>125.00	>125.00	X1
	ROD	>125.00	>125.00	X1
6c	IIIB	>125.00	>125.00	X1
	ROD	>125.00	>125.00	X1
6d	IIIB	>125.00	>125.00	X1
	ROD	>125.00	>125.00	X1
Nevirapine	IIIB	0.050	>4.00	>80
	ROD	>4.00	>4.00	<1
DDN/AZT	IIIB	0.0022	>25.00	>11587
	ROD	0.00094	>25.00	>26731

^aAnti-HIV-1 activity measured with strain III_B.

^bAnti-HIV-2 activity measured with strain ROD.

^cCompound concentration required to achieve 50% protection of MT-4 cells from the HIV-1- and 2-induced cytopathogenic effect.

^dCompound concentration that reduces the viability of mock-infected MT-4 cells by 50%.

^eSI, selectivity index (CC₅₀/EC₅₀).

Theoretical calculations and quantum structure-activity relationship

Semi-empirical self-consistent-field molecular orbital (SCF-MO) method at PM3¹⁸ level within restricted Hartree–Fock²⁵. Formalism has been considered to optimize fully the geometry of the 5-benzylthio-1,3,4-oxadiazole molecule in its ground state. Geometry optimization was carried out by using a conjugate gradient method (Polak-Ribiere algorithm²⁶). The SCF convergence was set at 0.001 kcal/mol and the RMS gradient was set to 0.001 kcal/(mol) in the calculations.

We performed all the calculations using the HyperChem-7.52 program (Hypercube Inc., USA). In addition, the correlation analysis and the regression analysis for quantum parameters were performed by using Minitab program release 11.11 (Minitab Inc., USA). all calculations were performed on a windows XP workstation in Pentium IV PC.

Acceptability of the regression model was judged by examining the correlation coefficient (r), squared correlation coefficient (R²), Fisher’s value (F) and standard deviation (s). The selected descriptors have obtained and listed in Tables 3 and 4.

Table 3.  Calculated value of descriptors.

Compound	LogP	P	V	S	EHOMO	ELUMO	ΔE	Etotal	μ	Binding energy	ΔΗ
75a	5.22	38.32	1095.9	611.90	−9.212	−0.995	8.217	−96002.3	4.015	−4719.94	−3.506
5b	6.01	40.95	1153	655.55	−9.32	−1.148	8.172	−103797.2	3.618	−4686.4	4.667
5c	5.36	38.23	1100.28	622.88	−9.366	−1.041	8.325	−105798.6	3.618	−4728.1	−44.92
5d	5.73	40.25	1130.56	645.94	−9.307	−1.013	8.294	−102950.7	3.508	−4701.0	−7.722
5e	5.27	38.42	1080.49	604.01	−9.321	−1.053	8.268	−99197.7	2.869	−4416.13	2.092
5f	6.06	41.04	1140.28	646.91	−9.418	−1.103	8.315	−107293.0	2.378	−4382.95	9.907
5g	5.41	38.33	1194.81	612.75	−9.423	−1.187	8.236	−109297	3.048	−4427.84	−42.831
5h	5.78	40.35	1129.09	637.29	−9.351	−1.174	8.177	−106451	3.189	−4402.25	−7.135
5i	5.20	44.99	1253.95	704.06	−8.956	−1.018	7.938	−107184.3	5.653	−5335.2	−2.178
5j	6.00	47.62	1310.64	746.42	−9.006	−1.046	7.96	−114977.57	5.4	−5300.0	7.649
5k	5.34	44.90	1258.38	714.86	−9.016	−1.053	7.963	−116980.66	5.516	−5343.4	−43.638
5l	5.72	46.92	1292.59	738.48	−9.008	−1.022	7.986	−114133.02	5.37	−5316.6	−6.766
5m	5.25	45.09	1243.09	698.25	−8.976	−1.099	7.877	−110681.36	4.649	−5033.0	1.768
5n	6.05	47.71	1299.70	739.96	−9.022	−1.053	7.969	−118474.66	4.176	−4997.9	11.562
5o	5.39	45.00	1249.18	708.36	−9.028	−1.147	7.881	−120477.72	4.197	−5041.3	−39.694
5p	5.77	47.02	1281.97	731.12	−9.019	−1.123	7.896	−117630.32	4.23	−5014.7	−3.060
5q	6.90	47.98	1304.85	679.53	−9.169	−0.964	8.205	−113803.33	4.063	−5924.5	25.629
5r	7.69	50.61	1360.85	725.56	−9.312	−0.994	8.318	−121597.32	3.473	−5890.1	34.726
5s	7.04	47.89	1309.33	692.79	−9.34	−0.979	8.361	−123599.93	3.657	−5933.0	−16.071
5t	7.42	49.91	1342.96	716.71	−9.292	−0.945	8.347	−120752.32	3.463	−5906.3	20.758

Binding energy in kcal/mol and heat of formation ΔH in kcal/mol of given series of compounds.

Energy difference (ΔE) in (eV); dipole moments (Δ) in Debye; frontier molecular orbitals energies (E_HOMO and E_LUMO); molecular surface (S); molecular volume (V); partition coefficient (LogP); polarizability (P); total energy E_total in kcal/mol.

Table 4.  Mulliken charges of the selected atoms.

Compound	Mulliken charges
	S1	O2	O3	N4	C5	C6	O7	C8	N9	N10	S11	C12
5a	2.252	−0.821	−0.845	−0.498	0.094	−0.032	−0.072	−0.133	−0.119	−0.072	0.169	−0.094
5b	2.245	−0.823	−0.845	−0.487	0.089	−0.027	−0.072	−0.134	−0.116	−0.073	0.172	0.099
5c	2.245	−0.823	−0.846	−0.486	0.089	−0.026	−0.072	−0.134	−0.113	−0.074	0.178	−0.105
5d	2.245	−0.823	−0.846	−0.486	0.089	−0.026	−0.072	−0.134	−0.113	−0.074	0.178	−0.105
5e	2.246	−0.823	−0.842	−0.489	0.089	−0.029	−0.071	−0.136	−0.110	−0.074	0.178	−0.103
5f	2.246	−0.824	−0.841	−0.491	0.088	−0.027	−0.070	−0.137	−0.109	−0.073	0.180	−0.108
5g	2.250	−0.828	−0.836	−0.498	0.091	−0.030	−0.075	−0.141	−0.100	−0.073	0.166	−0.098
5h	2.247	−0.829	−0.834	−0.501	0.091	−0.033	−0.072	−0.135	−0.113	−0.069	0.169	−0.097
5i	2.262	−0.818	−0.841	−0.513	0.099	−0.034	−0.069	−0.129	−0.124	−0.075	0.173	−0.096
5j	2.262	−0.819	−0.840	−0.512	0.096	−0.029	−0.071	−0.132	−0.119	−0.074	0.183	−0.109
5k	2.260	−0.819	−0.840	−0.509	0.095	−0.029	−0.071	−0.132	−0.118	−0.073	0.181	−0.104
5l	2.260	−0.820	−0.841	−0.508	0.094	−0.029	−0.073	−0.131	−0.118	−0.072	0.180	−0.104
5m	2.249	−0.819	−0.838	−0.493	0.087	−0.031	−0.072	−0.128	−0.121	−0.074	0.171	−0.093
5n	2.251	−0.820	−0.838	−0.495	0.086	−0.027	−0.073	−0.131	−0.116	−0.073	0.182	−0.108
5o	2.253	−0.820	−0.837	−0.497	0.087	−0.027	−0.074	−0.131	−0.115	−0.073	0.180	−0.102
5p	2.253	−0.820	−0.838	−0.497	0.087	−0.029	−0.073	−0.131	−0.116	−0.072	0.180	−0.103
5q	2.251	−0.821	−0.844	−0.499	0.082	−0.025	−0.070	−0.132	−0.119	−0.073	0.167	−0.093
5r	2.252	−0.822	−0.842	−0.502	0.080	−0.019	−0.064	−0.141	−0.106	−0.077	0.176	−0.108
5s	2.251	−0.822	−0.842	−0.500	0.077	−0.018	−0.066	−0.141	−0.104	−0.077	0.175	−0.105
5t	−2.249	−0.822	−0.842	−0.499	0.077	−0.017	−0.065	−0.143	−0.101	−0.078	0.174	−0.106

A data set of twenty compounds (5a–5t) concerning their anti-HIV activity was used for the present quantum structure-activity relationship (QSAR) study. QSAR studies of the 5-benzylthio-1,3,4-oxadiazoles series resulted in several QSAR equations. The four best equations are:

1 2 3 4

In the above equations, n is the number of compounds used to derive the model and q² is the predictive capability.

All the four models have one outlier’s compounds 6, because their residual values exceeded twice the standard error of estimate. When this outlier has been removed from the data set, four highly significant equations (5, 6, 7 and 8 respectively) have been obtained.

5 6 7 8

Model–5 shows a good correlation coefficient (r) of 0.913 between descriptors (LogP, E_HOMO, μ, and N₁₀) and the anti-HIV activity. Squared correlation coefficient (r²) of 0.834 explains 83.7% variance in biological activity. This model also indicates statistical significance > 99.9% with values F = 17.64. Cross-validated squared correlation coefficient (q²) of this model was 0.787, which shows remarkable internal predication power of this model.

Similarly, model–6 shows a remarkable correlation coefficient (r) of 0.909 between descriptors (ΔE, P, S, and N₁₀) and the anti-HIV activity. Squared correlation coefficient (r²) of 0.826 explains 82.6% variance in biological activity. This model also indicates statistical significance > 99.9% with values F = 16.56. Cross-validated squared correlation coefficient (q²) of this model was 0.776, which shows the good internal predication power of this model.

Further, model–7 demonstrates an interesting correlation coefficient (r) of 0.919 between descriptors (E_HOMO, P, S, and N₁₀) and anti-HIV activity. Squared correlation coefficient (r²) of 0.845 explains 84.5% variance in biological activity. This model also indicates statistical significance > 99.9% with values F = 19.09. Cross-validated squared correlation coefficient (q²) of this model was 0.801, which shows the good internal predication power of this model.

Finally, model–8 shows a desirable correlation coefficient (r) of 0.913 between descriptors (E_HOMO, μ, S and N₁₀) and the anti-HIV activity, where squared correlation coefficient (r²) of 0.834 explains 83.4% variance in biological activity. This model also indicates statistical significance > 99.9% with values F = 17.64. Cross-validated squared correlation coefficient (q²) of this model was 0.787, which shows reasonable internal predication power of this model.

According to 5, 6, 7, and 8 models, the calculated and experimental activities (EC₅₀) of the title compounds were obtained and listed in Table 5. These models showed good correlation between the experimental and calculated EC₅₀ (r = 0.893, 0.868, 0.903, and 0.912 for 5, 6, 7 and 8 models, respectively). Models 7 and 8 can be considered as most suitable models for predicting the anti-HIV activity with both statistical significant and excellent predictive ability (Figure 4).

Table 5.  Observed and calculated anti-HIV activity (EC₅₀) of given series of compounds.

Compound	Observed EC50	Calculated EC50
		Model-5	Model-6	Model-7	Model-8
5a	59.58	29.15748	40.01327	35.615	39.79637
5b	75.33	45.87267	37.56644	54.21975	50.27844
5c	70.80	88.92503	88.07061	96.79234	90.84148
5d	27.93	60.99637	68.70131	72.74313	65.39883
5e	65.63	70.53132	73.86845	82.64822	80.77886
5g	58.75	81.71542	54.0463	82.87232	81.30566
5h	14.08	18.78503	14.21674	19.24086	20.83762
5i	30.48	24.88479	25.41575	28.34484	29.27171
5j	11.75	18.13093	16.7519	20.8732	19.34272
5k	11.50	17.96007	16.52532	19.16386	19.09697
5l	13.00	11.702	11.35492	12.39915	12.21044
5m	12.67	18.77293	16.75089	22.12425	21.56269
5n	12.30	13.18797	13.03788	16.12007	13.70624
5o	13.65	16.59495	13.36934	19.46695	17.04569
5p	11.88	10.93604	9.004799	12.54827	11.20977
5q	11.67	18.95501	20.71958	21.57613	29.96061
5r	82.10	75.44735	61.08112	85.12498	86.30384
5s	90.83	105.547	85.42559	108.8894	117.8449
5t	99.40	97.89804	89.67306	112.2172	111.0916

Figure 4.  A plot between observed activity and calculated activity for 5, 6, 7, and 8 models. (A) Model-5: r = 0.89286. (B) Model-6: r = 0.86842. (C) Model-7: r = 0.90299. (D) Model-8: r = 0.91162.

Conclusion

In conclusion, the above data showed no selective anti-HIV activity. However, compounds 5f, j–5q did show some inhibitory activity against both HIV-1 and HIV-2 with EC₅₀ value ranging from >11.50 to >14.08 µg/mL, but with Si <1.

Scheme 1.  Reagents and conditions. (i) 4-Chloromethyl/methylbenzenesulphonyl chlorides, K₂CO₃, CHCl₃; (ii) MeOH, H₂SO₄, reflux 4 h; (iii) N₂H₄.H₂O, MeOH, reflux 3–4 h; (iv) CS2, KOH, MeOH, reflux 18–20 h; (v) 1.0 eq. YCH₂C₆H₄X, acetone, K₂CO₃, r.t.; (vi) 2.0 eq. YCH₂C₆H₄X, acetone, K₂CO₃, r.t.

Acknowledgements

The authors thank Professor C. Pannecouque of Rega institute for medical research, Katholieke Universiteit Leuven, Belgium for the anti-HIV screening.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.