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Synthesis, characterization, anticancer, anti-inflammatory activities, and docking studies of 3,5-disubstituted thiadiazine-2-thiones

  • Haleema Ali , Rasool Khan EMAIL logo , Xiandao Pan , Farzana Shaheen , Almas Jabeen , Abdur Rauf EMAIL logo , Muhammad Shah , Umer Rashid , Yahya S. Al-Awthan , Omar S. Bahattab , Mohammed A. Al-Duais and Mohammad S. Mubarak
Published/Copyright: March 14, 2023
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Green Processing and Synthesis
From the journal Green Processing and Synthesis Volume 12 Issue 1

Abstract

In the search for potent bioactive compounds, a series of tetrahydro-2H-1,3,5-thiadiazine-2-thiones (1–13) were synthesized in good yield and characterized by means of 1H NMR, 13C NMR, and mass spectral data. The anticancer activity of the compounds was evaluated against HeLa cell line and anti-inflammatory potential via nitric oxide (NO) inhibition. Among the screened compounds, 2-(5-(3-methoxypropyl)-6-thioxo-1,3,5-thiadiazinan-3-yl) propionic acid (3), 2-(5-cyclopropyl-6-thioxo-1,3,5-thiadiazinan-3-yl) propionic acid (5), 2-(5-cyclopropyl)-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid (6), and 2-(5-butyl-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid (9) were the most potent against HeLa cell line with IC50 values <4 µM, whereas the rest of the series exhibited moderate-to-good activities. All the compounds were potent NO inhibitors with IC50 values ranging from <0.4 to 14.9 µM. Docking studies, binding orientations, and interaction plots showed strong interaction of the studied compounds with the inducible NO synthase enzyme via strong hydrogen bonds and hydrophobic interactions, which authenticate the in vitro results. These newly synthesized compounds could lead to the discovery of anticancer drugs.

Keywords: thiadiazine thione; inducible nitric oxide synthase; HeLa cell line; docking studies

1 Introduction

The recent call of World Health Organization for the elimination of cervical cancer as a global health concern prompted medicinal chemists to search and develop potent molecules for treating cancer [1]. Cervical cancer is the fourth most common cancer in women, and the leading cause of death in low-resource countries [2]. According to recent research in chemotherapy, there is a pressing need for more compelling anticancer mediators since the effectiveness of chemotherapy is limited by tumor cells’ heterogeneity and drug resistance [3,4]. Nitric oxide (NO) is a liposoluble molecule, endogenously produced in the mammalian body during the metabolism of l-arginine to l-citrulline by the action of nitric oxide synthases (NOS) [5]. NO is a versatile intra- and intercellular messenger controlling diverse pathophysiological mechanisms in circulatory, neurological, and immune systems [6]. Despite biological mediators, NO, as an oxygen free radical, is cytotoxic in pathological processes, mainly in inflammatory ailments [7]. Furthermore, inflammation should be regulated because of its direct impact on chronic conditions, such as cancer, cardiovascular, and immunological diseases [8]. Thus, inflammatory diseases can be treated by NO inhibition [9].

Currently, NO is recognized as one of the most important molecules affecting the growth, development, and treatment of cancer. In tumor biology, NO has both positive and negative effects, as it has been associated with both endorsing and inhibiting cancer. Research findings indicated that the dual responses of NO toward cancer are due to its concentration-dependent ability in development, migration, incursion, persistence, and metastasis of tumor [10]. The exact molecular mechanism of NO involvement in cancer is not fully understood so far; however, studies found a significantly higher levels of NO in cervical cancer patients [11]. In addition, cervixes of women having cervical intraepithelial neoplasia were found with elevated levels of NO as well as NO-mediated mutagenesis [12]. These studies concluded mutagenic and carcinogenic activities of NO in cervical cancer.

Synthesis of novel molecules possessing pharmacophore moiety that resembles known biologically active compounds provides a leading approach toward the development of highly active agents. Among anticancer agents, dithiocarbamates [13,14,15,16,17] and isothiocyanate [18,19,20,21,22,23,24] gained great attention as promising anticancer candidates. In addition, tetrahydro-(2H)-1,3,5-thiadiazine-2-thione nucleus has been reported to exhibit anticancer [25,26,27,28,29], antileishmanial [30], antibacterial [31], trypanocidal [32], antimalarial [33], antifungal [34], herbicidal [35], antitubercular [36], antiepileptic [37], and antioxidant [38] activities. These activities were attributed to the formation of isothiocyanate and dithiocarbamic acid upon hydrolysis of this nucleus in biological systems [29,39].

On the basis of the previous discussion, the aim of the present work was to synthesize 3,5-disubstituted thiadiazine-2-thiones as potential anticancer agents. The anticancer activity of the synthesized compounds will be evaluated against human cervical cancer HeLa cell line. Previously, the anticancer activity of cyclopentyl, cyclohexyl, and furfuryl N-3 substituted and bis-disubstituted thiadiazine-2-thiones has been tested against HT-29 (Human colorectal adenocarcinoma), A549 (lung carcinoma), Hep3B (hepatocellular carcinoma), HepG2 (hepatocellular carcinoma), U-87MG (Brain (glioblastoma astrocytoma), normal cell line (fibroblast F180) [25], K562 (leukaemia cells), MCF12 (normal cells) [26], MCF-12A (normal breast cell line), MCF-7 and MDA-MB-468 (breast cancer cell line) [27], Hep G2 (human hepatoma), HT-29 (human colon carcinoma), and HeLa (human cervical carcinoma) [28,29]. These studies showed moderate-to-good activity of the tested derivatives of tetrahydro-2H-1,3,5-thiadiazine-2-thione. We, therefore, sought to synthesize more functionalized tetrahydro-2H-1,3,5-thiadiazine-2-thiones, which could be more potent than previously reported ones. Despite the wealth of literature that dealt with the biological properties of 1,3,5-thiadiazine-2-thione moiety, no anti-inflammatory activity has been assessed for this nucleus. Hence, this study deals with the anticancer and NO inhibitory potential along with the docking studies of the titled compounds to appraise the functional modification on the 1,3,5-thiadiazine-2-thione nucleus for the said activities.

2 Materials and methods

2.1 Chemistry

All chemicals and reagents were obtained from commercial suppliers and used as received without further purification. Reactions were monitored by thin-layer chromatography, achieved on silica gel plates (60 F-254); these plates were visualized under UV light. Melting points were determined using a Gallen Kamp melting point apparatus and are uncorrected. Dimethyl sulfoxide (DMSO), chloroform (CDCl3), and methanol (CD3OD) were used as solvents for NMR Spectra. 1H and 13C NMR spectra were recorded on Bruker AVNeo-NMR Spectrometers and using TMS as an internal standard. Chemical shifts are expressed in δ units, whereas coupling constants (J-values) are given in Hertz. Mass spectra were acquired on JEOL MS Route and Finnigan LTQ FTMS (ESI) spectrometer.

2.2 General procedure for synthesis of 3,5-disubstituted tetrahydrothiadiazine-2-thiones (1–13)

Compounds 1–13 were prepared by adding selected alkyl/cycloalkyl/aryl amine (20 mmol) to a 20% KOH aqueous solution followed by adding CS2 dropwise (20 mmol) at 30°C with stirring. After 4 h, 37% formaldehyde solution (40 mmol) was added and stirred for 1 h continuously, and the reaction mixture was then filtered and added, dropwise, to a suspension of amino acid or primary amines (20 mmol) in a 7.8 pH phosphate buffer and stirred for 1 h (Scheme 1). The mixture was then filtered and refrigerated for 1 h. The ice-chilled reaction mixture was acidified with hydrochloric acid up to pH 2.0 at 0–5°C. The precipitate formed was thoroughly washed with water followed by n-hexane and then dried. The desired product was recrystallized from ethanol to afford pure compounds 1–13. Using this general procedure, the following compounds were synthesized.

Scheme 1 General scheme for the synthesis of the title compounds.
Scheme 1

General scheme for the synthesis of the title compounds.

2.2.1 2-(5-butyl-6-thioxo-1,3,5-thiadiazinan-3-yl)-4-methylpentanoic acid (1)

Compound 1, acquired by n-butyl amine and l-leucine, was obtained as white solid recrystallized from ethanol. Yield: 76%, mp: 92–94°C. 1H NMR (600 MHz, DMSO-d 6): δ 0.89 (t, 9H, J = 6.4, CH3), 1.25–1.31 (m, 2H, CH3CH2CH2), 1.50–1.63 (m, 5H, CH2CH2CH2, CH3CHCH3, CHCH2CH), 3.50–3.53 and 3.79–3.98 (m, 2H, NCH2CH2,), 4.45–4.64 (m, 4H, NCH2NCH2S), 13C NMR (150 MHz, DMSO-d 6): δ 13.87 (CH3CH2), 19.69 (CH3CH2), 21.93, 23.43 (CH3CHCH3), 24.96 (CH3CHCH3), 28.37 (CH2CH2CH2), 38.67 (CHCH2CH), 51.48 (NCH2), 55.75 (C-6), 60.77 (NCH), 67.61 (C-4), 173.46 (CO), 190.58 (CS). MS (70 eV): m/z (%): m/z (%) = 304.2 (4.5) [M]+, 256.2 (11) [M–146]+, 140.0 (100) [M–200]+, 115.1 (100) [M–289]+.

2.2.2 2-(5-butyl-6-thioxo-1,3,5-thiadiazinan-3-yl) butanoic acid (2)

Compound 2 was obtained from n-butyl amine and DL-2-aminobutyric acid as a white solid recrystallized from ethanol. Yield: 72%, mp: 93–95°C (600 MHz, DMSO-d 6): δ 0.84–0.91 (m, 6H, CH3CH2, CH3CH2), 1.23–1, mp: 32 (m, 2H, CH3CH2CH2), 1.50–1.61 (m, 2H, CH2CH2CH2) 1.70–1.84 (m CH3CH2CH), 3.40–3.43 (m 1H, NCH), 3.69–3.76 and 4.02–4.09 (m, 2H, NCH2CH2,), 4.44–4.51 (m, 2H, NCH2S), 4.59–4.64 (m, 2H NCH2N), 13C NMR (150 MHz, DMSO-d 6): δ 9.28 (CH3CH2CH), 13.57 (CH3CH2CH2), 19.36 (CH3CH2CH2), 22.31 (CHCH2CH), 28.00 (CH2CH2CH2), 51.10 (NCH2), 55.45 (C-6), 61.74 (NCH), 67.44 (C-4), 172.50 (CO), 190.39 (CS). MS (70 eV): m/z (%) = 276.2 (10) [M]+, 246.2 (25) [M–30]+, 128.0 (45) [M–148]+, 115.0 (100) [M–161]+.

2.2.3 2-(5-(3-methoxypropyl)-6-thioxo-1,3,5-thiadiazinan-3-yl) propionic acid (3)

Compound 3 was synthesized from 3-methoxyropyl amine and β-alanine and obtained as a white solid. Yield: 72%, mp: 98–100°C. 1H NMR (400 MHz, MeOD): δ 1.96–2.02 (m, 2H, CH2CH2CH2), 2.58 (t, 2H, J = 8, NCH2CH2), 3.10 (t, 2H, J = 8, CH2CH2COOH), 3.34 (s, 3H, CH3O), 3.47 (t, 3H, J = 8, OCH2CH2), 4.07 (t, 2H, J = 8, NCH2CH2), 4.49 (s, 2H, NCH2S), 4.50 (s, 2H, NCH2N). 13C NMR (100 MHz, MeOD): δ 28.10 (CH2CH2CH2), 34.26 (CH2COOH), 47.63 (NCH), 51.10 (NCH2), 59.04 (CH3O), 59.14 (C-6), 71.22 (OCH2), 71.82 (C-4), 175.90 (CO), 193.72 (CS). High-resolution mass spectrometry (HRMS) (ESI) m/z: calculated for C10H19N2O3S2 [M+H]+ 279.08371; found 279.08344.

2.2.4 2-(5-(3-methoxypropyl)-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid (4)

Compound 4 was acquired by 3-methoxyropyl amine and glycine. Product obtained as white solid. Yield: 71%, mp: 101–103°C. 1H NMR (400 MHz, DMSO-d 6): δ 1.79–1.86 (m, 2H, CH2CH2CH2), 3.22 (s, 2H, NCH2COOH) 3.34 (t, 2H, J = 8, NCH2CH2), 3.53 (s, 3H, CH3O), 3.93 (t, 3H, J = 8, OCH2CH2), 4.51 (s, 2H, NCH2S), 4.52 (s, 2H, NCH2N). 13C NMR (100 MHz, DMSO-d 6): δ 35.63 (CH2CH2CH2), 58.50 (NCH), 60.16 (NCH2), 67.31 (CH3O), 67.48 (C-6), 78.77 (OCH2), 79.24 (C-4), 180.04 (CO), 199.69 (CS). HRMS (ESI) m/z: calculated for C9H17N2O3S2 [M+H]+ 265.06806; found 265.06744.

2.2.5 2-(5-cyclopropyl-6-thioxo-1,3,5-thiadiazinan-3-yl) propionic acid (5)

Compound 5 was acquired by cyclopropyl amine and dl-α-alanine. Product obtained as white solid. Yield: 69%, mp: 123–124°C. 1H NMR (400 MHz, DMSO-d 6): δ 0.78–0.90 (m, 4H, cyclopropyl ring protons), 2.50 (m, 3H, CH3CH), 2.88 (t, 1H, J = 8, CH3CH), 3.07–3.13 (m, 1H, NCH), 4.40 (s, 2H, NCH2S), 4.41 (s, 2H, NCH2N), 12.22 (s, COOH). 13C NMR (100 MHz, DMSO-d 6): δ 7.66 (cyclopropyl ring carbons), 32.29 (CH3CH), 35.06 (NCH), 45.14 (C-6) 56.19 (NCH), 70.22 (C-4), 172.65 (CO), 192.84 (CS). HRMS (ESI) m/z: calculated for C9H15N2O2S2 [M+H]+ 247.05749; found 247.05711.

2.2.6 2-(5-cyclopropyl)-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid (6)

Compound 6 was acquired by cyclopropyl amine and glycine. Product obtained as white solid. Yield: 72%, mp: 122–124°C. 1H NMR (400 MHz, DMSO-d 6): δ 0.74–0.88 (m, 4H, cyclopropyl ring protons), 3.04–3.09 (m, 1H, NCH), 3.49 (s, 2H, NCH2COOH), 4.42 (s, 2H, NCH2S), 4.46 (s, 2H, NCH2N), 12.65 (s, COOH). 13C NMR (100 MHz, DMSO-d 6): δ 8.10 (cyclopropyl ring carbons), 35.31 (NCH), 50.63 (NCH2), 57.10 (C-6), 70.44 (C-4), 170.69 (CO), 193.32 (CS). HRMS (ESI) m/z: calculated for C8H13N2O2S2 [M+H]+ 233.04184; found 233.07747.

2.2.7 2-(5-butyl-6-thioxo-1,3,5-thiadiazinan-3-yl) propionic acid (7)

Compound 7 was acquired by n-butyl amine and dl-α-alanine. Product obtained as white solid recrystallized from ethanol. Yield: 68%, mp: 98–100°C, 1H NMR (400 MHz, DMSO-d 6): δ 0.89 (t, 3H, J = 8.0 Hz, CH3CH2), 1.23–1.31 (m, 2H, J = 8.0 Hz, CH3CH2CH2), 1.35 (d, 3H, CH3CH), 1.49–1.63 (m, 2H, CH2CH2CH2), 3.53–3.58 (q, 1H, CH3CH), 3.65–3.72, and 4.08–4.15 (m, 2H, NCH2CH2), 4.44–4.65 (m, 4H, NCH2NCH2S). MS (ES) 262.2, calculated: 262.39. MS (ESI) m/z (%) = 262.2 (12) [M]+, 115.1 (47) [M–147]+, 57.0 (100) [C4H9]+

2.2.8 2-(5-propyl-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid (8)

Compound 8 was acquired by propyl amine and glycine. Product obtained as white solid, recrystallized from ethanol. Yield: 64%, mp: 109–111°C. 1H NMR (400 MHz, DMSO-d 6): δ 0.85 (t, 3H, J = 8 Hz, CH3CH2), 1.54–1.63 (m, 2H, CH3CH2CH2), 3.53 (s, 2H, CH2COOH), 3.85 (t, 2H, J = 8 Hz, NCH2CH2,), 4.51 (s, 2H, NCH2S), 4.52 (s, 2H, NCH2N), 12.69 (s, COOH); MS (ESI) m/z (%) = 234.2 (25) [M]+, 147.1 (15) [M–87]+, 101.1 (100) [M–133]+, 42.0 (90) [C3H6]+.

2.2.9 2-(5-butyl-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid (9)

Compound 9 was acquired by n-butyl amine and glycine. Product obtained as white solid, recrystallized from ethanol. Yield: 62%, mp: 98–99°C. 1H NMR (400 MHz, MEOD): δ 0.97 (t, J = 8.0 Hz, 3H, CH2CH3), 1.32–1.42 (m, 2H, CH2CH2CH3), 1.61–1.69 (m, 2H, CH2CH2CH2), 3.65 (s, 2H, CH2COOH), 3.99 (t, 2H, J = 8 Hz, NCH2CH2), 4.53 (s, 2H, NCH2S), 4.55 (s, 2H, NCH2N). 13C NMR (100 MHz, MEOD): δ 13.68 (CH3CH2), 20.56 (CH2CH2CH3), 29.16 (CH2CH2CH2), 51.55 (CH2CH2N), 52.47 (CH2COOH), 59.05 (C-6), 70.53 (C-4), 172.49 (CO), 191.47 (CS). HRMS (ESI) m/z: calculated for C9H17N2O2S2 [M+H]+ 249.07314; found 249.07227.

2.2.10 2-(5-hydroxyethyl)-3-phenyl-1,3,5-thiadiazinane-2-thione (10)

Compound 10 was acquired by aniline and ethanolamine. Product obtained as white solid, recrystallized from ethanol. Yield: 61%, mp: 124–126°C. 1H NMR (400 MHz, DMSO-d 6): δ 3.00 (t, 2H, J = 8.0 Hz, CH2CH2OH) 3.63 (t, 2H, J = 8 Hz, NCH2CH2), 4.67 (s, 2H, NCH2S), 4.72 (s, 2H, NCH2N), 7.23–7.47 (m, 5H, Ar–H). 13C NMR (100 MHz, DMSO-d 6): δ 52.11 (NCH2), 58.96 (CH2OH), 59.15 (C-6), 73.61 (C-4), 127.09–129.30 (Ar–CH), 144.40 (Ar–C), 192.95 (CS). HRMS (ESI) m/z: calculated for C11H15N2OS2 [M+H]+ 255.06; found 255.06.

2.2.11 2-(5-phenyl-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid (11)

Compound 11 was acquired by aniline and glycine. Product obtained as white solid, recrystallized from ethanol. Yield: 59%, mp: 97–99°C. 1H NMR (400 MHz, DMSO-d 6): δ 3.73 (s, 2H, CH2COOH), 4.65 (s, 2H, NCH2S), 4.71 (s, 2H, NCH2N), 7.15–7.44 (m, 5H, Ar−H). 13C NMR (100 MHz, DMSO-d 6): δ 50.99 (CH2COOH), 58.49 (C-6), 73.39 (C-4), 127.24, 127.85, and 129.61 (Ar−CH), 144.34 (Ar−C), 170.62 (C═O), 192.95 (C═S). HRMS (ESI) m/z: calculated for C11H13N2O2S2 [M+H]+ 269.04184; found 269.10989.

2.2.12 2-(5-phenyl-6-thioxo-1,3,5-thiadiazinan-3-yl) propanoic acid (12)

Compound 12 was acquired by aniline and dl-α-alanine. Product obtained as white solid recrystallized from ethanol. Yield: 63%, mp: 98–100°C. 1H NMR (400 MHz, DMSO-d 6): δ 1.36 (d, 3H, J = 8 Hz, CH3CH), 3.77 (q, 1H, CH3CH), 4.64–4.68 (m, 2H, NCH2S) 5.23–5.36 (m, 2H, NCH2N), 7.11–7.44 (m, 5H, Ar−H). 13C NMR (100 MHz, DMSO- d 6) δ 16.55 (CH3), 55.41(C-6), 69.84 (CH), 71.44 (C-4), 117.70, 127.48, 130.02 (Ar–CH), 144.56 (Ar–C), 174.09 (C═O), 194.02 (C═S). HRMS (ESI) m/z: calculated for C12H15N2O2S2 [M+H]+ 283.05749; found 283.09290.

2.2.13 2-(4-methyl-2-(5-phenyl-6-thioxo-1,3,5-thiadiazinan-3-yl) pentanoic acid (13)

Compound 13 was acquired by aniline and l-leucine. Product obtained as white solid recrystallized from ethanol. Yield: 79%, mp: 92–94°C. 1H NMR (400 MHz, DMSO-d 6): δ 0.85 (dd, 6H, CH3CH), 1.50–1.59 (m, 3H, CH3CHCH3, CHCH2CH), 3.67–3.70 (m, 1H, NCHCH2), 4.63–4.85 (m, 4H, NCH2S, and NCH2N), 7.21–7.44 (m, 5H, Ar−H). 13C NMR (100 MHz, DMSO-d 6): δ 22.33 (CH3CHCH3), 23.73 (CH3CHCH3), 25.27 (CHCH2CH), 56.66 (C-6), 61.27 (NCH), 71.32 (C-4), 127.53, 128.98, and 129.39 (Ar–CH), 144.77 (Ar–C), 173.83 (CO), 193.72 (CS). HRMS (ESI) m/z: calculated for C15H22N2O2S2 [M+2H]+ 326.11227; found 326.16510.

3 Biological activities

3.1 NO assay

The J774.2 (ECACC, UK) cells were obtained from Bio bank facility PCMD, ICCBS, University of Karachi. In IWAKI 75 cc flasks (Asahi Techno Glass, Japan), mouse (J774.2) macrophage cell lines (European Collection of Cell Cultures, UK) were cultured in Dulbecco’s modified eagle medium (DMEM) (Sigma-Aldrich, Steinheim, Germany) with 1% streptomycin/penicillin and 10% fetal bovine serum (FBS) (N.Y. U.S.; GIBCO) and were incubated at 5% CO2 at 37°C. Briefly, 150 µL·well−1 of 1 × 106 cells·mL−1 were added in 96-well flat bottom plates and cells were treated with Escherichia coli lipopolysaccharide (30 µg·mL−1) (DIFCO Laboratories, Michigan, USA) and different concentrations of compounds 1, 10, and 100 (µM). The plate was incubated for 48 h at 37°C in 5% carbon dioxide. After incubation, the collected supernatant was added with Griess reagent to measure the accumulation of nitrite. The plate was read at 540 nm in spectrophotometer [40].

3.2 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay

We employed the standard MTT colorimetric assay to assess the cytotoxicity of prepared compounds against the human cervical cancer HeLa cells (ATCC, Manassas, USA), which were obtained from Biobank facility PCMD and ICCBS. The cells were cultured in DMEM media supplemented with 10% FBS and 1% penicillin and streptomycin at 37°C in 5% CO2 incubator. The 96-well flat-bottom plates were added with 6 × 104 cells·mL−1 and incubated for 24 h to attach cells. Next day, the media was replaced and the test compounds were added in 1, 10, and 100 (µM) concentrations in triplicates and plates were incubated at 37°C in 5% CO2 incubator for 48 h. 50 µL of MTT (0.5 mg·mL−1) was added to each well followed by further incubation of 4 h. Upon aspiration of MTT, DMSO (100 µL) was then added to wells to dissolve formazan crystals. A spectrophotometer (Molecular Devices, Spectra Max plus, CA, USA) was used to measure the reduction of MTT to formazan by reading absorbance at 540 nm. The cytotoxic activity for HeLa cells was expressed as the half maximal inhibitory concentration (IC50), the concentration required to cause 50% growth inhibition.

3.3 Docking studies (methodology)

Docking studies were done using Molecular Operating Environment (2016.0802) [41]. The crystal structure of inducible nitric oxide synthase (iNOS) was taken from Protein Data Bank (PDB). 4NOS was the accession code. Preparation of three-dimensional (3-D) structures of synthesized compounds and the downloaded enzyme was carried out by using our previously reported methods [42,43,44]. Docking rums were carried out by using default parameters. Discovery Studio Visualizer (DS-2021) was used for the analysis of the docking results [45].

4 Results and discussion

The target 3,5-disubstituted-tetrahydro-thiadiazine-2-thiones (1–13) were synthesized according to Scheme 1 by the reaction of a primary amine with carbon disulfide in potassium hydroxide aqueous solution to afford their respective dithiocarbamate potassium salts, which were treated with formaldehyde followed by the addition of different amino acids and ethanolamine in phosphate buffer (pH = 7.8) to cause cyclocondensation of the dithiocarbamate intermediate. The desired products were obtained by lowering the temperature and pH of the reaction mixture.

4.1 Spectral discussion

Structures of the synthesized compounds were confirmed by spectroscopic methods including 1H NMR, 13C NMR, 2D-NMR, mass spectrometry, and HRMS. All the spectral results as detailed in the experimental part are in agreement with the proposed structures assigned to these compounds. Hence, the mass spectra of these compounds showed the correct molecular ions. In addition, the measured HR-MS data are in agreement with the calculated values. Furthermore, DEPT and 2D-NMR including COSY, NOESY, HSQC, and HMBC experiments showed correlations that facilitated in the 1H- and 13C-signal assignments to the different carbons and their attached, and/or neighboring hydrogens. All the functional analogues showed similar pattern in the chemical shifts of 1H and 13C NMR signals, which confirm the common molecular backbone of thiadiazine thione nucleus. 1H NMR spectra of all 1,3,5-thiadiazinethiones showed singlets at 4.40–4.46 ppm, for C-4 and C-6 protons while in case of compounds 1, 2, and 7, multiplet appeared in corresponding regions due to diastereotopicity being prompted by the branched substituent at N-5. Similarly, in the 13C NMR spectra, the (C═S) thiocarbonyl carbon appears in 190–193 ppm range, whereas signals due to C-4 and C-6 of the thiadiazinane-2-thione nucleus appeared at 67–79 and 55–58 ppm, respectively. On the other hand, the carboxylic carbons appeared at 171–173 ppm.

4.2 Cytotoxicity

The antitumor activity of the newly synthesized compounds 1–13 against human cervical cancer HeLa cell line was evaluated by conducting cell viability assay using tetrazolium dye MTT. In this method, cultures of the HeLa cell line were treated with the target compounds and the results are listed in Table 1. Results show that most of the prepared compounds exhibit anticancer activity. Compounds 3, 5, 6, and 9 were the most potent with IC50 values of <4 µM. Compound 10 was inactive whereas the rest of the series revealed significant anticancer activity with IC50 values in the range from 7.2 ± 0.7 to 149.7 ± 11.1 µM (Table 1). A comparison of the compounds anticancer activity against the HeLa cell line indicates that the activity of thiadiazine-2-thione nucleus was markedly affected by N-5 and N-3 substituents. The presence of the phenyl group at N-3 lowers the activity while the cyclopropyl and 3-methoxypropyl bearing moieties were found to be the most potent inhibitors. Similarly, in N-3 butyl substituted series, activity increases. On the other hand, changing the N-5 substituent from bulkier to less bulky groups increases the activity. Furthermore, results showed that activity increases with shorter chains of the acid on N5 (Figure 1).

Table 1

Cytotoxic and NO inhibition of tested series

Sample codes R1 R2 Cytotoxicity HeLa cells IC50 ± SD (µM) NO inhibition IC50 ± SD (µM)
1 CH3−CH2−CH2−CH2− 22.0 ± 0.3 ND
2 CH3−CH2−CH2−CH2− 13.7 ± 0.4 ND
3 CH3O−CH2−CH2−CH2− −CH2−CH2−COOH <4 <0.4
4 CH3O−CH2−CH2−CH2− −CH2−COOH 7.2 ± 0.7 <0.4
5 <4 <0.4
6 −CH2−COOH <4 2.15
7 CH3−CH2−CH2−CH2− 14.5 ± 3.0 ND
8 CH3−CH2−CH2− −CH2−COOH 36.3 ± 3.8 ND
9 CH3−CH2−CH2−CH2− −CH2−COOH <4 <0.4
10 C 6 H 5 − −CH2−CH2−OH >400 14.9
11 C 6 H 5 − −CH2−COOH 149.7 ± 11.1 ND
12 C 6 H 5 − 38.2 ± 6.0 <0.4
13 C 6 H 5 − 55.8 ± 15.1 ND
Doxorubicin 0.86 ± 0.08
l-NMMA 97.5 ± 3.2

l-NMMA = N G monomethyl l-arginine acetate.

Figure 1 Structural diversity and IC50 – a schematic SAR.
Figure 1

Structural diversity and IC50 – a schematic SAR.

4.3 NO activity

NO activity was assessed using J774.2 mouse macrophage cell line that was cultured in 75 cc flasks. 1, 10, and 100 µM concentration of the test compounds were added to 96-well plate incubated at 37°C in humidified air containing 5% CO2. Nitrite accumulation in grown culture was measured by Griess reagent. All the tested compounds sowed strong NO inhibitory activities with IC50 values ranging from <0.4 to 14.9 µM (Table 1). Compounds 3, 4, 5, 9, and 12 bearing butyric and butanoic acid moiety at N5 exhibit IC50 value <0.4 (µM) while compounds 6 and 10 showed 2.15 and 14.9 µM, IC50 values, respectively. It was observed that among the tested series compounds bearing propionic acid at N-5 were less active as compared to butyric and butanoic acid substituted. No structure–activity relationship observed for N-3 substituents.

4.4 Docking studies

Research findings indicated that the expression of iNOS can be observed in several malignant tumors, such as lung, breast, prostate, and malignant melanoma. We carried out docking simulations on the inhibition of iNOS using the Molecular Operating Environment (MOE 2016.0802) software [44]. The 3-D crystal structure of human iNOS was acquired from PDB with accession code number 4NOS. Docking protocol was validated by using the re-dock method. Native ligand ethylisothiourea (ITU) was re-docked into the binding site. The binding orientation of the re-docked ITU and experimental ITU was analyzed. The computed root-mean square deviation was 1.13 Å, which was found within the threshold limit (<2.0 Å). The superposed results of the re-dock experiment are shown in Figure 2a. The 3-D interaction plot of native ITU showed that it interacts with Trp372 and Glu377 (Figure 2b). We also docked control drug (NO inhibitor) in the binding site of iNOS. Two-dimensional (2-D) interaction plot showed that it interacts with amino acid residues Gly371 and Trp372 via hydrogen bond interactions (Figure 2c).

Figure 2 (a) Ribbon superposed model of native ITU (green carbon stick) and re-docked ITU (pink carbon stick); (b) 3-D interaction plots of native ITU in the binding site of iNOS (PDB ID = 4NOS); and (c) 2-D interaction plot of control drug N G monomethyl l-arginine in the binding site of iNOS. These 3-D/2-D interactions plots are modeled by using Discovery Studio Visualizer.
Figure 2

(a) Ribbon superposed model of native ITU (green carbon stick) and re-docked ITU (pink carbon stick); (b) 3-D interaction plots of native ITU in the binding site of iNOS (PDB ID = 4NOS); and (c) 2-D interaction plot of control drug N G monomethyl l-arginine in the binding site of iNOS. These 3-D/2-D interactions plots are modeled by using Discovery Studio Visualizer.

All synthesized compounds were docked into the active site of the human iNOS (PDB ID = 3NOS). The 3-D interaction plots of studied compounds are depicted in Figures 3 and 4. The studied compounds interact with amino acid residues via conventional hydrogen bonds and hydrophobic interactions. Within this context, compound 3 displayed strong hydrogen bonding interaction with Trp372, Ala351, and Glu377. In addition, a π–sulfur and π–alkyl types of interactions with Phe369 were observed (Figure 3a). Similarly, compound 4 exhibited conventional hydrogen bonding interactions with Gly371, Val352, and Ile201 (Figure 3b). On the other hand, compound 5 showed conventional hydrogen bonding interaction with Glu377 along with a bifurcated π–sulfur interaction with Trp372 (Figure 3c). In contrast, compound 6 exhibited conventional hydrogen bonding interactions with Glu377, Ile201, and Cys200 in addition to two π–sulfur interactions with Trp372 and Trp194 (Figure 3d).

Figure 3 (a–d) 3-D interaction plots of compounds 3–6 modeled by using Discovery Studio Visualizer in the binding site of iNOS (PDB ID = 4NOS).
Figure 3

(a–d) 3-D interaction plots of compounds 3–6 modeled by using Discovery Studio Visualizer in the binding site of iNOS (PDB ID = 4NOS).

Figure 4 (a–d) 3-D interaction plots of compounds 9, 10, 12, and 13 modeled by using Discovery Studio Visualizer in the binding site of iNOS (PDB ID = 4NOS).
Figure 4

(a–d) 3-D interaction plots of compounds 9, 10, 12, and 13 modeled by using Discovery Studio Visualizer in the binding site of iNOS (PDB ID = 4NOS).

Compound 9 displayed one conventional hydrogen bonding interaction with Trp32 and Glu377, and two π–sulfur interactions with Trp372 and Trp194 as shown in Figure 4a. Compound 10 showed π–π stacked interaction with Trp194 and Phe369, in addition to a π–sulfur interaction with Phe369 (Figure 4b). Similarly, compound 12 showed one conventional hydrogen bonding interaction and π–sigma interaction with Gly202, and hydrogen bond interactions with Ile201. It additionally exhibited two π–sulfur interactions with Phe369 and a π–π stacked interaction with Trp372 (Figure 4c). Similarly, compound 13 exhibited a conventional hydrogen bonding interaction with Gly371, a π–sulfur interaction with Met434, and a π–alkyl interaction with Gly202 (Figure 4d). All the binding energy values in kcal mol−1 and type of interactions are presented in Table 2.

Table 2

Interacting residues and binding energy of the docked compounds in the binding site of iNOS (PDB ID = 4NOS)

Interacting residues
Comp. no. Hydrogen bond π–π stack π–sulfur π–alkyl/π–σ Binding energy (kcal·mol−1)
3 Trp372, Ala351, Glu377 — Phe369 Phe369 −6.32
4 Gly371, Val352, and Ile201 — Trp372 − −6.04
5 Glu377 — Trp372 (bifurcated) — −6.16
6 Glu377, Ile201, and Cys200 — Trp372, Trp194 — −6.29
9 Trp32 and Glu377 — Trp372, Trp194 — −6.49
10 — Trp194 and Phe369 Phe369 — −4.22
12 Ile201 Trp372 — Gly202 −5.67
13 Gly371 — Met434 — −5.19
Control Gly371 and Trp372 — — — −4.05

5 Conclusions

In summary, we have synthesized a total of thirteen tetrahydro-2H-1,3,5-thiadiazine-2-thiones and have characterized by different spectroscopic methods. The prepared compounds were screened for their anticancer activity against the HeLa cell line, and NO inhibitory potential. Results revealed that most of the prepared compounds exhibit significant potential. Compounds 3, 5, 6, and 9 were the most potent with IC50 values of <4 µM. In addition, our findings showed that all the screened compounds are strong NO inhibitors (IC50 values range between <0.4 and 14.9 µM). Docking studies related to iNOS showed that the studied compounds interact with the enzyme via strong hydrogen bonds and hydrophobic interactions. These findings could encourage the researchers for further insight in search of their anticancer potential or as leads in the development of anticancer drugs.

Acknowledgment

The authors are thankful to Higher Education Commission of Pakistan for providing fund for a part of this project under project no. NRPU-4165.

  1. Funding information: This research project was funded by the Higher Education Commission under project no. NRPU-4165.

  2. Author contributions: Haleema Ali synthesized the compounds and wrote paper under the supervision of Rasool Khan; Xiandao Pan and Farzana Shaheen did the NMR and mass analysis; Almas Jabeen did anticancer and nitric oxide activity of synthesized compounds; Abdur Rauf, Muhammad Shah, and Umer Rashid involved in docking analysis of bioactive compounds; Yahya S. Al-Awthan, Omar S. Bahattab, and Mohammed A. Al-Duais did the analysis; and Mohammad S. Mubarak involved in analysis and writing this paper. All authors read the article and approved for submission.

  3. Conflict of interest: One of the corresponding authors (Abdur Rauf) is a member of the Editorial Board of Green Processing and Synthesis.

  4. Data availability statement: The data associated to this work are a part of PhD thesis and can be obtain from the corresponding authors upon request.

  5. Supporting information: The supporting information is available online (see supplementary file).

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Received: 2022-11-09
Revised: 2023-01-13
Accepted: 2023-02-12
Published Online: 2023-03-14

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  74. Separation of graphene oxides of different sizes by multi-layer dialysis and anti-friction and lubrication performance
  75. Visible-light-assisted base-catalyzed, one-pot synthesis of highly functionalized cinnolines
  76. The experimental study on the air oxidation of 5-hydroxymethylfurfural to 2,5-furandicarboxylic acid with Co–Mn–Br system
  77. Highly efficient removal of tetracycline and methyl violet 2B from aqueous solution using the bimetallic FeZn-ZIFs catalyst
  78. A thermo-tolerant cellulase enzyme produced by Bacillus amyloliquefaciens M7, an insight into synthesis, optimization, characterization, and bio-polishing activity
  79. Exploration of ketone derivatives of succinimide for their antidiabetic potential: In vitro and in vivo approaches
  80. Ultrasound-assisted green synthesis and in silico study of 6-(4-(butylamino)-6-(diethylamino)-1,3,5-triazin-2-yl)oxypyridazine derivatives
  81. A study of the anticancer potential of Pluronic F-127 encapsulated Fe2O3 nanoparticles derived from Berberis vulgaris extract
  82. Biogenic synthesis of silver nanoparticles using Consolida orientalis flowers: Identification, catalytic degradation, and biological effect
  83. Initial assessment of the presence of plastic waste in some coastal mangrove forests in Vietnam
  84. Adsorption synergy electrocatalytic degradation of phenol by active oxygen-containing species generated in Co-coal based cathode and graphite anode
  85. Antibacterial, antifungal, antioxidant, and cytotoxicity activities of the aqueous extract of Syzygium aromaticum-mediated synthesized novel silver nanoparticles
  86. Synthesis of a silica matrix with ZnO nanoparticles for the fabrication of a recyclable photodegradation system to eliminate methylene blue dye
  87. Natural polymer fillers instead of dye and pigments: Pumice and scoria in PDMS fluid and elastomer composites
  88. Study on the preparation of glycerylphosphorylcholine by transesterification under supported sodium methoxide
  89. Wireless network handheld terminal-based green ecological sustainable design evaluation system: Improved data communication and reduced packet loss rate
  90. The optimization of hydrogel strength from cassava starch using oxidized sucrose as a crosslinking agent
  91. Green synthesis of silver nanoparticles using Saccharum officinarum leaf extract for antiviral paint
  92. Study on the reliability of nano-silver-coated tin solder joints for flip chips
  93. Environmentally sustainable analytical quality by design aided RP-HPLC method for the estimation of brilliant blue in commercial food samples employing a green-ultrasound-assisted extraction technique
  94. Anticancer and antimicrobial potential of zinc/sodium alginate/polyethylene glycol/d-pinitol nanocomposites against osteosarcoma MG-63 cells
  95. Nanoporous carbon@CoFe2O4 nanocomposite as a green absorbent for the adsorptive removal of Hg(ii) from aqueous solutions
  96. Characterization of silver sulfide nanoparticles from actinobacterial strain (M10A62) and its toxicity against lepidopteran and dipterans insect species
  97. Phyto-fabrication and characterization of silver nanoparticles using Withania somnifera: Investigating antioxidant potential
  98. Effect of e-waste nanofillers on the mechanical, thermal, and wear properties of epoxy-blend sisal woven fiber-reinforced composites
  99. Magnesium nanohydroxide (2D brucite) as a host matrix for thymol and carvacrol: Synthesis, characterization, and inhibition of foodborne pathogens
  100. Synergistic inhibitive effect of a hybrid zinc oxide-benzalkonium chloride composite on the corrosion of carbon steel in a sulfuric acidic solution
  101. Review Articles
  102. Role and the importance of green approach in biosynthesis of nanopropolis and effectiveness of propolis in the treatment of COVID-19 pandemic
  103. Gum tragacanth-mediated synthesis of metal nanoparticles, characterization, and their applications as a bactericide, catalyst, antioxidant, and peroxidase mimic
  104. Green-processed nano-biocomposite (ZnO–TiO2): Potential candidates for biomedical applications
  105. Reaction mechanisms in microwave-assisted lignin depolymerisation in hydrogen-donating solvents
  106. Recent progress on non-noble metal catalysts for the deoxydehydration of biomass-derived oxygenates
  107. Rapid Communication
  108. Phosphorus removal by iron–carbon microelectrolysis: A new way to achieve phosphorus recovery
  109. Special Issue: Biomolecules-derived synthesis of nanomaterials for environmental and biological applications (Guest Editors: Arpita Roy and Fernanda Maria Policarpo Tonelli)
  110. Biomolecules-derived synthesis of nanomaterials for environmental and biological applications
  111. Nano-encapsulated tanshinone IIA in PLGA-PEG-COOH inhibits apoptosis and inflammation in cerebral ischemia/reperfusion injury
  112. Green fabrication of silver nanoparticles using Melia azedarach ripened fruit extract, their characterization, and biological properties
  113. Green-synthesized nanoparticles and their therapeutic applications: A review
  114. Antioxidant, antibacterial, and cytotoxicity potential of synthesized silver nanoparticles from the Cassia alata leaf aqueous extract
  115. Green synthesis of silver nanoparticles using Callisia fragrans leaf extract and its anticancer activity against MCF-7, HepG2, KB, LU-1, and MKN-7 cell lines
  116. Algae-based green AgNPs, AuNPs, and FeNPs as potential nanoremediators
  117. Green synthesis of Kickxia elatine-induced silver nanoparticles and their role as anti-acetylcholinesterase in the treatment of Alzheimer’s disease
  118. Phytocrystallization of silver nanoparticles using Cassia alata flower extract for effective control of fungal skin pathogens
  119. Antibacterial wound dressing with hydrogel from chitosan and polyvinyl alcohol from the red cabbage extract loaded with silver nanoparticles
  120. Leveraging of mycogenic copper oxide nanostructures for disease management of Alternaria blight of Brassica juncea
  121. Nanoscale molecular reactions in microbiological medicines in modern medical applications
  122. Synthesis and characterization of ZnO/β-cyclodextrin/nicotinic acid nanocomposite and its biological and environmental application
  123. Green synthesis of silver nanoparticles via Taxus wallichiana Zucc. plant-derived Taxol: Novel utilization as anticancer, antioxidation, anti-inflammation, and antiurolithic potential
  124. Recyclability and catalytic characteristics of copper oxide nanoparticles derived from bougainvillea plant flower extract for biomedical application
  125. Phytofabrication, characterization, and evaluation of novel bioinspired selenium–iron (Se–Fe) nanocomposites using Allium sativum extract for bio-potential applications
  126. Erratum
  127. Erratum to “Synthesis, characterization, and evaluation of nanoparticles of clodinofop propargyl and fenoxaprop-P-ethyl on weed control, growth, and yield of wheat (Triticum aestivum L.)”
https://doi.org/10.1515/gps-2022-8136
Keywords for this article
thiadiazine thione; inducible nitric oxide synthase; HeLa cell line; docking studies
Creative Commons
BY 4.0

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  3. High removal efficiency of volatile phenol from coking wastewater using coal gasification slag via optimized adsorption and multi-grade batch process
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  73. The enhanced adsorption properties of phosphorus from aqueous solutions using lanthanum modified synthetic zeolites
  74. Separation of graphene oxides of different sizes by multi-layer dialysis and anti-friction and lubrication performance
  75. Visible-light-assisted base-catalyzed, one-pot synthesis of highly functionalized cinnolines
  76. The experimental study on the air oxidation of 5-hydroxymethylfurfural to 2,5-furandicarboxylic acid with Co–Mn–Br system
  77. Highly efficient removal of tetracycline and methyl violet 2B from aqueous solution using the bimetallic FeZn-ZIFs catalyst
  78. A thermo-tolerant cellulase enzyme produced by Bacillus amyloliquefaciens M7, an insight into synthesis, optimization, characterization, and bio-polishing activity
  79. Exploration of ketone derivatives of succinimide for their antidiabetic potential: In vitro and in vivo approaches
  80. Ultrasound-assisted green synthesis and in silico study of 6-(4-(butylamino)-6-(diethylamino)-1,3,5-triazin-2-yl)oxypyridazine derivatives
  81. A study of the anticancer potential of Pluronic F-127 encapsulated Fe2O3 nanoparticles derived from Berberis vulgaris extract
  82. Biogenic synthesis of silver nanoparticles using Consolida orientalis flowers: Identification, catalytic degradation, and biological effect
  83. Initial assessment of the presence of plastic waste in some coastal mangrove forests in Vietnam
  84. Adsorption synergy electrocatalytic degradation of phenol by active oxygen-containing species generated in Co-coal based cathode and graphite anode
  85. Antibacterial, antifungal, antioxidant, and cytotoxicity activities of the aqueous extract of Syzygium aromaticum-mediated synthesized novel silver nanoparticles
  86. Synthesis of a silica matrix with ZnO nanoparticles for the fabrication of a recyclable photodegradation system to eliminate methylene blue dye
  87. Natural polymer fillers instead of dye and pigments: Pumice and scoria in PDMS fluid and elastomer composites
  88. Study on the preparation of glycerylphosphorylcholine by transesterification under supported sodium methoxide
  89. Wireless network handheld terminal-based green ecological sustainable design evaluation system: Improved data communication and reduced packet loss rate
  90. The optimization of hydrogel strength from cassava starch using oxidized sucrose as a crosslinking agent
  91. Green synthesis of silver nanoparticles using Saccharum officinarum leaf extract for antiviral paint
  92. Study on the reliability of nano-silver-coated tin solder joints for flip chips
  93. Environmentally sustainable analytical quality by design aided RP-HPLC method for the estimation of brilliant blue in commercial food samples employing a green-ultrasound-assisted extraction technique
  94. Anticancer and antimicrobial potential of zinc/sodium alginate/polyethylene glycol/d-pinitol nanocomposites against osteosarcoma MG-63 cells
  95. Nanoporous carbon@CoFe2O4 nanocomposite as a green absorbent for the adsorptive removal of Hg(ii) from aqueous solutions
  96. Characterization of silver sulfide nanoparticles from actinobacterial strain (M10A62) and its toxicity against lepidopteran and dipterans insect species
  97. Phyto-fabrication and characterization of silver nanoparticles using Withania somnifera: Investigating antioxidant potential
  98. Effect of e-waste nanofillers on the mechanical, thermal, and wear properties of epoxy-blend sisal woven fiber-reinforced composites
  99. Magnesium nanohydroxide (2D brucite) as a host matrix for thymol and carvacrol: Synthesis, characterization, and inhibition of foodborne pathogens
  100. Synergistic inhibitive effect of a hybrid zinc oxide-benzalkonium chloride composite on the corrosion of carbon steel in a sulfuric acidic solution
  101. Review Articles
  102. Role and the importance of green approach in biosynthesis of nanopropolis and effectiveness of propolis in the treatment of COVID-19 pandemic
  103. Gum tragacanth-mediated synthesis of metal nanoparticles, characterization, and their applications as a bactericide, catalyst, antioxidant, and peroxidase mimic
  104. Green-processed nano-biocomposite (ZnO–TiO2): Potential candidates for biomedical applications
  105. Reaction mechanisms in microwave-assisted lignin depolymerisation in hydrogen-donating solvents
  106. Recent progress on non-noble metal catalysts for the deoxydehydration of biomass-derived oxygenates
  107. Rapid Communication
  108. Phosphorus removal by iron–carbon microelectrolysis: A new way to achieve phosphorus recovery
  109. Special Issue: Biomolecules-derived synthesis of nanomaterials for environmental and biological applications (Guest Editors: Arpita Roy and Fernanda Maria Policarpo Tonelli)
  110. Biomolecules-derived synthesis of nanomaterials for environmental and biological applications
  111. Nano-encapsulated tanshinone IIA in PLGA-PEG-COOH inhibits apoptosis and inflammation in cerebral ischemia/reperfusion injury
  112. Green fabrication of silver nanoparticles using Melia azedarach ripened fruit extract, their characterization, and biological properties
  113. Green-synthesized nanoparticles and their therapeutic applications: A review
  114. Antioxidant, antibacterial, and cytotoxicity potential of synthesized silver nanoparticles from the Cassia alata leaf aqueous extract
  115. Green synthesis of silver nanoparticles using Callisia fragrans leaf extract and its anticancer activity against MCF-7, HepG2, KB, LU-1, and MKN-7 cell lines
  116. Algae-based green AgNPs, AuNPs, and FeNPs as potential nanoremediators
  117. Green synthesis of Kickxia elatine-induced silver nanoparticles and their role as anti-acetylcholinesterase in the treatment of Alzheimer’s disease
  118. Phytocrystallization of silver nanoparticles using Cassia alata flower extract for effective control of fungal skin pathogens
  119. Antibacterial wound dressing with hydrogel from chitosan and polyvinyl alcohol from the red cabbage extract loaded with silver nanoparticles
  120. Leveraging of mycogenic copper oxide nanostructures for disease management of Alternaria blight of Brassica juncea
  121. Nanoscale molecular reactions in microbiological medicines in modern medical applications
  122. Synthesis and characterization of ZnO/β-cyclodextrin/nicotinic acid nanocomposite and its biological and environmental application
  123. Green synthesis of silver nanoparticles via Taxus wallichiana Zucc. plant-derived Taxol: Novel utilization as anticancer, antioxidation, anti-inflammation, and antiurolithic potential
  124. Recyclability and catalytic characteristics of copper oxide nanoparticles derived from bougainvillea plant flower extract for biomedical application
  125. Phytofabrication, characterization, and evaluation of novel bioinspired selenium–iron (Se–Fe) nanocomposites using Allium sativum extract for bio-potential applications
  126. Erratum
  127. Erratum to “Synthesis, characterization, and evaluation of nanoparticles of clodinofop propargyl and fenoxaprop-P-ethyl on weed control, growth, and yield of wheat (Triticum aestivum L.)”
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