General information

All chemicals and solvents were purchased from Sigma Aldrich and Merck and were used without any further purification. Infrared spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer with a universal ATR sampling accessory. NMR analysis was recorded on a Bruker AVANCE III 400 MHz spectrometer (400 MHz for 1H, 100 MHz for 13 C, and 376.498 MHz for 19 F). Chemical shifts (δ) were reported in parts per million (ppm). The chemical shifts for 1H and 13 C are referenced to DMSO‑d6 at 2.50 ppm and 39.51 ppm, and CDCl3 at 7.2 ppm and 77.3 ppm, respectively. Spin multiplicities are abbreviated as follows: singlet (s), doublet (d), doublet of doublet of doublets (ddd), doublet of doublets (dd), and triplet (t). Melting points of compounds were determined in an electrothermal melting point apparatus (Electrothermal IA9100) using a sealed capillary tube and are uncorrected. High-resolution mass data were obtained using a Bruker microTQF-Q II ESI instrument operated at ambient temperatures.

Synthesis of dibenzylidenehydrazine derivatives

To a solution of ethanol (30 mL) containing corresponding benzaldehydes 10 mmol, hydrazine monohydrate 20 mmol was added, and the reaction mixture was stirred for 3–4 hours until the consumption of benzaldehydes as indicated by thin layer chromatography (TLC). The formed precipitates were filtered and recrystallized from ethanol to afford dibenzylidenehydrazine derivatives.

Synthesis of thiazolidinone derivatives

Excess thioglycolic acid 1 ml was added to the dibenzylidenehydrazine derivatives (1a-t) 1 mmol in a test tube. The mixture was then subjected to ultrasound irradiation using scientecultrasonic cleaner at 70 °C for 1–1.5 hours until dibenzylidenehydrazine derivatives have been consumed as indicated by TLC. Then, 10 ml of ethyl acetate was added and the solids crushed out were filtered in vacuo and washed with 10% washed NaHCO3 and water. The solids products were then washed with ice-cold diethyl ether to furnish the target compounds.

(E)-3-(benzylideneamino)-2-phenylthiazolidin-4-one 2a

white solid; Chemical Formula; C16H14N2OS; Molecular Weight: 281,37; Yield: 89%

FTIR νmax (cm−1): 1693.25 (C = O), 1496.82 (C = N), 1047.23 (C–N).

1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H, N = CH), 7.63 (d, 2H, Ar-H) 7.46-7.36 (m, 8H, Ar-H), 6.56 (s, 1H, thiazolidine-4-one-CH), 4.07 (d, J = 16.08 Hz, 1H, thiazolidine-4-one-CH2), 4.03 (d, J = 16.06 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.08 (C = O), 151.11 (C = N), 140.07, 134.10, 131.18, 129.51, 129.33, 128.95, 127.77, 126,47 (Aromatic), 60.90 (thiazolidine-4-one-CH), 30.52 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H14N2OS (M + Na)+: 305.0725; found 305.0731.

(E)-3-((4-chlorobenzylidene)amino)-2-(4-chlorophenyl)thiazolidin-4-one 2b

White solid; Chemical Formula: C16H12C12N2OS: Molecular Weight: 351,25; Yield: 91%

FTIR νmax (cm−1): 1683.04 (C = O), 1593.59 (C = N), 1086.27 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.22 (s, 1H, N = CH), 7.62 (d, J = 8.10, 2H, Ar-H) 7.47-7.40 (m, 6H, Ar-H), 6.49 (s, 1H, thiazolidine-4-one-CH), 4.02 (d, J = 16.08 Hz, 1H, thiazolidine-4-one-CH2), 3.83 (d, J = 16.08 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.07 (C = O), 149.95 (C = N), 139.06, 133.74, 133.01, 129.51, 129.47, 129.43, 128.50 (Aromatic), 60.41 (thiazolidine-4-one-CH), 30.46 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12C12N2OS (M + Na)+: 372.9945; found 372.9955.

(E)-3-((3-chlorobenzylidene)amino)-2-(3-chlorophenyl)thiazolidin-4-one 2c

white solid; Chemical Formula: C16H12Cl2N2OS: Molecular Weight: 351,25; Yield: 92%

FTIR νmax (cm−1): 1694.85 (C = O), 1562.31 (C = N), 1099.73 (C–N).)

1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H, N = CH), 7.70 (s, 1H, Ar-H), 7.62 (d, J = 7.26 Hz, 1H, Ar-H), 7.53-7.43 (m, 5H, Ar-H), 7.38 9 (d, J = 7.61 Hz, 1H, Ar-H), 6.52 (s, 1H,thiazolidine-4-one-CH), 4.13 (d, J = 15.98 Hz, 1H, thiazolidine-4-one-CH2), 3.89 (d, J = 15.98 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.20 (C = O), 149.26 (C = N), 142.46, 136.29, 134.15, 134.10, 131.44, 131.29, 130.85, 129.03, 126.98, 126.53, 125.05 (Aromatic), 60.27(thiazolidine-4-one-CH), 30.37 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12C12N2OS (M + Na)+: 372.9945; found 372.9955.

(E)-3-((2-chlorobenzylidene)amino)-2-(2-chlorophenyl)thiazolidin-4-one 2d

white solid; Chemical Formula: C16H12Cl2N2OS: Molecular Weight: 351,25; Yield: 90%

FTIR νmax (cm−1): 1720.20 (C = O), 1468.75 (C = N), 1042.01 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.20 (s, 1H, N = CH), 7.87 (d, J = 7.98, 1H, Ar-H), 7.58-7.56 (1H, Ar-H), 7.46-7.36 (m, 5H, Ar-H), 7.22 (s, 1H, Ar-H), 6.73 (s, 1H,thiazolidine-4-one-CH), 4.01 (d, J = 16.23 Hz, 1H, thiazolidine-4-one-CH2), 3.88 (d, J = 16.26 Hz, 1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.51 (C = O), 145.57 (C = N), 136.04, 134.08, 132.62, 131.72, 131.29. 130.66, 130.38, 128.64, 128.18, 127.37, 127.20 (Aromatic), 58.37 (thiazolidine-4-one-CH), 30.22 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12C12N2OS (M + Na)+: 372.9945; found 372.9956.

(E)-3-((2,4-dichlorobenzylidene)amino)-2-(2,4-dichlorophenyl)thiazolidin-4-one 2e

white solid; Chemical Formula: C16H10Cl4N2OS; Molecular Weight: 420,14; Yield: 91%

FTIR νmax (cm−1): 1682.78 (C = O), 1585.85 (C = N), 1045.14 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.23 (s, 1H, N = CH), 7.86 (d, J = 8.52 Hz, 2H, Ar-H), 7.76 (d, J = 2.13 Hz, 1H, Ar-H), 7.66 (d, J = 2.09 Hz, 1H, Ar-H), 7.50-7.44 (m, 2H, Ar-H), 7.27 (d, J = 8.42 Hz, 1H, Ar-H), 6.71 (s, 1H,thiazolidine-4-one-CH), 4.02 (dd, J = 16.13, 0.95 Hz, 1H,thiazolidine-4-one-CH2), 3.89 (d, J = 16.21 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.54 (C = O), 168.52 (C = N), 144.74, 136.38, 135.21, 134.80, 134.35, 132.77, 130.20, 129.91, 128.85, 128.65, 128.56 (Aromatic), 58.04 (thiazolidine-4-one-CH), 30.20 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H10Cl4N2OS (M + Na)+: 442.9137; found 442.9136.

(E)-3-((4-fluorobenzylidene)amino)-2-(4-fluorophenyl)thiazolidin-4-one 2f

white solid; Chemical Formula: C16H12F2N2OS; Molecular Weight: 318,34; Yield: 95%

FTIR νmax (cm−1): 1683.16 (C = O), 1600.66 (C = N), 1050.90 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.23 (s, 1H, N = CH), 7.67 (dd, 6.03, 3.09 Hz, 2H, Ar-H), 7.47 (dd, 5.48, 3.5 Hz, 2H, Ar-H), 7.26-7.19 (m, 4H, Ar-H), 6.48 (s, 1H,thiazolidine-4-one-CH), 4.03 (d, J = 16.25 Hz, 1H, thiazolidine-4-one-CH2), 3.84 (d, J = 16.27 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 197.98 (C = O), 165.18, 163.56, 162.71, 161.13 (Aromatic), 150.60 (C = N), 136.28, 136.25, 130.71, 130.78, 130.11, 130.03, 129.93, 116.56, 116.45, 116.34 (Aromatic), 60.57 (thiazolidine-4-one-CH), 30.53 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12F2N2OS (M + Na)+: 341.0544; found 341.0536.

(E)-3-((3-fluorobenzylidene)amino)-2-(3-fluorophenyl)thiazolidin-4-one 2g

white solid; Chemical Formula: C16H12F2N2OS; Molecular Weight: 318,34; Yield: 94%

FTIR νmax (cm−1): 1697.84 (C = O), 1580.99 (C = N), 1048.45 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.26 (s, 1H, N = CH), 7.47-7.39 (m, 4H Ar-H), 7.30 (m, 4H, Ar-H), 6.49 (s, 1H, thiazolidine-4-one-CH), 4.07 (d, J = 16.22 Hz, 1H, thiazolidine-4-one-CH2),3.84 (d, J = 16.28 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.07 (C = O), 164.07, 163.98, 161.63, 161.55, 149.50 (Aromatic), 149.47 (C = N), 142.93, 142.89, 136.64, 136,56, 124,30, 124,27, 122.46. 122.44, 118.11, 117.90, 116.04, 115.83, 113.64, 113.49, 113.41, 60.31 (Aromatic), 60.29 (thiazolidine-4-one-CH), 30.38 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12F2N2OS (M + Na)+: 341.0545; found 341.0536.

(E)-3-((2-fluorobenzylidene)amino)-2-(2-fluorophenyl)thiazolidin-4-one 2h

white solid; Chemical Formula: C16H12F2N2OS; Molecular Weight: 318,34; Yield: 93%

FTIR νmax (cm−1): 1700.24 (C = O), 1609.09 (C = N), 1052.87 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.36 (s, 1H, N = CH), 7.81 (ddd, 1H Ar-H), 7.51–7.20 (m, 7H, Ar-H), 6.75 (s, 1H, thiazolidine-4-one-CH), 4.00 (d, J = 16.18 Hz, 1H, thiazolidine-4-one-CH2), 3.89 (d, J = 16.20 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.2 (C = O), 162.59, 161.24, 160.10, 158,78 (Aromatic), 142,79 (C = N), 133.31, 133.22, 131.29, 131.20, 128.12, 128.09, 126.80, 126,80, 126,78, 126,61, 126,49, 125.58,125,54, 125.48, 125.45, 121.67, 121.57, 116.76, 116,65, 116.44, 55.77 (Aromatic), 55,74 (thiazolidine-4-one-CH), 30.52 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12F2N2OS (M + Na)+: 341.0544; found 341.0536.

(E)-3-((2,4-difluorobenzylidene)amino)-2-(2,4-difluorophenyl)thiazolidin-4-one 2i

White solid; Chemical Formula: C16H10F4N2OS; Molecular Weight: 354,32; Yield: 89%

FTIR νmax (cm−1): 1691.70 (C = O), 1612.08 (C = N), 1052.40 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.46 (s, 1H, N = CH), 7.88 (q, J = 14.88, 7.62, H Ar-H), 7.50 (q, J = 14.52, 7.75, 1H, Ar-H), 7.41 (q, J = 21.77, 10.83, 2H, Ar-H), 7.22-7.16 (m, 2H, Ar-H), 6.74 (s, 1H,thiazolidine-4-one-CH), 4.04 (d, J = 16.01 Hz, 1H, thiazolidine-4-one-CH2), 3.92 (d, J = 16.01 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.12 (C = O), 165.09, 163.62, 163.41, 163.33, 162.42, 161.97, 161.89, 161.13, 160.83, 160.83, 160.75, 159.47, 159.39 (Aromatic), 142.89 (C = N), 129.75, 128.58, 128.51, 123.18, 123.10, 113.29, 113.15, 112.73, 112.58, 105.48, 105.31, 105.26, 105.09, 104.92, 55.82 (thiazolidine-4-one-CH0, 30.59 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H10F4N2OS (M + Na)+: 377.0352; found 377.0348.

(E)-3-((4-(trifluoromethyl)benzylidene)amino)-2-(4-(trifluoromethyl)phenyl)thiazolidin-4-one 2j

White solid; Chemical Formula: C18H12F6N2OS; Molecular Weight: 418,36; Yield: 95%

FTIR νmax (cm−1): 1688.82 (C = O), 1619.63 (C = N), 1065.28 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.35 (s, 1H, N = CH), 7.87 (d, J = 8.16 Hz, 2H, Ar-H), 7.82 (d, J = 7.38 Hz, 4H, Ar-H), 7.66 (d, J = 8.04 Hz, 2H, Ar-H), 6.68 (s, 1H,thiazolidine-4-one-CH), 4.10 (d, J = 16.14 Hz, 1H,thiazolidine-4-one-CH2), 3.92 (d, J = 16.20 Hz, 1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.39 (C = O), 148.79 (C = N), 144.55, 137.95, 130.93, 130.61, 130.30, 129.53, 129.21, 128.41, 127.28, 126.54, 126.51, 126.28, 126.24, 128.80, 125.75, 123.09, 123.05 (Aromatic), 60.04 (thiazolidine-4-one-CH), 30.30 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C18H12F6N2OS (M + Na)+: 441.0479; found 441.0484.

(E)-3-((2-(trifluoromethyl)benzylidene)amino)-2-(2-(trifluoromethyl)phenyl)thiazolidin-4-one 2k

White solid; Chemical Formula: C18H12F6N2OS; Molecular Weight: 418,36; Yield: 93%

FTIR νmax (cm−1): 1720.45 (C = O), 1585.82 (C = N), 1030.51 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.06 (d, J = 7.86 Hz, 1H, Ar-H), 8.01 (s, 1H, N = CH), 7.85 (d, J = 7.86 Hz, 1H, Ar-H), 7.74-7.68 (m, 3H, Ar-H), 7.62-7.56 (m, 2H, Ar-H), 7.43 (d, J = 7.86, 1H, Ar-H),), 6.62 (s, 1H,thiazolidine-4-one-CH), 4.07 (d, J = 16.14 Hz, 1H,thiazolidine-4-one-CH2), 3.90 (d, J = 16.20 Hz, 1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.72 (C = O), 143.62 (C = N), 137.61, 134.44, 133.40, 131.72, 131.19, 129.72, 127.79, 127.49, 127.41, 127.20, 127.15, 127.09, 127.04, 126.49, 126.42, 126.36, 126.31, 125.97, 125.72, 125.42, 125.12, 123.25, 123.25, 122.70 (Aromatic), 56.86 (thiazolidine-4-one-CH), 29.93 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C18H12F6N2OS (M + Na)+: 441.0479; found 441.0484.

(E)-3-((4-bromobenzylidene)amino)-2-(4-bromophenyl)thiazolidin-4-one 2l

White solid; Chemical Formula: C16H12Br2N2OS; Molecular Weight: 440,15; Yield: 93%

FTIR νmax (cm−1): 1686.90 (C = O), 1590.38 (C = N), 1068.55 (C–N).

1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H, N = CH), 7.62–7.53 (m, 6H, Ar-H), 7.35 (d, J = 8.46, 2H, Ar-H), 6.47 (s, 1H,thiazolidine-4-one-CH), 4.02 (dd, J = 16.25, 0.89 Hz, 1H,thiazolidine-4-one-CH2),3.84 (d, J = 16.25 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (101 MHz, DMSO-d6) δ 168.10 (C = O), 149.85 (C = N), 139.46, 133.33, 132.44, 132.40, 129.63, 128.76, 124.59, 122.05 (Aromatic), 60.35 (thiazolidine-4-one-CH), 30.42 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12Br2N2OS (M + Na)+: 462.8910; found 462.8914.

(E)-3-((3-bromobenzylidene)amino)-2-(3-bromophenyl)thiazolidin-4-one 2m

White solid; Chemical Formula: C16H12Br2N2OS; Molecular Weight: 440,15; Yield: 94%

FTIR νmax (cm−1): 1693.71 (C = O), 1570.95 (C = N), 1069.02 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.20 (s, 1H, N = CH), 7.80 (s, 1H, Ar-H), 7.62 (t, J = 7.18 Hz, 3H, Ar-H), 7.52 (d, J = 6.18 Hz, 1H, Ar-H), 7.38–7.33 (m, 3H, Ar-H), 6.46 (s, 1H,thiazolidine-4-one-CH), 4.07 (d, J = 16.27 Hz, 1H, thiazolidine-4-one-CH2), 3.83 (d, J = 16.38 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.21 (C = O), 149.09 (C = N), 142.62, 136.50, 133.74, 131.71, 131.56, 129.88, 129.37, 126.91, 125.39, 122.62 (Aromatic), 60.12 (thiazolidine-4-one-CH), 30.35 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12Br2N2OS (M + Na)+: 462.8925; found 462.8914.

(E)-3-((2-bromobenzylidene)amino)-2-(2-bromophenyl)thiazolidin-4-one 2n

white yield; Chemical Formula: C16H12Br2N2OS; Molecular Weight: 440,15; Yield: 89%

FTIR νmax (cm−1): 1719.34 (C = O), 1585.09 (C = N), 1020.22 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.07 (s, 1H, N = CH), 7.86 (dd, J = 1.65, 7.80 Hz, 1H, Ar-H), 7.74(d, J = 7.80 Hz, 1H, Ar-H), 7.62 (d, J = 7.80 Hz, 1H, Ar-H), 7.45–7.23 (m, 4H), 7.16 (d, J = 7.59 Hz, Ar-H), 6.62 (s, 1H,thiazolidine-4-one-CH), 4.00 (d, J = 16.35 Hz, 1H, thiazolidine-4-one-CH2), 3.87 (d, J = 16.31 Hz,1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.58 (C = O), 147.88 (C = N), 137.37, 133.96, 133.60, 132.85, 132.75, 130.88, 129.22, 128.70, 127.76, 124.42, 121.89 (Aromatic), 60.82 (thiazolidine-4-one-CH), 30.12 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12Br2N2OS (M + Na)+: 462.8920; found 462.8914.

(E)-3-((4-nitrobenzylidene)amino)-2-(4-nitrophenyl)thiazolidin-4-one 2o

Brown solid; Chemical Formula: C16H12N4O5S; Molecular Weight: 372,36; Yield: 91%

FTIR νmax (cm−1): 1691.56 (C = O), 1596.46 (C = N), 1055.35 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.03 (s, 1H, N = CH), 8.25 (d, J = 8.57 Hz, 4H, Ar-H), 7.87 (d, J = 8.39 Hz, 2H, Ar-H), 7.68 (d, J = 8.52 Hz, 4H, Ar-H), 6.68 (s, 1H,thiazolidine-4-one-CH), 4.08 (d, J = 16.28 Hz, 1H, thiazolidine-4-one-CH2), 3.90 (d, J = 16.30 Hz, 1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.43 (C = O), 148.78 (Aromatic), 147.91 (C = N), 147.88, 147.13, 140.12, 128.82, 127.77, 124.54 (Aromatic), 59.85 (thiazolidine-4-one-CH), 30.29 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12N4O5S (M + Na)+: 395.0434 found 395.0433.

(E)-3-((3-nitrobenzylidene)amino)-2-(3-nitrophenyl)thiazolidin-4-one 2p

Yellow solid; Chemical Formula: C16H12N4O5S; Molecular Weight: 372,36; Yield: 93%

FTIR νmax (cm−1): 1706.06 (C = O), 1512.27 (C = N), 1054.22 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H, Ar-H), 8.35 (s, 1H, N = CH), 8.27 (s, 1H, Ar-H) 8.24 (d, J = 7.98 Hz, 1H, Ar-H), 8.18 (d, J = 6.36 Hz, 1H, Ar-H), 8.05 (d, J = 7.50 Hz, 1H, Ar-H), 7.82 (d, J = 7.56, 1H, Ar-H), 7.71–7.68 (m, 2H, Ar-H), 6.65 (s, 1H,thiazolidine-4-one-CH), 4.09 (d, J = 16.14 Hz, 1H, thiazolidine-4-one-CH2), 3.87 (d, J = 16.20 Hz, 1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.45 (C = O), 148.64, 148.61 (Aromatic), 148.34 (C = N) 142.03, 135.83, 133.78, 132.78, 131.29, 130.99, 125.43, 123.97, 122.07, 121.60 (Aromatic), 59.90 (thiazolidine-4-one-CH), 30.24 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12N4O5S (M + Na)+: 395.0434 found 395.0433.

(E)-3-((2-nitrobenzylidene)amino)-2-(2-nitrophenyl)thiazolidin-4-one 2q

Yellow solid; Chemical Formula: C16H12N4O5S; Molecular Weight: 372,36; Yield: 95%

FTIR νmax (cm−1): 1712.27 (C = O), 1513.40 (C = N), 1054.10 (C–N).

1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.14 Hz, 1H,Ar-H), 8.22 (s, 1H, N = CH), 7.99 (d, J = 8.18 Hz, 1H, Ar-H,) 7.92 (d, J = 7.65 Hz, 1H, Ar-H), 7.84 (t, J = 8.01, 1H, Ar-H) 7.80 (t, J = 7.65, 1H, Ar-H), 7.67–7.64 (m, 2H, Ar-H) 7.30 (d, J = 7.53 Hz,1H, Ar-H), 6.78 (s, 1H, thiazolidine-4-one-CH), 3.98 (d, J = 16.44 Hz, 1H, thiazolidine-4-one-CH2), 3.82 (d, J = 16.40 Hz, 1H, thiazolidine-4-one-CH2).

13C NMR (151 MHz, DMSO-d6) δ 168.91 (C = O), 148.77, 146.44 (Aromatic), 146.01 (C = N), 135.84, 134.68, 134.32, 131.70, 130.35, 128.94, 128.65. 126.74, 126.44, 125.11 (Aromatic), 57.18 (thiazolidine-4-one-CH), 29.54 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C16H12N4O5S (M + Na)+: 95.0431 found 95.0433.

(E)-3-((3-methoxybenzylidene)amino)-2-(3-methoxyphenyl)thiazolidin-4-one 2r

White solid; Chemical Formula: C18H18N2O3S; Molecular Weight: 342,41; Yield: 89%

FTIR νmax (cm−1): 1713.24 (C = O), 1573.05 (C = N), 1041.79 (C–N).

1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H, N = CH), 7.34 (q, J = 7.84, 2H, Ar-H), 7.1.6 (s, 2H, Ar-H), 7.00 (d, J = 8.20, 1H, Ar-H), 9.93–6.87 (m, 3 h, Ar-H), 6.46 (s, 1H, thiazolidine-4-one-CH), 4.03 (d, J = 16.04 Hz, 1H, thiazolidine-4-one-CH2), 3.82 (d, J = 16.12 Hz, 1H, thiazolidine-4-one-CH2), 3.75 (s, 3H, CH3), 3.74 (s, 3H, CH3).

13C NMR (101 MHz, DMSO-d6) δ 168.09 (C = O), 160.12, 159.96 (Aromatic), 150.77 (C = N), 141.66, 135.55, 130.74, 130.46, 120.69, 118.29, 117.25, 114.21, 112.21, 112.02 (Aromatic), 60.70 (thiazolidine-4-one-CH), 55.64 (OCH3), 55.62 (OCH3), 30.48 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C18H18N2O3S (M + Na)+: 365.0939; found 365.0942.

(E)-3-((3-methylbenzylidene)amino)-2-(m-tolyl)thiazolidin-4-one 2s

White solid; Chemical Formula: C18H18N2OS; Molecular Weight: 310,41; Yield: 91%

FTIR νmax (cm−1): 1698.66 (C = O), 1580.15 (C = N), 1060.37 (C–N).

1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H, N = CH), 7.41 (s, 1H, Ar-H), 7.38 (d, J = 7.36 Hz, 1H, Ar-H), 7.30–7.11 (m, 6H, Ar-H), 6.46 (s, 1H, thiazolidine-4-one-CH), 4.02 (d, J = 16.30 Hz, 1H, thiazolidine-4-one-CH2), 3.82 (d, J = 16.22 Hz, 1H, thiazolidine-4-one-CH2), 2.29 (s, 6H, 2CH3)

13C NMR (101 MHz, DMSO-d6) δ 168.07 (C = O), 150.84 (C =n), 140.06, 138.61, 134.08, 131.84, 129.65, 129.39, 129.21, 128.02, 126.71, 125.23, 123.46 (Aromatic), 60.69 (thiazolidine-4-one-CH), 30.74 (CH2), 21.46 (CH3), 24.24 (CH3).

HRMS: (ESI+-MS, m/z) calcd for C18H18N2OS (M + Na)+: 333.1043; found 333.1038.

(E)-3-((2,3,4-trimethoxybenzylidene)amino)-2-(2,3,4-trimethoxyphenyl)thiazolidin-4-one 2t

White solid; Chemical Formula: C22H26N2O7S; Molecular Weight: 462,52; Yield: 89%

FTIR νmax (cm−1): 1689.96 (C = O), 1578.01 (C = N), 1119.01 (C–N).

1H NMR (600 MHz, DMSO-d6) δ 8.23 (s, 1H, N = CH), 6.95 (s, 2H, Ar-H), 6.69 (s, 2H, Ar-H), 6.36 (s, 1H, thiazolidine-4-one-CH), 4.08 (d, J = 15.96 Hz, 1H, thiazolidine-4-one-CH2), 3.77 (13H, thiazolidine-4-one-CH2, 4OCH3,), 3.67 (s, 3H, OCH3), 3.64 (s, 3H, OCH3).

13C NMR (151 MHz, DMSO-d6) δ 167.90 (C = O), 153.89, 153.43 (Aromatic), 152.75, 140.76, 138.39, 134.46, 129.04, 105.11, 103.12 (Aromatic), 63.74 (thiazolidine-4-one-CH), 60.94 (OCH3), 60.86 (OCH3), 56.31 (OCH3), 56.25 (OCH3), 31.34 (CH2).

HRMS: (ESI+-MS, m/z) calcd for C22H26N2O7S (M + Na)+: 442.9137; found 442.9136.

Pharmacological assaysNitric Oxide (NO) activity

The antioxidant capacity of the compounds to mop up nitric oxide radicals was determined with the modified protocol utilized by Kurian et al. [52]. Briefly, 250 μL of sodium nitroprusside (10 mM) prepared in Sodium phosphate buffer (pH 7.4) was added to 500 μL of the compounds (250 - 2000 mM) solution or distilled water (control). The resulting solution was incubated at 37 °C for 2 h. Then, 250 μL of Griess reagent was added to the reaction mixture before the absorbance was measured at 540 nm. The % nitric oxide scavenging activity of the compounds was calculated with the formula:

$$}( \% )=\left(1-\frac}}}}\right)\times 100$$

2,2′-diphenyl-1-picrylhydrazyl (DPPH) activity

The compounds were evaluated on their ability to scavenge stable DPPH radicals by adopting the method of Turkoglu et al. [53] with slight modifications. 2 mL of varied concentrations (250 - 2000 mM) of the compounds or Trolox was added to 2 mL 0.3 mM DPPH prepared in methanol. After thorough mixing, the solution was kept in the dark chamber at room temperature (25 °C) for 30 min. Then, the absorbance was measured at 517 nm, and the DPPH radical mopping activity was calculated as follows:

$$}( \% )=\left(1-\frac}}}}\right)\times 100$$

Ferric reducing antioxidant (FRAP)power

The ferric-reducing antioxidant power of the chemical compounds was evaluated using the modified method by Oyaizu [54]. 500 μL of varying concentrations of the compounds or Trolox (250 - 2000 mM) was added to 250 μL distilled water, 100 μL of 200 mM phosphate buffer (pH = 6.6), and 100 μL of 1% potassium ferricyanide [K3Fe (CN)6]. The mixture was incubated at 50 °C for 20 min, followed by acidification with 100 μL trichloroacetic acid (10%). After centrifugation at 3500 rpm for 10 min, 200 μL of the supernatant was transferred into another test tube containing 200 μL distilled water and 0.8 mL of FeCl3 (0.1%). Finally, the absorbance was read at 700 nm, and the total reductive antioxidant power was calculated thus:

$$}( \% )=\frac}}}2000}}\times 100$$

α-glucosidase inhibitory activity

The α- glucosidase inhibitory activity was evaluated with the previous method of Ademiluyi and Oboh [55] with slight modifications. Briefly, 100 µL aliquot) of each compound or acarbose (75–600 μM) was added to α-glucosidase (1.0 U/mL) solution in 100 mM sodium phosphate buffer (pH 6.8). The reaction was incubated at 37 °C for 15 min before adding 50 µL of para nitrophenyl β-D-glucopyranoside solution (5 mM). After further incubation at 37 °C for another 30 min, the absorbance of the resulting solution was measured at 405 nm. The compounds’ inhibitory activity was calculated as the percentage of the control sample using the expression below:

$$\% }=\left(1-\frac}}}}\right)\times 100$$

α-amylase inhibitory activity

α-Amylase inhibitory activity was determined according to Ibitoye et al. [56] with slight modifications. Briefly, 200 μL of the compounds or acarbose (75–600 μM) was incubated at 25 °C for 10 min with 200 μL solution of porcine pancreatic amylase (0.5 mg/mL) prepared in 200 mM sodium phosphate buffer (pH 6.8). Then, 500 μL of 1% starch solution was added before further incubation at 25 °C for 15 min. The reaction in the mixture was terminated with a 1 mL dinitrosalicylate reagent before boiling for 10 min. The cooled mixture was diluted with 5 mL of distilled water, and the absorbance was read at 540 nm. The inhibitory activity was calculated using the formula below:

$$\% }=\left(1-\frac}}}}\right)\times 100$$

Molecular modeling protocols

The Schrödinger molecular modeling suite (release 2021-3) and OPLS4 force were used for all computations.

Ligand preparation

The structures of compounds 2q, 2h, 2g, 2k and acarbose were saved as chemdraw files and imported onto the software, the 3D models with low energy conformation were then generated with LigPrep [57] while their protonation states were assigned using Epik [58] at pH 7 ± 2.0.

Protein preparation

The three-dimensional structure (3D) of α-amylase was retrieved from Protein Data Bank and the structure was prepared using Protein Preparation Wizard [59] using default workflow.

Induced-fit docking and MM-GBSA binding free energy

The prepared ligands were docked at the active site of the human pancreatic α-amylase enzyme (PDB ID: 2QV4) by employing the induced-fit docking (IFD) [60] procedure following standard protocol. The usual protocol parameters included defining the receptor’s grid box as the centroid of the native ligand of ligands size of ≤20 Å with a conformational sampling at a 2.5 kcal mol−1 energy window. The initial docking stage with glide constituted generating poses that can be docked on the receptor and followed by Prime refinement to an RMSD of 1.8 Å. Subsequently, structures with an energy of 30 kcal.mol−1 were submitted for glide redocking with extra precision to account for fall positives. Thereafter, the best receptor-ligand complex was redocked to improve the final pose. Complexes presenting the best poses were selected based on docking score, glide emodel and glide energy and then used as input structures to calculate ligand binding free energy using Prime Molecular Mechanics-Generalized Borne Surface Area (MM-GBSA) [61].