Novel thiosemicarbazone derivatives containing benzimidazole moiety: Green synthesis and anti-malarial activity

1 Introduction

Malaria is endemic in over 100 countries, affecting especially tropical areas of Africa, Asia and Latin America. It is responsible for high mortality and morbidity in these regions, being especially lethal to children and pregnant women. (De Oliveira et al., 2008) According to World Health Organization up to one million people die of malaria worldwide, every year (WHO, Geneva, 2006). Human malaria is caused by four different species of Plasmodium: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. The most severe form is caused by P. falciparum, which leads to the death of about 1% of infected patients. Although the use of drugs has effectively resulted in successful treatment of Plasmodium infections, drug resistances in Plasmodium have been reported (Bloland, 2001; Gogtay et al., 2006; Kshirsagar, 2006). Owing to growing resistance, the development of potent antimalarials is recommended to fulfil this challenge. Recently there have been a lot of studies using iron-chelating agents as a possible treatment for malaria (Cabantchik, 1994; Kontoghiorghes et al., 2010). Thiosemicarbazones are known iron-chelating agents by bonding through the sulphur and azomethine nitrogen atoms (Walcourt et al., 2004). Their activity against extracellular protozoan such as P. falciparum, Trichomonas vaginalis, Trypanosoma cruzi, and other parasites was demonstrated by several researchers (Bharti et al., 2002; Greenbaum et al., 2004).

On the other hand, the structural similarities between benzimidazole nucleus and various biological compounds such as purine base of the DNA and its presence in vitamin B₁₂ have made it important in the pharmaceutical industry. As a result of this, benzimidazoles have been termed as key structures for drug design (Panda et al., 2012). Thus, because of its increasing medicinal importance, great efforts have been made to develop an efficient and economical method for the synthesis of its large number of new derivatives. This inspired us to study the biological activities of thiosemicarbazone analogues of benzimidazole. In this research article, we have reported the synthesis of new benzimidazole-thiosemicarbazone derivatives. These compounds were tested for in vitro antimalarial screening.

2 Materials and methods

2.1

2.1 Chemistry

Melting points were determined on a Büchi 535 melting point apparatus and are uncorrected. A CEM Discover microwave synthesizer (Model No. 908010) operating at 180/264 V and 50/60 Hz with a microwave power maximum level of 700 W and microwave frequency of 2455 MHz was employed for microwave-assisted experiments done in this work. Infrared spectra were recorded on a Perkin-Elmer 841 using samples in potassium bromide discs. The ¹H NMR and ¹³C NMR spectra were recorded on a Bruker 400 MHz spectrometer using DMSO-d₆ as a solvent and TMS as an internal standard. Mass spectra were recorded on a TSQ-Quantum Access Mass spectrometer by ESI (electron spray ionization) method. Elemental analyses were performed on a Micro Variant CHN elemental analyser. TLC was performed on a Merck DC Alufolien with Kieselgel 60F₂₅₄ from Merck Co., Germany. All the raw-materials were purchased from Sigma–Aldrich Co, Germany.

2.1.1

2.1.1 Synthesis of 1-(5-Chloro-1H-benzimidazol-2-yl) ethanol (3a) (Patel et al., 2013)

In a 50 mL glass round bottomed flask, 4-Chlorobenzene-1,2-diamine (2a) (0.003 mmol) and d,l-lactic acid (1) (88% approx.) (8 mL) were mixed. To this mixture, ethylene glycol (5 mL) was added. The reaction mixture was heated by an open vessel method in the Discover Microwave Synthesizer (CEM Matthews Inc., USA) at 300 W with total irradiation time of 35 min. On cooling, the reaction mixture was treated with a saturated solution of NaHCO₃. (pH 8). After neutralization, the residue obtained was dissolved in methanol and filtered. The filtrate was concentrated to dryness. The residue was then collected by filtration as a yellow solid form. The yield was 78% and product was further used after crystallization from alcohol, m.p. was taken at 168–170 °C. Reaction progress was checked by TLC plates using ethyl acetate: toluene (4:1) as the mobile phase. IR (KBr): 3360 (NH), 3077 (C–H benzene), 1599 (C⚌C & C⚌N), 1113 (C–O)cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 1.49–1.51 (d, 3H, J = 8 Hz,CH₃), 4.68–4.75 (m, 1H, CH), 5.77–5.79 (d, 1H, J = 8 Hz, OH), 7.14–7.16 (d, 1H, J = 8 Hz, Ar-H), 7.80–7.82 (d, 1H, J = 7.9 Hz, Ar-H), 8.38–8.41 (d, 1H, J = 8.9 Hz, Ar-H), 13.05 (s, 1H, NH). HRMS (m/z, ESI): M⁺ 196.05, [M+2] 198.05. Anal. Calcd. for C₉H₉ClN₂O (Mol. Wt. 196.63): C, 54.97; H, 4.61; N, 14.25. Found: C, 54.94; H, 4.58; N, 14.23.%.

2.1.1.1

2.1.1.1 Synthesis of 1-(1H-benzimidazol-2-yl) ethanol (3b)

Similarly, we have synthesized compound (3b) by taking compound (2b) as a starting material. The product was isolated as a light yellow solid with 75% yield and m.p. was taken at 165–167 °C. IR (KBr): 3420 (NH), 3107 (C–H benzene), 1492 (C⚌C & C⚌N), 1125 (C–O)cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 1.56–1.58 (d, 3H, J = 8 Hz, CH₃), 4.75–4.84 (m, 1H, CH), 5.68–5.70 (d, 1H, J = 8 Hz, OH), 7.25–7.27 (d, 1H, J = 8 Hz, Ar-H), 7.35–7.40 (t, 1H, J = 7.5 Hz, Ar-H), 8.52–8.54 (d, 1H, J = 8 Hz, Ar-H), 12.96 (s, 1H, NH). HRMS (m/z, ESI): M⁺ 162.10, [M+1] 163.10. Anal. Calcd. for C₉H₁₀N₂O (Mol. Wt. 162.19): C, 66.65; H, 6.21; N, 17.27. Found: C, 66.62; H, 6.18; N, 17.25.%.

2.1.2

2.1.2 Synthesis of 1-(5-chloro-1H-benzimidazol-2-yl) ethanone (4a)

To a solution of 1-(5-chloro-1H-benzimidazol-2-yl) ethanol (3a) (0.001 mmol) in glacial acetic acid (10 mL) was added gradually a solution of 4% sodium hypochlorite solution (NaOCl) (0.0013 mmol/25 mL) in an ice bath because of the exothermic reaction. After addition of NaOCl, the reaction mixture was stirred for 20 min at room temperature. It was necessary to stir the mixture vigorously as the reaction mixture was two-phased. The reaction mixture was then tested for excess hypochlorite with starch-iodide paper. The addition of 0.5 mL of a saturated sodium bisulphite (Na₂SO₃) solution was done to remove the blue-black color. The mixture was swirled after addition and then tested again until the complete removal of hypochlorite. After that the reaction was neutralized with the help of 6 M NaOH. The product was then obtained via the extraction process. In a separating funnel, product was extracted with 3 × 5 mL portions of methylene dichloride (CH₂Cl₂). An aqueous layer was removed and the combined organic layer was dried with Na₂SO₄ for about 5–10 min with occasional stirring and then sodium sulphate was isolated with Buchner funnel. The remaining organic extract was taken in a rotary evaporator to remove the solvent under reduced pressure. The yellow precipitates were collected in 75% yield and dried further. The product started decomposing before reaching its M.P. The reaction progress was checked by TLC using Ethyl acetate: Toluene (4:1) as solvents; IR (KBr): 3368 (NH), 3060 (C–H benzene), 1699 (C⚌O) cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 2.70 (s, 3H, CH₃), 7.35–7.39 (d, 1H, J = 8 Hz, Ar-H), 7.78–7.80 (d, 1H, J = 8 Hz, Ar-H), 8.24 (s, 1H, Ar-H), 13.5 (s, 1H, NH). HRMS (m/z, ESI): M⁺ 194.02, [M+2] 196.05. Anal. Calcd. for C₉H₇ClN₂O (Mol. Wt. 194.62): C, 55.54; H, 3.63; N, 14.39. Found: C, 55.50; H, 3.60; N, 14.36.%.

2.1.2.1

2.1.2.1 Synthesis of 1-(1H-benzimidazol-2-yl) ethanone (4b)

Similarly, 1-(1H-benzimidazol-2-yl) ethanone (4b) was synthesized by taking 1-(1H-benzimidazol-2-yl) ethanol (3b) as a starting material. The yellow precipitates were obtained in 76% yield. The product started decomposing before reaching its M.P. IR (KBr): 3375 (N–H), 3054 (C–H benzene), 1685 (C⚌O) cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 2.48 (s, 3H, CH₃), 7.28–7.30 (d, 1H, J = 8 Hz, Ar-H), 7.68–7.70 (d, J = 8 Hz, Ar-H), 8.50 (s, 1H, Ar-H), 13.28 (s, 1H, NH). HRMS (m/z, ESI): M⁺ 160.06, [M+1] 161.07. Anal. Calcd. for C₉H₈N₂O (Mol. Wt. 160.17): C, 67.49; H, 5.03; N, 17.49. Found: C, 67.46; H, 5.00; N, 17.47.%.

2.1.3

2.1.3 General procedure for the synthesis of N⁴-alkyl and aryl thiosemicarbazides (6a–6t)

The alkyl or aryl isothiocyanate (0.001 mmol) was added dropwise in a solution of hydrazine (0.001 mmol) in methanol (6 mL). The reaction was irradiated by microwaves in a Discover Microwave Synthesizer (CEM Matthews Inc., USA) at 180 W with a total irradiation time of 3–5 min. The excess solvent was then removed by evaporation in vacuo and the crude product was dissolved in chloroform (5 mL) and this solution was added into multifold volume of petroleum ether (40–60 °C) at constant stirring. The precipitates obtained were used directly for the next step. All thiosemicarbazides (6a–6t) were obtained by the general method described above.

2.1.4

2.1.4 General procedure illustrating the synthesis of (E)-2-[1-(5-chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-hydrazine carbothioamide (7a–7t)

An alkyl or aryl thiosemicarbazide (6a–6t) (0.001 mmol) and 10 drops of glacial acetic acid were added to a solution of 1-(5-chloro-1H-benzimidazol-2-yl) ethanone (4a) in methanol (6 mL). The reaction mass was heated in a Discover Microwave Synthesizer (CEM Matthews Inc., USA) at 180 W with a total irradiation time of 25–35 min. The product was obtained upon cooling, and then dried. The reaction progress was checked by TLC taking Ethyl acetate: Toluene (4:1) as the mobile phase. The product was re-crystallized by 95% ethanol. The product was obtained as a brown colored solid in good yield which was further characterized by FT-IR, ¹H NMR, Mass spectra and elemental analysis. A series of all compounds (7a–7t) were synthesized by the above described method.

2.1.4.1

2.1.4.1 (E)-2-(1-[5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] hydrazine carbothioamide (7a) (Patel et al., 2013)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a light brown solid; 75% yield; m.p. 214–215 °C; IR (cm⁻¹, KBr): 3454 (–NH), 1213 (C⚌S), 1531 (C⚌N), 1584 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.38 (s, 3H, –CH₃), 7.07–7.55 (m, 1H, Ar-H), 7.67–7.65 (d, 1H, J = 7.6 Hz, Ar-H), 7.92 (s, 1H, Ar-H), 8.57 (s, 2H, –NH₂), 10.73 (s, 1H, –NH), 12.88 (s, 1H, –NH); ¹³C NMR (100 MHz, DMSO-d₆) Benzimidazole C: [152.65 (C), 140.48 (C), 138.89 (C), 130.07 (C–Cl), 126.56 (CH), 117.29 (CH), 116.34 (CH)], 180.34 (C⚌S), 157.60 (N⚌CH), 25.46 (CH₃); HRMS (m/z, ESI): M⁺ 267.03, [M+2] 269.03. Anal. Calcd. for C₁₀H₁₀ClN₅S (Mol. Wt. 267.73): C, 44.86; H, 3.76; N, 26.12. Found: C, 44.84; H, 3.73; N, 26.10%.

2.1.4.2

2.1.4.2 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-phenylhydrazine carbothioamide (7b) (Patel et al., 2013)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a light brown solid; 85% yield; m.p. at 161–162 °C; IR (cm⁻¹, KBr): 3205 (NH), 1189 (C⚌S), 1514 (C⚌N), 1596 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.48 (s, 3H, CH₃), 7.24–7.26 (d, 1H, J = 8 Hz, Ar-H), 7.40–7.44 (t, 1H, J = 7.9 Hz, Ar-H), 7.49–7.51 (d, 1H, J = 8 Hz, Ar-H), 7.59–7.64 (d, 1H, J = 7.6 Hz, Ar-H), 8.36 (s, 1H, Ar-H), 10.40 (s, 1H, NH), 11.07 (s, 1H, NH), 13.02 (s, 1H, NH); ¹³C NMR (100 MHz, DMSO-d₆) Benzimidazole C: [152.45 (C), 140.28 (C), 137.39 (C), 130.17 (C–Cl), 126.78 (CH), 117.56 (CH), 116.49 (CH)], Arom-C: [140.33 (C), 127.58 (CH), 128.44 (C), 129.26 (CH), 184.34 (C⚌S), 156.58 (N⚌CH), 25.50 (CH₃); HRMS (m/z, ESI): M⁺ 342.9, [M+2] 344.9. Anal. Calcd. for C₁₆H₁₄ClN₅S (Mol. Wt. 343.83): C, 55.89; H, 4.10; N, 20.37. Found: C, 55.87; H, 4.06; N, 20.33%.

2.1.4.3

2.1.4.3 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-ethylhydrazine carbothioamide (7c) (Patel et al., 2013)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a light Brown solid; 83% yield; m.p. 223–224 °C; IR (cm⁻¹, KBr): 3435 (NH), 1199 (C⚌S), 1492 (C⚌N), 1549 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.38–2.46 (s, 3H, CH₃), 1.16–1.20 (t, 3H, J = 6.8 Hz, CH₂), 3.66–3.68 (t, 2H, J = 6.8 Hz, CH₃), 7.24 (d, 1H, J = 7.5 Hz, Ar-H), 7.55 (d, 1H, J = 7.5 Hz, Ar-H), 7.70 (s, 1H, Ar-H), 8.96 (s, 1H, NH), 10.68 (s, 1H, NH), 12.82 (s, 1H, NH); ¹³C NMR (100 MHz, DMSO-d₆) Benzimidazole C: [152.25 (C), 139.98 (C), 137.86 (C), 130.53 (C–Cl), 126.95 (CH), 117.87 (CH), 116.93 (CH)], 180.15 (C⚌S), 156.45 (N⚌CH), 42.50 (CH₂), 25.48(CH₃), 28.56 (CH₃); HRMS (m/z, ESI): M⁺ 296.10, [M+2] 298.10. Anal. Calcd. for C₁₂H₁₄ClN₅S (Mol. Wt. 295.79): C, 48.73; H, 4.77; N, 23.68. Found: C, 48.71; H, 4.75; N, 23.65.%.

2.1.4.4

2.1.4.4 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(n-butyl) hydrazine carbothioamide (7d) (Patel et al., 2013)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a brown solid; 69% yield; m.p. 203–204 °C; IR (cm⁻¹, KBr): 3448 (NH), 1216 (C⚌S), 1419 (C⚌N), 1541 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 0.88–0.91 (t, 3H, J = 6.8 Hz, CH₃), 1.30–1.35 (m, 2H, CH₂), 1.57–1.87 (m, 2H, CH₂), 2.40–2.42 (t, 1H, J = 7.9 Hz, CH₂), 3.62 (s, 2H, CH₃), 7.27–7.28 (d, 1H, J = 7.5 Hz, Ar-H), 7.55 (d, 1H, J = 7.8 Hz, Ar-H), 7.71 (s, 1H, Ar-H), 8.94 (s, 1H, NH), 10.68 (s, 1H, NH), 12.83 (s, 1H, NH); ¹³C NMR (100 MHz, DMSO-d₆) Benzimidazole C: [152.30 (C), 140.25 (C), 137.97 (C), 130.32 (C–Cl), 126.92 (CH), 117.85 (CH), 116.96 (CH)], 179.45 (C⚌S), 156.66 (N⚌CH), Butyl C: [48.76 (CH₂), 42.59 (CH₂), 31.48(CH₂)], 25.56 (CH₃); HRMS (m/z, ESI): M⁺ 323.04, [M+2] 325.04. Anal. Calcd. for C₁₄H₁₈ClN₅S (Mol. Wt. 323.84): C, 51.92; H, 5.60; N, 21.63. Found: C, 51.90; H, 5.58; N, 21.61%.

2.1.4.5

2.1.4.5 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-cyclohexyl hydrazine carbothioamide (7e) (Patel et al., 2013)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a brown solid; 85% yield; m.p. 215–216 °C; IR (cm⁻¹, KBr): 3420 (NH), 1206 (C⚌S), 1519 (C⚌N), 1594 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆):δ 1.22–1.89 (m, 11H, Cyclohex-H), 2.40–2.46 (s, 3H, CH₃), 7.28–7.31 (d, 1H, J = 7.9 Hz, Ar-H), 7.51–7.53 (d, 1H, J = 8 Hz, Ar-H), 7.71–7.77 (s, 1H, Ar-H), 9.80 (s, 1H, NH), 10.55 (s, 1H, NH), 13.10 (s, 1H, NH); ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.36 (C), 140.28 (C), 137.98 (C), 130.38 (C–Cl), 126.96 (CH), 117.75 (CH), 116.87 (CH)], 179.15 (C⚌S), 156.68 (N⚌CH), Cyclohexyl C: [60.05 (CH), 42.15 (CH₂), 35.19 (CH₂), 35.05 (CH₂)], 25.66 (CH₃); HRMS (m/z, ESI): M⁺ 349.11, [M+2] 351.11. Anal. Calcd. for C₁₆H₂₀ClN₅S (Mol. Wt. 349.88): C, 54.92; H, 5.76; N, 20.02. Found: C, 54.90; H, 5.74; N, 20.00%.

2.1.4.6

2.1.4.6 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(4-chlorophenyl) hydrazine carbothioamide (7f)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 77% yield; m.p. 178–180 °C; IR (cm⁻¹, KBr): 3375 (NH), 1215 (C⚌S), 1560 (C⚌N), 1620 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆):δ 2.50 (s, 3H, CH₃), 7.26–7.28 (d, 1H, J = 8 Hz, Ar-H), 7.33–7.35 (d, 1H, J = 8 Hz, Ar-H), 7.53–7.55 (d, 1H, J = 8 Hz, Ar-H), 7.59–7.61 (d, 1H, J = 8.5 Hz, Ar-H), 7.75–7.77 (d, 1H, J = 8 Hz, Ar-H), 7.89 (s, 1H, Ar-H), 10.46 (s, 1H, NH), 11.25 (s, 1H, NH), 13.15 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.34 (C), 140.42 (C), 137.60 (C), 130.30 (C–Cl), 126.52 (CH), 117.32 (CH), 116.34 (CH)], 184.36 (C⚌S), 157.22 (N⚌CH), Arom-C: [144.48 (C), 142.54 (C–Cl), 128.78 (CH, CH), 127.88 (CH,CH)], 25.54 (CH₃); HRMS (m/z, ESI): M⁺ 378.03, [M+2] 380.03. Anal. Calcd. for C₁₆H₁₃Cl₂N₅S (Mol. Wt. 378.28): C, 50.80; H, 3.46; N, 18.51. Found: C, 50.00; H, 3.43; N, 18.43%.

2.1.4.7

2.1.4.7 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(4-nitrophenyl) hydrazine carbothioamide (7g)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 75% yield; m.p. 205–208 °C; IR (cm⁻¹, KBr): 3320 (NH), 1195 (C⚌S), 1525 (C⚌N), 1605 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.68 (s, 3H, CH₃), 7.39–7.41 (d, 1H, J = 8 Hz, Ar-H), 7.72–7.74 (d, 1H, J = 8 Hz, Ar-H), 7.84–7.86 (d, 1H, J = 8 Hz, Ar-H), 8.04–8.06 (d, 1H, J = 8 Hz, Ar-H), 8.20 (s, 1H, Ar-H), 9.62 (s, 1H, NH), 10.77 (s, 1H, NH), 13.07 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.26 (C), 140.38 (C), 137.58 (C), 130.28 (C–Cl), 126.44 (CH), 117.25 (CH), 116.27 (CH)], 184.25 (C⚌S), 157.08 (N⚌CH), Arom-C: [144.60 (C), 125.16 (CH, CH), 125.78 (CH, CH), 143.94 (C–NO₂)], 25.56 (CH₃); HRMS (m/z, ESI): M⁺ 388.03, [M+2] 390.03. Anal. Calcd. for C₁₆H₁₃ClN₆O₂S (Mol. Wt. 388.83): C, 49.42; H, 3.37; N, 21.61. Found: C, 49.38; H, 3.33; N, 21.58%.

2.1.4.8

2.1.4.8 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(4-methoxyphenyl) hydrazine carbothioamide (7h)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 75% yield; m.p. 192–194 °C; IR (cm⁻¹, KBr): 3350 (NH), 1215 (C⚌S), 1570 (C⚌N), 1630 (C⚌C), 1274 (C–O–C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (s, 3H, CH₃), 3.80 (s, 3H, OCH₃), 6.86–6.88 (d, 1H, J = 8 Hz, Ar-H), 7.26–7.28 (d, 1H, J = 8 Hz, Ar-H), 7.33–7.35 (d, 1H, J = 8 Hz, Ar-H), 7.73–7.76 (d, 1H, J = 8 Hz, Ar-H), 7.82 (s, 1H, Ar-H), 10.38 (s, 1H, NH), 11.07 (s, 1H, NH), 13.15 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.28 (C), 140.41 (C), 137.62 (C), 130.30 (C–Cl), 126.48 (CH), 117.28 (CH), 116.30 (CH)], 184.28 (C⚌S), 157.18 (N⚌CH), Arom-C: [160.10 (C), 132.48 (C), 127.96 (CH, CH), 114.85 (CH, CH)], 59.25 (OCH₃), 25.56 (CH₃); HRMS (m/z, ESI): M⁺ 373.12, [M+2] 375.12. Anal. Calcd. for C₁₇H₁₆ClON₅S (Mol. Wt. 373. 85): C, 54.61; H, 4.31; N, 18.73. Found: C, 50.43; H, 4.29; N, 18.71%.

2.1.4.9

2.1.4.9 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(isopropyl) hydrazine carbothioamide (7i)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a brown solid; 72% yield; m.p. 220–222 °C; IR (cm⁻¹, KBr): 3373 (NH), 2974(C(CH₃)), 1220 (C⚌S), 1580 (C⚌N), 1620 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 1.27–1.29 (d, 6H, J = 8 Hz,(CH₃)₂), 2.56 (s, 3H, CH₃), 4.25–4.30 (m, 1H, CH), 7.12–7.14 (d, 1H, J = 8 Hz, Ar-H), 7.38–7.40 (d, 1H, J = 8 Hz, Ar-H), 7.82 (s, 1H, Ar-H), 10.55 (s, 1H, NH), 11.17 (s, 1H, NH), 13.25 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.44 (C), 140.48 (C), 137.70 (C), 130.56 (C–Cl), 126.52 (CH), 117.34 (CH), 116.47 (CH)], 178.58 (C⚌S), 157.35 (N⚌CH), Isopropyl C: [52.10 (CH), 33.24 (CH_3, CH₃)], 25.35 (CH₃); HRMS (m/z, ESI): M⁺ 309.11, [M+2] 311.11. Anal. Calcd. for C₁₃H₁₆ClN₅S (Mol. Wt. 309.81): C, 50.40; H, 5.21; N, 22.60. Found: C, 50.37; H, 5.19; N, 22.57%.

2.1.4.10

2.1.4.10 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(tert-butyl) hydrazine carbothioamide (7j)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a brown solid; 85% yield; m.p. 211–214 °C; IR (cm⁻¹, KBr): 3298 (NH), 1235 (C⚌S), 1565 (C⚌N), 1593 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 1.52–1.68 (m, 9H, (CH₃)₃), 2.64 (s, 3H, CH₃), 7.08–7.10 (d, 1H, J = 8 Hz, Ar-H), 7.28–7.31 (d, 1H, J = 7.9 Hz, Ar-H), 7.74 (s, 1H, Ar-H), 9.46 (s, 1H, NH), 12.77 (s, 1H, NH), 13.53 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.45 (C), 140.48 (C), 137.76 (C), 130.66 (C–Cl), 126.58(CH), 117.58 (CH), 116.67 (CH)], 178.38 (C⚌S), 157.55 (N⚌CH), t-butyl C: [62.36 (C), 40.26 (CH_3, CH_3, CH₃)], 25.30 (CH₃); HRMS (m/z, ESI): M⁺ 323.15, [M+2] 325.15. Anal. Calcd. for C₁₄H₁₈ClN₅S (Mol. Wt. 323.84): C, 51.92; H, 5.60; N, 21.63. Found: C, 51.89; H, 5.58; N, 21.60%.

2.1.4.11

2.1.4.11 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(benzyl) hydrazine carbothioamide (7k)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 65% yield; m.p. 218–219 °C; IR (cm⁻¹, KBr): 3379 (NH), 1236 (C⚌S), 1546 (C⚌N), 1583 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (s, 3H, CH₃), 4.72 (s, 2H, CH₂), 7.23–7.75 (m, 5H, Ar-H), 8.31 (s, 1H, Ar-H), 9.70 (s, 1H, NH), 11.03 (s, 1H, NH), 13.13 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.48 (C), 140.52 (C), 137.78 (C), 130.60 (C–Cl), 126.58(CH), 117.57 (CH), 116.69 (CH)], 178.45 (C⚌S), 157.58 (N⚌CH), Arom-C: [138.72 (C), 129.95 (CH, CH), 127.30 (CH, CH), 126.98 (C)], 55.34 (CH₂), 25.25 (CH₃); HRMS (m/z, ESI): M⁺ 357.26, [M+2] 359.26. Anal. Calcd. for C₁₇H₁₆ClN₅S (Mol. Wt. 357.86): C, 57.06; H, 4.51; N, 19.57. Found: C, 57.00; H, 4.48; N, 19.55%.

2.1.4.12

2.1.4.12 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(2,4-dichlorophenyl) hydrazine carbothioamide (7l)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 68% yield; m.p. 180–182 °C; IR (cm⁻¹, KBr): 3375 (NH), 1242 (C⚌S), 1543 (C⚌N), 1581 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H, CH₃), 7.27 (d, 1H, J = 8.5 Hz, Ar-H), 7.40–7.44 (d, 1H, J = 8.5 Hz, Ar-H), 7.66–7.68 (d, 1H, J = 7.9 Hz, Ar-H), 7.88–7.90 (d, 1H, J = 7.9 Hz, Ar-H), 8.37 (s, 1H, Ar-H), 8.42 (s, 1H, NH), 9.85 (s, 1H, NH), 10.68 (s, 1H, NH), 13.09 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.42 (C), 140.48 (C), 137.75 (C), 130.58 (C–Cl), 126.63(CH), 117.62 (CH), 116.74 (CH)], 185.28 (C⚌S), 157.63 (N⚌CH), Arom-C: [135.60 (C), 134.23 (C–Cl), 133.86 (CH), 133.18 (C–Cl), 132.54 (CH), 125.58 (CH)], 25.32 (CH₃); HRMS (m/z, ESI): M⁺ 412.28, [M+2] 414.28. Anal. Calcd. for C₁₆H₁₂Cl₃N₅S (Mol. Wt. 412.72): C, 46.56; H, 2.93; N, 16.97. Found: C, 46.54; H, 2.90; N, 16.95%.

2.1.4.13

2.1.4.13 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(2-methoxyphenyl) hydrazine carbothioamide (7m)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 72% yield; m.p. 192–193 °C; IR (cm⁻¹, KBr): 3312 (NH), 1204 (C⚌S), 1597 (C⚌N), 1620 (C⚌C), 1274 (C–O–C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H, CH₃), 3.84 (s, 3H, OCH₃), 6.90–7.26 (m, 4H, Ar-H), 7.42–7.50 (t, 1H, J = 8 Hz, Ar-H), 8.29 (s, 1H, Ar-H), 9.22 (s, 1H, NH), 10.27 (s, 1H, NH), 13.15 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.42 (C), 140.44 (C), 137.76 (C), 130.56 (C–Cl), 126.66(CH), 117.65 (CH), 116.74 (CH)], 185.15 (C⚌S), 156.93 (N⚌CH), Arom-C: [154.60 (C), 130.12 (C), 128.43 (CH), 127.98 (CH), 124.34 (CH), 119.38 (CH)], 58.64 (OCH ₃), 25.25 (CH₃); HRMS (m/z, ESI): M⁺ 373.15, [M+2] 375.15. Anal. Calcd. for C₁₇H₁₆ClON₅S (Mol. Wt. 373. 85): C, 54.61; H, 4.31; N, 18.73. Found: C, 50.43; H, 4.29; N, 18.71%.

2.1.4.14

2.1.4.14 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(3-methoxyphenyl) hydrazine carbothioamide (7n)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 70% yield; m.p. 190–192 °C; IR (cm⁻¹, KBr): 3277 (NH), 1202 (C⚌S), 1562 (C⚌N), 1610 (C⚌C), 1280 (C–O–C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (s, 3H, CH₃), 3.81 (s, 3H, OCH₃), 6.77–6.97 (m, 3H, Ar-H), 7.01–7.13 (t, 1H, J = 7.9 Hz, Ar-H), 7.21–7.50 (m, 2H, Ar-H), 7.66–7.68 (d, 1H, J = 8 Hz, Ar-H), 7.97 (s, 1H, Ar-H), 10.26 (s, 1H, NH), 11.25 (s, 1H, NH), 13.15 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.43 (C), 140.46 (C), 137.74 (C), 130.52 (C–Cl), 126.69(CH), 117.59 (CH), 116.76 (CH)], 185.26 (C⚌S), 156.98 (N⚌CH), Arom-C: [160.90 (C), 138.24 (C), 130.03 (CH), 120.18 (CH), 121.54 (CH), 119.35 (CH)], 58.67 (OCH ₃), 25.22 (CH₃); HRMS (m/z, ESI): M⁺ 373.36, [M+2] 375.36. Anal. Calcd. for C₁₇H₁₆ClON₅S (Mol. Wt. 373. 85): C, 54.61; H, 4.31; N, 18.73. Found: C, 50.43; H, 4.29; N, 18.71%.

2.1.4.15

2.1.4.15 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(benzoyl) hydrazine carbothioamide (7o)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 65% yield; m.p. 203–204 °C; IR (cm⁻¹, KBr): 3136 (NH), 1224 (C⚌S), 1577 (C⚌N), 1616 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (s, 3H, CH₃), 7.46 (d, 1H, J = 7.9 Hz, Ar-H), 7.52 (d, 1H, J = 8 Hz, Ar-H), 7.82–7.92 (t, 1H, J = 8 Hz, Ar-H), 8.02 (s, 1H, Ar-H), 9.89 (s, 1H, NH), 13.71 (s, 1H, NH), 13.95 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.35 (C), 140.54 (C), 137.64 (C), 130.48 (C–Cl), 126.55(CH), 117.49 (CH), 116.66 (CH)], 184.22 (C⚌S), 165.77 (C⚌O), 156.85 (N⚌CH), Arom-C: [135.23 (C), 134.84 (CH), 130.37 (CH, CH), 127.68 (CH, CH)], 25.33 (CH₃); HRMS (m/z, ESI): M⁺ 371.06, [M+2] 373.06. Anal. Calcd. for C₁₇H₁₄ClON₅S (Mol. Wt. 371. 86): C, 54.91; H, 3.79; N, 18.83. Found: C, 54.37; H, 3.77; N, 18.80%.

2.1.4.16

2.1.4.16 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(4-fluorophenyl) hydrazine carbothioamide (7p)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 75% yield; m.p. 195–197 °C; IR (cm⁻¹, KBr): 3246 (NH), 1217 (C⚌S), 1583 (C⚌N), 1618(C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (s, 3H, CH₃), 6.54–6.83 (m, 2H, Ar-H), 7.13–7.15 (d, 1H, J = 8 Hz, Ar-H), 7.42–8.05 (m, 4H, Ar-H), 9.38 (s, 1H, NH), 10.07 (s, 1H, NH), 13.03 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.40 (C), 140.55 (C), 137.68 (C), 130.51 (C–Cl), 126.58 (CH), 117.52 (CH), 116.67 (CH)], 184.30 (C⚌S), 156.95 (N⚌CH), Arom-C: [165.35 (C–F), 135.18 (C), 130.27 (CH, CH), 116.68 (CH, CH)], 25.36 (CH₃); HRMS (m/z, ESI): M⁺ 361.25, [M+2] 363.25. Anal. Calcd. for C₁₆H₁₃ClFN₅S (Mol. Wt. 361.82): C, 53.11; H, 3.62; N, 19.36. Found: C, 53.08; H, 3.60; N, 19.33%.

2.1.4.17

2.1.4.17 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(4-iodophenyl) hydrazine carbothioamide (7q)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 78% yield; m.p. 198–199 °C; IR (cm⁻¹, KBr): 3246 (NH), 1218 (C⚌S), 1583 (C⚌N), 1616 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (s, 3H, CH₃), 6.40–6.42 (d, 1H, J = 8 Hz, Ar-H), 7.15–7.27 (m, 2H, Ar-H), 7.43–7.87 (m, 2H, Ar-H), 7.95–7.98 (d, 1H, J = 7.9 Hz, Ar-H), 8.29 (s, 1H, Ar-H), 9.25 (s, 1H, NH), 11.37 (s, 1H, NH), 13.14 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.45 (C), 140.44 (C), 137.75 (C), 130.48 (C–Cl), 126.53 (CH), 117.57 (CH), 116.71 (CH)], 184.05 (C⚌S), 156.98 (N⚌CH), Arom-C: [139.21 (CH, CH), 138.33 (C), 127.56 (CH, CH), 95.32 (C–I)], 25.40 (CH₃); HRMS (m/z, ESI): M⁺ 468.93, [M+2] 470.93. Anal. Calcd. for C₁₆H₁₃ClIN₅S (Mol. Wt. 469.73): C, 40.91; H, 2.79; N, 14.91. Found: C, 40.88; H, 2.77; N, 14.89%.

2.1.4.18

2.1.4.18 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(4-tosyl) hydrazine carbothioamide (7r)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 73% yield; m.p. 190–192 °C; IR (cm⁻¹, KBr): 3240 (NH), 1218 (C⚌S), 1572 (C⚌N), 1610 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.38 (s, 3H, CH₃), 2.51 (s, 3H, CH₃), 7.28–7.74 (m, 6H, Ar-H) 7.98 (s, 1H, Ar-H), 8.23 (s, 1H, NH), 10.07 (s, 1H, NH), 12.23 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.46 (C), 140.62 (C), 137.74 (C), 130.55 (C–Cl), 126.64 (CH), 117.58 (CH), 116.70 (CH)], 184.28 (C⚌S), 157.15 (N⚌CH), Arom-C: [142.16 (C), 141.78 (C), 130.54 (CH, CH), 127.48 (CH, CH)], 35.65 (CH₃), 25.46 (CH₃); HRMS (m/z, ESI): M⁺ 357.18, [M+2] 359.18. Anal. Calcd. for C₁₇H₁₆ClN₅S (Mol. Wt. 357. 86): C, 57.06; H, 4.51; N, 19.57. Found: C, 57.00; H, 4.48; N, 19.55%.

2.1.4.19

2.1.4.19 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(2,3-dichlorophenyl) hydrazine carbothioamide (7s)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 68% yield; m.p. 182–184 °C; IR (cm⁻¹, KBr): 3296 (NH), 1217 (C⚌S), 1572 (C⚌N), 1583 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (s, 3H, CH₃), 6.51–6.53 (d, 1H, J = 8 Hz, Ar-H), 7.15–7.17 (d, 1H, J = 7.9 Hz, Ar-H), 7.19–8.30 (m, 3H, Ar-H), 8.48 (s, 1H, Ar-H), 9.55 (s, 1H, NH), 10.41 (s, 1H, NH), 12.92 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.34 (C), 140.69 (C), 137.77 (C), 130.54 (C–Cl), 126.69 (CH), 117.63 (CH), 116.74 (CH)], 184.16 (C⚌S), 157.22 (N⚌CH), Arom-C: [139.03 (C), 138.36 (C–Cl), 134.54 (C–Cl), 134.50 (CH), 133.22 (CH), 130.47 (CH)], 25.55 (CH₃); HRMS (m/z, ESI): M⁺ 411.92, [M+2] 413.92. Anal. Calcd. for C₁₆H₁₂Cl₃N₅S (Mol. Wt. 412.72): C, 46.56; H, 2.93; N, 16.97. Found: C, 46.54; H, 2.90; N, 16.95%.

2.1.4.20

2.1.4.20 (E)-2-[1-(5-Chloro-1H-benzo[d]imidazol-2-yl)ethylidene] N-(3,4-dichlorophenyl) hydrazine carbothioamide (7t)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 65% yield; m.p. 183–184 °C; IR (cm⁻¹, KBr): 3321 (NH), 1217 (C⚌S), 1581 (C⚌N), 1618 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (s, 3H, CH₃), 7.31–7.33 (d, 1H, J = 7.9 Hz, Ar-H), 7.54–7.83 (m, 4H, Ar-H), 8.46 (s, 1H, Ar-H), 9.65 (s, 1H, NH), 10.02 (s, 1H, NH), 12.52 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [152.56(C), 140.75 (C), 137.80 (C), 130.55 (C–Cl), 126.71 (CH), 117.68 (CH), 116.77 (CH)], 184.32 (C⚌S), 157.30 (N⚌CH), Arom-C: [139.12 (C), 138.39 (CH), 134.58 (C–Cl), 133.42 (C–Cl), 133.12 (CH), 126.03 (CH)], 25.42 (CH₃); HRMS (m/z, ESI): M⁺ 411.95, [M+2] 413.95. Anal. Calcd. for C₁₆H₁₂Cl₃N₅S (Mol. Wt. 412.72): C, 46.56; H, 2.93; N, 16.97. Found: C, 46.54; H, 2.90; N, 16.95%.

2.1.5

2.1.5 General procedure illustrating the synthesis of (E)-2-[1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-hydrazine carbothioamide (8a–8t)

Another series of compounds (8a–8t) were also synthesized and purified similarly by the general method described in Section 2.1.4, taking compound 4b as a starting material. (Refer Scheme 1).

Close

Scheme 1 Synthesis route for desired thiosemicarbazone derivatives.

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2.1.5.1

2.1.5.1 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene]hydrazine carbothioamide (8a)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a light brown solid; 77% yield; m.p. 216 °C; IR (cm⁻¹, KBr): 3354 (NH), 1215 (C⚌S), 1535 (C⚌N), 1596 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.48 (s, 3H, CH₃), 7.16–7.18(d, 1H, J = 8 Hz, Ar-H), 7.39–7.42 (d, 1H, J = 8.5 Hz, Ar-H), 7.77–7.95 (m, 2H, Ar-H), 8.64 (s, 2H, NH₂), 10.70 (s, 1H, NH), 12.86 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [153.24 (C), 136.25 (C, C), 128.57 (CH, CH), 118.63 (CH, CH)], 178.19 (C⚌S), 157.35 (N⚌CH), 25.24 (CH₃); HRMS (m/z, ESI): M⁺ 233.03, [M+1] 234.03. Anal. Calcd. for C₁₀H₁₁N₅S (Mol. Wt. 233.29): C, 51.48; H, 4.75; N, 30.02. Found: C, 51.42; H, 4.70; N, 29.98.%.

2.1.5.2

2.1.5.2 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-phenyl hydrazine carbothioamide (8b)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown color solid in 82% yield and m.p. at 165–167 °C; IR (cm⁻¹, KBr): 3225 (NH), 1202 (C⚌S), 1519 (C⚌N), 1599 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.48 (s, 3H, CH₃), 7.27–7.29 (d, 1H, J = 7.9 Hz, Ar-H), 7.40–7.44 (t, 1H, J = 7.5 Hz, Ar-H), 7.51–7.54 (d, 1H, J = 8.5 Hz, Ar-H), 7.59–7.62 (d, 1H, J = 8 Hz, Ar-H), 8.35–8.37 (d, 1H, J = 8 Hz, Ar-H), 10.38 (s, 1H, NH), 11.07 (s, 1H, NH), 13.05 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [153.28 (C), 136.30 (C, C), 128.60 (CH, CH), 118.68 (CH, CH)], 185.14 (C⚌S), 157.44 (N⚌CH), Arom-C: [140.10 (C), 132.33 (CH, CH), 130.67 (CH), 127.46 (CH)], 25.36 (CH₃); HRMS (m/z, ESI): M⁺ 309.12, [M+1] 310.13. Anal. Calcd. for C₁₆H₁₅N₅S (Mol. Wt. 309.38): C, 62.11; H, 4.89; N, 22.64. Found: C, 62.08; H, 4.85; N, 22.62%.

2.1.5.3

2.1.5.3 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-ethyl hydrazine carbothioamide (8c)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a brown solid; 69% yield; m.p. 226–228 °C; IR (cm⁻¹, KBr): 3437 (NH), 1213 (C⚌S), 1525 (C⚌N), 1589 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H, CH₃), 1.14–1.22 (t, 3H, J = 8 Hz, CH ₃), 3.59–3.92 (m, 2H, CH₂) 7.20–7.82 (m, 4H, Ar-H), 9.01 (s, 1H, NH), 10.68 (s, 1H, NH), 12.69 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.69 (C), 136.45 (C, C), 128.65 (CH, CH), 118.73 (CH, CH)], 178.31 (C⚌S), 157.48 (N⚌CH), 46.07 (CH₂), 28.49 (CH₃), 25.46 (CH₃); HRMS (m/z, ESI): M⁺ 261.11, [M+1] 262.11. Anal. Calcd. for C₁₂H₁₅N₅S (Mol. Wt. 261.34): C, 55.15; H, 5.79; N, 26.80. Found: C, 55.13; H, 5.76; N, 26.78%.

2.1.5.4

2.1.5.4 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(n-butyl) hydrazine carbothioamide (8d)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a brown solid; 68% yield; m.p. 210 °C; IR (cm⁻¹, KBr): 3453 (NH), 1216 (C⚌S), 1419 (C⚌N), 1541 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 1.26–1.97 (m, 5H, CH₃CH₂), 2.46 (s, 3H, CH ₃), 4.03–4.45 (m, 2H, CH₂), 7.21–7.68 (m, 6H, Ar-H), 8.98 (s, 1H, NH), 10.65 (s, 1H, NH), 12.78 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.72 (C), 136.50 (C, C), 128.70 (CH, CH), 118.78 (CH, CH)], 178.71 (C⚌S), 157.56 (N⚌CH), n-butyl:[46.22 (CH₂), 35.79 (CH₂), 30.66 (CH₂), 25.39 (CH₃)], 25.43 (CH₃); HRMS (m/z, ESI): M⁺ 289.14, [M+1] 290.14. Anal. Calcd. for C₁₄H₁₉N₅S (Mol. Wt. 289.39): C, 58.10; H, 6.62; N, 24.20. Found: C, 58.02; H, 6.60; N, 24.15%.

2.1.5.5

2.1.5.5 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-cyclohexyl hydrazine carbothioamide (8e)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a brown solid; 72% yield; m.p. 214 °C; IR (cm⁻¹, KBr): 3369 (NH), 1211 (C⚌S), 1500 (C⚌N), 1581 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆):δ 1.26–1.91 (m, 11H, cyclohex), 2.50 (s, 3H, CH ₃), 7.21–7.24 (d, 1H, J = 7.9 Hz, Ar-H), 7.51–7.54 (d, 1H, J = 8.5 Hz, Ar-H), 7.68–7.70 (d, 1H, J = 8 Hz, Ar-H), 8.58 (s, 1H, NH), 10.53 (s, 1H, NH), 12.76 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.74 (C), 136.54 (C, C), 128.75 (CH, CH), 118.80 (CH, CH)], 178.77 (C⚌S), 157.66 (N⚌CH), cyclohexyl C:[60.21 (C), 45.66 (CH_2,CH₂)], 36.32 (CH₂), 30.33 (CH₂, CH₂)], 25.45 (CH₃); HRMS (m/z, ESI): M⁺ 315.15, [M+1] 316.15. Anal. Calcd. for C₁₆H₂₁N₅S (Mol. Wt. 315.43): C, 60.92; H, 6.71; N, 22.20. Found: C, 60.90; H, 6.68; N, 22.15.%.

2.1.5.6

2.1.5.6 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(4-chlorophenyl) hydrazine carbothioamide (8f)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 62% yield; m.p. 175–176 °C; IR (cm⁻¹, KBr): 3458 (NH), 1201 (C⚌S), 1541 (C⚌N), 1597 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H, CH₃), 7.10–7.12 (d, 1H, J = 8 Hz, Ar-H), 7.21–7.70 (m, 6H, Ar-H), 9.24 (s, 1H, NH), 11.23 (s, 1H, NH), 13.03 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.72 (C), 136.59 (C, C), 128.70 (CH, CH), 118.75 (CH, CH)], 185.07 (C⚌S), 157.46 (N⚌CH), Arom-C: [140.23 (C), 135.67 (C–Cl), 130.12 (CH, CH), 128.88 (CH, CH)], 25.48 (CH₃); HRMS (m/z, ESI): M⁺ 343.07, [M+2] 345.07. Anal. Calcd. for C₁₆H₁₄ClN₅S (Mol. Wt. 343.83): C, 55.89; H, 4.10; N, 20.37. Found: C, 55.85; H, 4.05; N, 20.35%.

2.1.5.7

2.1.5.7 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(4-nitrophenyl) hydrazine carbothioamide (8g)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 60% yield; m.p. 204–206 °C; IR (cm⁻¹, KBr): 3203 (NH), 1199 (C⚌S), 1546 (C⚌N), 1595 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.56 (s, 3H, CH₃), 7.12–7.15 (d, 1H, J = 8.9 Hz, Ar-H), 7.23–7.26 (d, 1H, J = 9 Hz, Ar-H), 7.72–7.75 (d, 1H, J = 8.9 Hz, Ar-H), 7.85–7.88 (d, 1H, J = 8.9 Hz, Ar-H), 8.17–8.20 (d, 1H, J = 8 Hz, AR-H), 9.63 (s, 1H, NH), 10.67 (s, 1H, NH), 12.94 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.78 (C), 136.63 (C, C), 128.74 (CH, CH), 118.81 (CH, CH)], 185.16 (C⚌S), 157.55 (N⚌CH), Arom-C: [150.06 (C), 152.27 (C–NO₂), 130.22 (CH, CH), 130.58 (CH, CH)], 25.51 (CH₃); HRMS (m/z, ESI): M⁺ 354.08, [M+1] 355.08. Anal. Calcd. for C₁₆H₁₄N₆O₂S (Mol. Wt. 354.38): C, 54.23; H, 3.98; N, 23.71. Found: C, 54.20; H, 3.95; N, 23.66%.

2.1.5.8

2.1.5.8 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(4-methoxyphenyl) hydrazine carbothioamide (8h)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 78% yield; m.p. 196–198 °C; IR (cm⁻¹, KBr): 3444 (NH), 1202 (C⚌S), 1539 (C⚌N), 1602 (C⚌C), 1249 (C–O–C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.51 (s, 3H, CH₃), 3.79 (s, 3H, OCH₃), 6.51–6.55 (d, 1H, J = 9.5 Hz, Ar-H), 7.01–7.05 (d, 1H, J = 9.5 Hz, Ar-H), 7.20–7.24 (d, 1H, J = 9.5 Hz, Ar-H), 7.66–7.68 (d, 1H, J = 8 Hz, Ar-H), 8.62–8.84 (d, 1H, J = 8 Hz, Ar-H), 10.38 (s, 1H, NH), 11.01 (s, 1H, NH), 12.87 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.75 (C), 136.65 (C, C), 128.76 (CH, CH), 118.75 (CH, CH)], 185.34 (C⚌S), 157.59 (N⚌CH), Arom-C: [162.45 (C–OCH₃), 142.37 (C), 130.28 (CH, CH), 120.08 (CH, CH)], 58.50 (OCH₃), 25.54 (CH₃); HRMS (m/z, ESI): M⁺ 339.12, [M+1] 340.12. Anal. Calcd. for C₁₇H₁₇ON₅S (Mol. Wt. 339.39): C, 60.16; H, 5.05; N, 20.63. Found: C, 60.10; H, 4.98; N, 20.60%.

2.1.5.9

2.1.5.9 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(isopropyl) hydrazine carbothioamide (8i)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a brown solid; 75% yield; m.p. 224–226 °C; IR (cm⁻¹, KBr): 3448 (NH), 2978(C(CH₃)), 1211 (C⚌S), 1498 (C⚌N), 1530 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 1.30–1.33 (d, 6H, J = 9.5 Hz, (CH ₃)₂), 2.50 (s, 3H, CH₃), 4.36–4.64 (m, 1H, CH), 7.12–7.69 (m, 4H, Ar-H), 8.61 (s, 1H, NH), 10.68 (s, 1H, NH), 12.78 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.77 (C), 136.62 (C, C), 128.72 (CH, CH), 118.78 (CH, CH)], 179.33 (C⚌S), 157.60 (N⚌CH), iso-propyl-C:[58.67 (CH), 36.56 (CH_3,CH₃)], 25.56 (CH₃); HRMS (m/z, ESI): M⁺ 275.10, [M+1] 276.10. Anal. Calcd. for C₁₃H₁₇N₅S (Mol. Wt. 275.37): C, 56.70; H, 6.22; N, 25.43. Found: C, 56.67; H, 6.19; N, 25.40%.

2.1.5.10

2.1.5.10 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(tert-butyl) hydrazine carbothioamide (8j)

The reaction mass was heated in MW at 180 W with a total irradiation time of 25 min. The product was a brown solid; 72% yield; m.p. 220–222 °C; IR (cm⁻¹, KBr): 3381 (NH), 1230 (C⚌S), 1514 (C⚌N), 1560 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 1.37–1.71 (m, 9H, (CH₃)₃), 2.50 (s, 3H, CH₃), 7.12–7.98 (m, 8H, Ar-H), 8.45–8.48 (d, 1H, J = 8.5 Hz, Ar-H), 10.28 (s, 1H, NH), 12.82 (s, 1H, NH), 13.78 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.67 (C), 136.60 (C, C), 128.68 (CH, CH), 118.73 (CH, CH)], 179.27 (C⚌S), 157.55 (N⚌CH), t-butyl-C:[65.20 (C), 32.48 (CH_3,CH_3,CH₃)], 25.52 (CH₃); HRMS (m/z, ESI): M⁺ 289.14, [M+1] 290.14. Anal. Calcd. for C₁₄H₁₉N₅S (Mol. Wt. 289.39): C, 58.10; H, 6.62; N, 24.20. Found: C, 58.05; H, 6.60; N, 24.18%.

2.1.5.11

2.1.5.11 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(benzyl) hydrazine carbothioamide (8k)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 60% yield; m.p. 219–220 °C; IR (cm⁻¹, KBr): 3383 (NH), 1211 (C⚌S), 1523 (C⚌N), 1573 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H, CH₃), 4.28–4.45 (m, 2H, CH₂), 7.21–7.69 (m, 4H, Ar-H), 8.43–8.58 (d, 1H, J = 9.5 Hz, Ar-H), 9.05 (s, 1H, NH), 10.53 (s, 1H, NH), 12.77 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.68 (C), 136.66 (C, C), 128.70 (CH, CH), 118.75 (CH, CH)], 183.30 (C⚌S), 157.58 (N⚌CH), Arom-C: [142.35 (C), 132.38 (CH, CH), 131.65 (CH, CH), 130.85 (CH)], 55.08 (CH₂), 25.32 (CH₃); HRMS (m/z, ESI): M⁺ 323.12, [M+1] 324.12. Anal. Calcd. for C₁₇H₁₇N₅S (Mol. Wt. 323.41): C, 63.13; H, 5.30; N, 21.65. Found: C, 63.10; H, 5.25; N, 21.62%.

2.1.5.12

2.1.5.12 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(2,4-dichlorophenyl) hydrazine carbothioamide (8l)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 68% yield; m.p. 185–187 °C; IR (cm⁻¹, KBr): 3389 (NH), 1240 (C⚌S), 1545 (C⚌N), 1583 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆):δ 2.50 (s, 3H, CH₃), 7.28–7.81 (m, 5H, Ar-H), 8.39 (d, 1H, Ar-H), 9.55 (s, 1H, Ar-H), 10.39 (s, 1H, NH), 11.39 (s, 1H, NH), 12.77 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.62 (C), 136.56 (C, C), 128.72 (CH, CH), 118.77 (CH, CH)], 185.40 (C⚌S), 157.68 (N⚌CH), Arom-C: [138.15 (C), 137.43 (C–Cl), 136.85 (CH), 135.65 (C–Cl), 134.88 (CH), 126.25 (CH)], 25.44 (CH₃); HRMS (m/z, ESI): M⁺ 377.57, [M+2] 379.57. Anal. Calcd. for C₁₆H₁₃Cl₂N₅S (Mol. Wt. 378.27): C, 50.80; H, 3.46; N, 18.51. Found: C, 50.75; H, 3.43; N, 18.45%.

2.1.5.13

2.1.5.13 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(2-methoxyphenyl) hydrazine carbothioamide (8m)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 65% yield; m.p. 194–196 °C; IR (cm⁻¹, KBr): 3296 (NH), 1242 (C⚌S), 1575 (C⚌N), 1599 (C⚌C), 1275 (C–O–C); ¹H NMR (400 MHz, DMSO-d₆):δ 2.50 (s, 3H, CH₃), 3.84 (s, 3H, OCH₃), 6.63–7.65 (d, 1H, J = 8 Hz, Ar-H), 7.13–7.89 (m, 1H, Ar-H), 7.93–7.95 (d, 1H, J = 7.9 Hz, Ar-H), 7.95–7.99 (t, 1H, J = 7.9 Hz, Ar-H), 8.02–8.06 (d, 1H, J = 8 Hz, Ar-H), 8.13–8.32 (d, 1H, J = 8.5 Hz, Ar-H), 8.53–8.76 (d, 1H, J = 8.2 Hz, Ar-H), 9.84 (s, 1H, NH), 10.47 (s, 1H, NH), 12.83 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.65 (C), 136.52 (C, C), 128.77 (CH, CH), 118.79 (CH, CH)], 185.57 (C⚌S), 157.71 (N⚌CH), Arom-C: [160.44 (C–OCH₃), 135.13 (CH), 134.84 (C), 134.18 (CH), 130.56 (CH), 120.24 (CH)], 62.45 (OCH₃), 25.56 (CH₃); HRMS (m/z, ESI): M⁺ 339.16, [M+1] 340.16. Anal. Calcd. for C₁₇H₁₇ON₅S (Mol. Wt. 339.41): C, 60.16; H, 5.05; N, 20.63. Found: C, 60.14; H, 5.00; N, 20.60%.

2.1.5.14

2.1.5.14 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(3-methoxyphenyl) hydrazine carbothioamide (8n)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 69% yield; m.p. 194–196 °C; IR (cm⁻¹, KBr): 3273 (NH), 1195 (C⚌S), 1576 (C⚌N), 1598 (C⚌C), 1280 (C–O–C); ¹H NMR (400 MHz, DMSO-d₆):δ 2.50 (s, 3H, CH₃), 3.80 (s, 3H, CH₃), 6.66 (d, 1H, J = 7.9 Hz, Ar-H), 6.88 (d, 1H, J = 8.5 Hz, Ar-H), 7.13–7.70 (m, 6H, Ar-H), 9.17 (s, 1H, NH), 10.42 (s, 1H, NH), 11.08 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.45 (C), 136.48 (C, C), 128.72 (CH, CH), 118.74 (CH, CH)], 185.53 (C⚌S), 157.65 (N⚌CH), Arom-C: [163.58 (C–OCH₃), 140.22 (C), 132.68 (CH), 120.13 (CH), 118.55 (CH), 116.45 (CH)], 65.20 (OCH₃), 25.36 (CH₃); HRMS (m/z, ESI): M⁺ 339.09, [M+1] 340.09. Anal. Calcd. for C₁₇H₁₇ON₅S (Mol. Wt. 339.41): C, 60.16; H, 5.05; N, 20.63. Found: C, 60.14; H, 5.00; N, 20.60%.

2.1.5.15

2.1.5.15 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(benzoyl) hydrazine carbothioamide (8o)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 60% yield; m.p. 205–207 °C; IR (cm⁻¹, KBr): 3145 (NH), 1228 (C⚌S), 1580 (C⚌N), 1612 (C⚌C), 1725(C⚌O); ¹H NMR (400 MHz, DMSO-d₆):δ 2.51 (s, 3H, CH₃), 7.14–7.92 (m, 5H, Ar-H), 8.02 (d, 1H, J = 8 Hz, Ar-H), 9.87 (s, 1H, NH), 13.74 (s, 1H, NH), 13.86 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.48 (C), 136.52 (C, C), 128.75 (CH, CH), 118.78 (CH, CH)], 185.44 (C⚌S), 172.45 (C⚌O), 157.62 (N⚌CH), Arom-C: [139.33 (C), 138.11 (CH), 132.65 (CH, CH), 131.83 (CH, CH)], 25.46 (CH₃); HRMS (m/z, ESI): M⁺ 337.14, [M+1] 338.14. Anal. Calcd. for C₁₇H₁₅ON₅S (Mol. Wt. 337.39): C, 60.52; H, 4.48; N, 20.76. Found: C, 60.49; H, 4.45; N, 20.73%.

2.1.5.16

2.1.5.16 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(4-fluorophenyl) hydrazine carbothioamide (8p)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 73% yield; m.p. 198–199 °C; IR (cm⁻¹, KBr): 3313 (NH), 1213 (C⚌S), 1548 (C⚌N), 1583 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆):δ 2.51 (s, 3H, CH₃), 6.68 (d, 1H, J = 7.5 Hz, Ar-H), 7.12 (d, 1H, J = 8 Hz, Ar-H), 7.46–7.98 (m, 4H, Ar-H), 9.16 (s, 1H, NH), 10.25 (s, 1H, NH), 13.03 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.52 (C), 136.60 (C, C), 128.80 (CH, CH), 118.82 (CH, CH)], 185.53 (C⚌S), 157.65 (N⚌CH), Arom-C: [166.23 (C–F), 138.33 (C), 132.12 (CH, CH), 118.89 (CH, CH)], 25.56 (CH₃); HRMS (m/z, ESI): M⁺ 327.10, [M+1] 328.10. Anal. Calcd. for C₁₆H₁₄FN₅S (Mol. Wt. 327.37): C, 58.70; H, 4.31; N, 21.39. Found: C, 58.65; H, 4.27; N, 21.36%.

2.1.5.17

2.1.5.17 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(4-iodophenyl) hydrazine carbothioamide (8q)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 75% yield; m.p. 197–199 °C; IR(cm⁻¹, KBr): 3294 (NH), 1202 (C⚌S), 1548 (C⚌N), 1596 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆):δ 2.50 (s, 3H, CH₃), 6.41–6.44 (d, 1H, J = 9 Hz, Ar-H), 7.12–7.80 (m, 5H, Ar-H), 9.25 (s, 1H, NH), 10.43 (s, 1H, NH), 12.94 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.45 (C), 136.67 (C, C), 128.82 (CH, CH), 118.85 (CH, CH)], 185.48 (C⚌S), 157.63 (N⚌CH), Arom-C: [143.22 (CH, CH), 142.97 (C), 134.49 (CH, CH), 95.77 (C–I)], 25.67 (CH₃); HRMS (m/z, ESI): M⁺ 435.02, [M+1] 436.02. Anal. Calcd. for C₁₆H₁₄IN₅S (Mol. Wt. 435.28): C, 44.15; H, 3.24; N, 16.09. Found: C, 44.10; H, 3.22; N, 16.02%.

2.1.5.18

2.1.5.18 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(4-tosyl) hydrazine carbothioamide (8r)

The reaction mass was heated in MW at 180 W with a total irradiation time of 30 min. The product was a brown solid; 70% yield; m.p. 195–197 °C; IR (cm⁻¹, KBr): 3298 (NH), 1234 (C⚌S), 1548 (C⚌N), 1585 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆):δ 2.37 (s, 3H, CH₃), 2.51 (s, 3H, CH₃), 7.10–7.48 (m, 1H, Ar-H), 7.68–7.72 (d, 1H, J = 9 Hz, Ar-H), 7.79 (d, 1H, J = 7.9 Hz, Ar-H), 7.89 (d, 1H, J = 7.9 Hz, Ar-H), 9.12 (s, 1H, NH), 10.15 (s, 1H, NH), 12.34 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.48 (C), 136.68 (C, C), 128.78 (CH, CH), 118.82 (CH, CH)], 185.54 (C⚌S), 157.62 (N⚌CH), Arom-C: [142.32 (C–CH₃), 135.67 (C), 130.56 (CH, CH), 126.47 (CH, CH)], 32.46 (CH₃), 25.67 (CH₃); HRMS (m/z, ESI): M⁺ 323.06, [M+1] 324.06. Anal. Calcd. for C₁₇H₁₇N₅S (Mol. Wt. 323.41): C, 63.13; H, 5.30; N, 21.65. Found: C, 63.10; H, 5.25; N, 21.63%.

2.1.5.19

2.1.5.19 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(2,3-dichlorophenyl) hydrazine carbothioamide (8s)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 66% yield; m.p. 185–187 °C; IR (cm⁻¹, KBr): 3246 (NH), 1180 (C⚌S), 1533 (C⚌N), 1594 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆):δ 2.5 (s, 3H, CH₃), 7.12 (d, 1H, J = 8.9 Hz, Ar-H), 7.35 (d, 1H, J = 9.5 Hz, Ar-H), 7.43 (d, 1H, J = 9 Hz, Ar-H), 8.27 (d, 1H, J = 8.9 Hz, Ar-H), 9.70 (s, 1H, NH), 10.38 (s, 1H, NH), 12.92 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.52 (C), 136.70 (C, C), 128.76 (CH, CH), 118.81 (CH, CH)], 185.59 (C⚌S), 157.66 (N⚌CH), Arom-C: [142.18 (C), 141.35 (C–Cl), 140.73 (C–Cl), 139.97 (CH), 135.05 (CH), 130.28 (CH)], 25.66 (CH₃); HRMS (m/z, ESI): M⁺ 377.37, [M+2] 379.38. Anal. Calcd. for C₁₆H₁₃Cl₂N₅S (Mol. Wt. 378.27): C, 50.80; H, 3.46; N, 18.51. Found: C, 50.75; H, 3.43; N, 18.47%.

2.1.5.20

2.1.5.20 (E)-2-[1-(1H-Benzo[d]imidazol-2-yl)ethylidene] N-(3,4-dichlorophenyl) hydrazine carbothioamide (8t)

The reaction mass was heated in MW at 180 W with a total irradiation time of 35 min. The product was a brown solid; 68% yield; m.p. 186–188 °C; IR (cm⁻¹, KBr): 3296 (NH), 1213 (C⚌S), 1566 (C⚌N), 1598 (C⚌C); ¹H NMR (400 MHz, DMSO-d₆):δ 2.50 (s, 3H, CH₃), 6.52–6.54 (d, 1H, J = 8 Hz, Ar-H), 6.84 (d, 1H, J = 8 Hz, Ar-H), 7.17–7.98 (m, 4H, Ar-H), 8.07–8.10 (d, 1H, J = 8.5 Hz, Ar-H), 9.40 (s, 1H, NH), 10.04 (s, 1H, NH), 12.56 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ Benzimidazole C: [151.57 (C), 136.74 (C, C), 128.79 (CH, CH), 118.77 (CH, CH)], 185.62 (C⚌S), 157.68 (N⚌CH), Arom-C: [140.35 (C), 139.69 (CH), 135.85 (C–Cl), 135.25 (C–Cl), 135.08 (CH), 125.18 (CH)], 25.58 (CH₃); HRMS (m/z, ESI): M⁺ 377.45, [M+2] 379.47. Anal. Calcd. for C₁₆H₁₃Cl₂N₅S (Mol. Wt. 378.27): C, 50.80; H, 3.46; N, 18.51. Found: C, 50.75; H, 3.43; N, 18.47%.

3 Results and discussion

In the present work, thiosemicarbazone derivatives containing the benzimidazole moiety were prepared according to reaction as in Scheme 1. The condensation reaction between commercially available substituted benzene-1,2-diamine (2a–2b) with lactic acid (1) gives 1-(substituted-1H-benzimidazol-yl) ethanol (3a–3b) (refer Scheme 1) in quantitative yield. Originally, this reaction was performed conventionally for 4 h in a nitrogen environment at 140–150 °C (Mylonas and Mamalis, 2005). Patel et al. (2013) had developed this reaction in microwave where they gave microwave irradiation at 140 °C (300 W). Due to this compounds (3a–3b) were synthesized in 35 min only without any by-products. An introduction of ethylene glycol in reaction mass was justified for the temperature enhancement (because of its high dielectric constant of 38.66) during the reaction so that reaction could reach its optimum temperature within the short period of time. The IR spectra of compounds (3a–3b) showed sharp absorption bands, appearing between 3350 and 3430 cm⁻¹, was attributed to the NH function of compounds and other, observed between 1111 and 1130 cm⁻¹, was assigned to C–O stretching frequency. The ¹H NMR spectrum of compounds (3a–3b) exhibited two different signals between 5.60 and 5.80 ppm (OH) and near 13.0 ppm (NH), respectively. The signals of aromatic proton of compound were observed between 7.14 and 8.54 ppm.

Further oxidation of the sec-alcohol (3a–3b) gave the corresponding ketone (4a–4b) (refer Scheme 1). Here, we used bleach, which is a cheap, nontoxic reagent whose active component sodium hypochlorite (NaOCl) is an excellent oxidizing agent, instead of original reagent chromium trioxide (CrO₃). In earlier reported method (Patel et al., 2013) the product loss was occurring due to the usage of CrO₃ which has overcome by using NaOCl as an oxidizing agent in mild acidic condition also the previous harmful waste product has been taken care by this change. The spectral data of 4a–4b showed IR band near 1670 cm⁻¹ confirming the formation of ketone (C⚌O). Further, ¹H NMR of compounds 4a–4b shown the presence of a singlet between 13.0 and 13.25 ppm indicating the amino group present (NH), 7.28–8.50 ppm shown the presence of aromatic protons.

The N⁴-monosubstituted thiosemicarbazides (6a–6t) were synthesized as outlined in Scheme 1. Previously, these compounds were synthesized conventionally at room temperature (Mylonas and Mamalis, 2005; Patel et al.). We have performed this reaction under microwave irradiation which was more rapid and gave ample amount of pure product. Thiosemicarbazides were formed from hydrazine and various isothiocyanates (5a–5t) which were commercially available in the market (Mylonas and Mamalis, 2005). Patel et al. (2013) have already synthesized 7a–7e by simple condensation reaction between compound 4a and different thiosemicarbazides (6a–6e). The time for this conventional condensation was approx. 4 h. In this present work the method is modified by usage of microwave irradiation to increase the rate of reaction. A series of final compounds 7a–7t were synthesized by condensation reaction between compound 4a and 6a–6t, while 8a–8t were synthesized by condensation reaction between compound 4b and 6a–6t. The product obtained from the reaction was at its best purity without any by-products. Title compounds 7a–7t and 8a–8t showed IR bands at 3250–3460 cm⁻¹ which confirmed the formation of the benzimidazole ring which was further substantiated with the help of ¹H NMR data with the peaks at 12.50–13.30 ppm and 9.20–10.98 ppm for the protons of the amino group. Peaks between 7.05 and 8.70 ppm were observed for respective aromatic protons. Synthesis of final compounds was also confirmed by ¹³C NMR data, peaks between 179 and 186 ppm have confirmed the formation of C⚌S. Peaks between 115–165 and 25.20–25.65 ppm confirmed the presence of aromatic carbons and methyl carbon, respectively. Title compounds were further confirmed by mass spectral data and elemental analysis.

The synthesized compounds 7a–7t and 8a–8t were screened for their in vitro antimalarial activity against P. falciparum by measuring the minimum inhibitory concentration (μg/mL) as shown in Table 1, respectively. Compounds 7o (0.023 μg/mL), 7p (0.003 μg/mL), 7q (0.012 μg/mL), 7r (0.025 μg/mL) and 7s (0.005 μg/mL) against standard Chloroquine (0.020 μg/mL) showed excellent activity. Compounds 7a (0.095 μg/mL), 7e (0.047 μg/mL), 7g (0.098 μg/mL), 7k (0.093 μg/mL), 8a (0.088 μg/mL), 8e (0.053 μg/mL), 8h (0.073 μg/mL), 8i (0.057 μg/mL) and 8n (0.096 μg/mL) showed moderate activity against Chloroquine (0.020 μg/mL). Compounds 7f (0.26 μg/mL) and 7h (0.15 μg/mL) against standard quinine (0.268 μg/mL) showed excellent activity, while remaining compounds showed moderate to very less activity against quinine (0.268 μg/mL). As structure activity relationship (SAR) study of all compounds was taken into account, it was observed that compounds having electron withdrawing functional groups like chloro, fluoro and iodo showed excellent activity. Compounds containing moderate electron releasing groups like substituted methoxy exhibited good antimalarial potency. The presence of some other groups like cyclohexyl and isopropyl seems to be important for the antimalarial activity.

4 Conclusion

We have demonstrated that the thiosemicarbazone derivatives 7a–7t and 8a–8t can be synthesized by making modifications in the reported method. The production was successful with less time duration and improved quality and quantity than the old method. Environmental issues are also resolved because of the use of the microwave and the green oxidizing agent NaOCl (Bleach) in the method. A common parameter was observed between all active compounds that they all contained electron withdrawing functional groups in their moiety. Among the compounds tested 7o, 7p, 7q, 7r, 7s, 8a, 8e, 8i, 8n and 8h exhibited good antimalarial activity in vitro. Finally, it is conceivable that further derivatization of such compounds with high and moderate electron withdrawing functional groups will be of interest with good hope to get more selective antimalarial agents.