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Proceeding Paper

Synthesis, Spectral Characteristics, and Molecular Docking Studies of 2,4-Dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide †

by
Valeriia V. Pavlova
,
Pavlo V. Zadorozhnii
*,
Vadym V. Kiselev
and
Aleksandr V. Kharchenko
Department of Pharmacy and Technology of Organic Substances, Ukrainian State University of Chemical Technology, Gagarin Ave. 8, 49005 Dnipro, Ukraine
*
Author to whom correspondence should be addressed.
†
Presented at the 26th International Electronic Conference on Synthetic Organic Chemistry, 15–30 November 2022; Available online: https://sciforum.net/event/ecsoc-26.
Chem. Proc. 2022, 12(1), 8; https://doi.org/10.3390/ecsoc-26-13642
Published: 16 November 2022
(This article belongs to the Proceedings of The 26th International Electronic Conference on Synthetic Organic Chemistry)
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Abstract

:
Derivatives of 1,3,4-thiadiazole are of great interest for scientific and practical human activities as biologically active substances, dyes, components for creating semiconductors, energy accumulators, liquid crystals, polymers, nanomaterials, etc. Here we report the synthesis of 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide based on N,N’-disubstituted hydrazinecarbothioamide—2,4-dichloro-N-(2,2,2-trichloro-1-(2-(phenylcarbamothioyl)-hydrazine-1-carbothioamido)ethyl)benzamide. The method for obtaining the target product is based on the dehydrosulfurization reaction of the starting hydrazinecarbothioamide under the action of a mixture of iodine and triethylamine in a DMF medium. A new derivative of 1,3,4-thiadiazole was obtained in 84% yield, and its structure was confirmed by 1H and 13C NMR spectroscopy data. Molecular docking studies were carried out with the structure of the resulting compound and dihydrofolate reductase (DHFR) in the AutoDock Vina program. The resulting compound is a potential inhibitor of DHFR and surpasses several known analogues in terms of the strength of the complex formed with the active site of this enzyme.

1. Introduction

Derivatives of 1,3,4-thiadiazole are widely used in medicine, agriculture, materials science, and other areas of science and technology [1]. These compounds are of particular interest as biologically active compounds [2]. Among the derivatives of 1,3,4-thiadiazole are substances with antitumor [3,4,5,6,7,8,9,10,11], antiviral [11,12,13,14,15,16,17], antimicrobial [10,18,19,20,21,22,23,24,25,26,27,28,29,30], antioxidant [29,30], neuroprotective [31], antiprotozoal [32], and anti-inflammatory [33,34] activity. In addition, these substances act as inhibitors of acetylcholinesterase [35,36], α-glucosidase [37], and carbonic anhydrase [38]. Substances containing the 1,3,4-thiadiazole ring are also of interest as pesticides [39,40,41].
Derivatives of 1,3,4-thiadiazoles are widely used in coordination chemistry as ligands [42,43,44], in the synthesis of polymers [45], and the creation of polymer films [46,47]. The prospects of using 1,3,4-thiadiazoles in optoelectronics [48], in the purification of water from heavy metal ions [49], for the separation of minerals by the flotation method [50], and the creation of corrosion-resistant coatings [51] are discussed in the literature. A large number of works are devoted to the development of dyes and fluorescent markers based on 1,3,4-thiadiazoles [46,52,53].
In this paper, we report the synthesis of a new member of the class of 1,3,5-thiadiazoles, which contains an alkylamide fragmen—2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide, as well as molecular docking investigations of the obtained compound with the enzyme dihydrofolate reductase (DHFR).

2. Materials and Methods

2.1. Chemistry

1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were measured for solutions in DMSO-d6 on a Varian VXR-400 spectrometer. Elemental analysis was performed on a LECO CHNS-900 instrument (see Supplementary Materials). The reaction and purity of the compounds were monitored by TLC on Silufol UV-254 plates using a chloroform/acetone mixture (3:1) as an eluent.
Synthesis of 2,4-dichloro-N-(2,2,2-trichloro-1-(2-(phenylcarbamothioyl)hydrazine-1-carbothioamido)ethyl)benzamide (3). An equimolar amount (1.67 g) of N-phenylhydrazinecarbothioamide (2) [54] was added to 10 mmol (3.78 g) of 2,4-dichloro-N-(2,2,2-trichloro-1-isothiocyanatoethyl)benzamide (1) [55,56] in 35 mL of acetonitrile. The mixture was refluxed for 1–3 min and then left for 24 h. The precipitate formed was filtered, washed with acetonitrile (2 × 10 mL), and dried. The product was purified by recrystallization from acetonitrile. White solid; yield 87% (4.75 g); mp 198–200 °C (MeCN); Rf = 0.28. 1H NMR: δ 10.28 (brs, 1H, NH), 9.99 (brs, 1H, NH), 9.86 (brs, 1H, NH), 9.49 (brs, 1H, NH), 7.97 (brs, 1H, NH), 7.76–7.31 (m, 8H, arom.), 7.16 (dd, J = 6.4, 6.4 Hz, 1H, CH). 13C NMR: δ 182.8 (C=S), 182.3 (C=S), 164.6 (C=O), 138.9, 135.4, 134.1, 131.4, 130.5, 129.5, 128.1, 127.4, 125.2, 122.7 (arom.), 101.1 (CCl3), 69.9 (CH). Anal. Calcd (%) for C17H14Cl5N5OS2 (545.70): C, 37.42; H, 2.59; N, 12.83; S, 11.75. Found: C, 37.45; H, 2.56; N, 12.87; S, 11.79.
Synthesis of 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide (4). Ten mmol (5.46 g) of N,N’-disubstituted hydrazinecarbothioamide (3) was dissolved in 20 mL of DMF, a solution of 11 mmol (2.79 g) of iodine and 30 mmol (4.2 mL) of triethylamine in 10 mL of DMF was added in portions to the resulting solution with stirring. The reaction mixture was left at room temperature for 1–1.5 h. The precipitated sulfur was filtered. The product was precipitated from the filtrate with 1% aqueous sodium thiosulfate (250 mL). The precipitate formed was filtered, washed with water (2 × 50 mL), and dried. The product was purified by recrystallization from acetonitrile. Beige solid; yield 84% (4.30 g); mp 162–164 °C (MeCN); Rf = 0.38. 1H NMR: δ 9.73 (s, 1H, NH), 9.59 (brs, 1H, NH), 8.12 (d, J = 7.8 Hz, 1H, NH), 7.70 (s, 1H, arom.), 7.52–7.50 (m, 3H, arom.), 7.43–7.41 (m, 1H, arom.), 7.30–7.26 (m, 2H, arom.), 6.93–6.89 (m, 1H, arom.), 6.76 (dd, J = 9.3, 7.8 Hz, 1H, CH). 13C NMR: δ 165.4 (C=O), 157.9 (C=N), 156.6 (C=N), 141.2, 134.9, 134.6, 131.3, 130.4, 129.1, 128.9, 127.2, 120.9, 116.6 (arom.), 101.0 (CCl3), 69.7 (CH). Anal. Calcd (%) for C17H12Cl5N5OS (511.63): C, 39.91; H, 2.36; N, 13.69; S, 6.27. Found: C, 39.88; H, 2.33; N, 13.72; S, 6.30.

2.2. Molecular Docking Studies

The dihydrofolate reductase enzyme, whose structure was downloaded from the Protein Data Bank (PDB ID: 1DLS) [57], was used as a potential biological target for molecular docking. The preparation of the enzyme structure for docking was carried out using the Chimera 1.14 program [58], while water and Methotrexate molecules were removed. The ligand structures were constructed and optimized by the PM3 method [59] in the ArgusLab 4.0.1 program [60,61,62,63,64]. Molecular docking was performed using the AutoDock Vina program [65] implemented in PyRx 0.8. During the docking procedure, the center of the grid, whose coordinates were: X = 23.4 Å, Y = 16.7 Å, and Z = 1.7 Å, was centered on the amino acids Ile 5, Ala 6, Ala 7, Asp 27, Leu 28, Phe 31, Lys 32, Ser 49, Ile 50, Arg 52, Leu 54, Arg 57, Ile 94, Tyr 100, and Thr 113 [66]. The grid dimensions were 25.0 × 25.0 × 25.0 Å.

3. Results and Discussion

3.1. Chemistry

The starting 2,4-dichloro-N-(2,2,2-trichloro-1-(2-(phenylcarbamothioyl)hydrazine-1-carbothioamido)ethyl)benzamide (3) was obtained by the addition reaction of N-phenylhydrazinecarbothioamide (2) [54] to 2,4-dichloro-N-(2,2,2-trichloro-1-isothiocyanatoethyl)benzamide (1) [55,56] (Scheme 1). The reaction was carried out in an acetonitrile medium, bringing the reaction mass to a boil, and then leaving it for 24 h. Hydrazinecarbothioamide (3) precipitated quantitatively from the reaction mass. The yield of the product purified by recrystallization from acetonitrile was 87%. Under the action of iodine on hydrazinecarbothioamide (3) in a DMF medium, sulfur was eliminated, HI was formed, and the target 1,3,4-thiadiazole cycle was closed. The resulting sulfur precipitated, and HI bound to the corresponding salt with triethylamine. After removing the precipitated sulfur by filtration, the target product, 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide (4), was precipitated from the filtrate with 1% aqueous sodium thiosulfate solution. The target derivative of 1,3,4-thiadiazole was quantitatively precipitated with water, and after recrystallization from acetonitrile, the yield was 84%.
The 1H NMR spectrum of the starting hydrazinecarbothioamide (3) showed five broadened singlet NH proton signals at 10.28–7.97 ppm (Figure S1), while the spectrum of compound 4 showed three NH proton signals, a singlet at 9.73 ppm, a broadened singlet at 9.59 ppm, and a doublet at 8.12 ppm (Figure S2). The 13C NMR spectrum of compound 3 was characterized by two closely located C=S carbon signals at 182.8 and 182.3 ppm (Figure S3). In turn, in the spectrum of compound 4, there were no C=S carbon signals, but two C=N carbon signals could be observed at 157.9 and 156.6 ppm (Figure S4). All of the above points to the formal elimination of H2S and the closure of the 1,3,4-thiadiazole ring.

3.2. Molecular Docking Studies

Recently, a large number of works have appeared, devoted to the inhibition of dihydrofolate reductase (DHFR) enzyme by 1,3,4-thiadiazole derivatives, which makes these compounds potential agents for combating malignant tumors [66,67,68,69,70]. Therefore, we chose this enzyme as a potential biological target for molecular docking. We took N-(4-((Z)-1-(((Z)-5-(4-methoxyphenyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)ethyl)phenyl)-4-methylbenzenesulfonamide (Figure 1a) [66] and (E)-5-benzylidene-1-(5-(3,5-dinitrophenyl)-1,3,4-thiadiazol-2-yl)-3-phenyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (Figure 1c) [70]. According to the results of molecular docking, N-(4-((Z)-1-(((Z)-5-(4-methoxyphenyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)ethyl)phenyl)-4-methylbenzenesulfonamide formed a complex with the DHFR active site with a ∆G value of -8.2 kcal/mol. The inhibitor molecule was effectively fixed in the cavity of the active site due to four intermolecular hydrogen bonds, three of which were formed with the participation of the sulfamide group and the amino acid Glu 30 (bond lengths—3.1, 3.2, and 3.6 Å), and one more with the participation of the methoxy group and Gln 35 (bond length—3.0 Å) (Figure 1b). In turn, the molecule (E)-5-benzylidene-1-(5-(3,5-dinitrophenyl)-1,3,4-thiadiazol-2-yl)-3-phenyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione formed six intermolecular hydrogen bonds with the DHFR active site (Figure 1d), three of which involved the thiopyrimidinone fragment and amino acids Leu 28 and Gln 35 (bond lengths—2.7, 2.7, and 3.2 Å), and the remaining three hydrogen bonds were formed by the nitro group with the amino acids Asp 21 and Ser 59 (bond lengths—2.9, 3.1, and 3.3 Å). The value of ∆G was −8.4 kcal/mol.
Based on the results of molecular docking, the resulting 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide (4) (Figure 1e) surpasses the reference compounds in the strength of the complex formed with DHFR (∆G = −9.0 kcal/mol). The compound 4 molecule is fixed in the active site of the enzyme via three intermolecular hydrogen bonds, two of which are formed with the participation of the thiadiazole ring and the amino acids Asp 21 and Ser 59 (bond lengths are 3.1 and 2.8 Å, respectively) and the third hydrogen bond 3.2 Å long is formed by the secondary amino group and Tyr 22 (Figure 1f).
According to the results of molecular docking, the resulting 1,3,4-thiadiazole derivative is a potential inhibitor of DHFR and can be recommended for further in vitro investigations. Further work in the development of DHFR inhibitors based on 1,3,4-thiadiazole derivatives containing an alkylamide fragment seems to be very promising.

4. Conclusions

In this work, we have obtained a new representative of the series of 1,3,4-thiadiazoles -2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide based on 2,4-dichloro-N-(2,2,2-trichloro-1-(2-(phenylcarbamothioyl)hydrazine-1-carbothioamido)ethyl)benzamide. The structure of the target and starting compounds has reliably been confirmed by 1H and 13C NMR spectroscopy data. The obtained 1,3,4-thiadiazole derivative is promising as a potential inhibitor of dihydrofolate reductase.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ecsoc-26-13642/s1, Figure S1: 1H NMR spectra of 2,4-dichloro-N-(2,2,2-trichloro-1-(2-(phenylcarbamothioyl)hydrazine-1-carbothioamido)ethyl)benzamide (3); Figure S2: 13C NMR spectra of 2,4-dichloro-N-(2,2,2-trichloro-1-(2-(phenylcarbamothioyl)hydrazine-1-carbothioamido)ethyl)benzamide (3); Figure S3: 1H NMR spectra of 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide (4); Figure S4: 13C NMR spectra of 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide (4).

Author Contributions

V.V.P.; methodology, formal analysis, investigation. P.V.Z.; conceptualization, methodology, writing—original draft, formal analysis, investigation, visualization, project administration. V.V.K.; validation, resources, writing—review and editing. A.V.K.; validation, supervision, writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

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Chemproc 12 00008 sch001 550
Scheme 1. Synthesis of 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide (4). Reagents and conditions: (a) CH3CN, reflux 1–3 min, r.t. 24 h; (b) I2, Et3N, DMF, r.t. 1–1.5 h.
Scheme 1. Synthesis of 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide (4). Reagents and conditions: (a) CH3CN, reflux 1–3 min, r.t. 24 h; (b) I2, Et3N, DMF, r.t. 1–1.5 h.
Chemproc 12 00008 sch001
Chemproc 12 00008 g001a 550Chemproc 12 00008 g001b 550
Figure 1. Results of molecular modeling investigations of reference substances and the resulting 1,3,4-thiadiazole derivative: (a) geometry optimization of N-(4-((Z)-1-(((Z)-5-(4-methoxyphenyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)ethyl)phenyl)-4-methylbenzenesulfonamide and its position in the DHFR active site (b) [66]; (c) geometry optimization of (E)-5-benzylidene-1-(5-(3,5-dinitrophenyl)-1,3,4-thiadiazol-2-yl)-3-phenyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione and its position in the DHFR active site (d) [70]; (e) geometry optimization of 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide and its position in the DHFR active site (f).
Figure 1. Results of molecular modeling investigations of reference substances and the resulting 1,3,4-thiadiazole derivative: (a) geometry optimization of N-(4-((Z)-1-(((Z)-5-(4-methoxyphenyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)ethyl)phenyl)-4-methylbenzenesulfonamide and its position in the DHFR active site (b) [66]; (c) geometry optimization of (E)-5-benzylidene-1-(5-(3,5-dinitrophenyl)-1,3,4-thiadiazol-2-yl)-3-phenyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione and its position in the DHFR active site (d) [70]; (e) geometry optimization of 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide and its position in the DHFR active site (f).
Chemproc 12 00008 g001aChemproc 12 00008 g001b
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Pavlova, V.V.; Zadorozhnii, P.V.; Kiselev, V.V.; Kharchenko, A.V. Synthesis, Spectral Characteristics, and Molecular Docking Studies of 2,4-Dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide. Chem. Proc. 2022, 12, 8. https://doi.org/10.3390/ecsoc-26-13642

AMA Style

Pavlova VV, Zadorozhnii PV, Kiselev VV, Kharchenko AV. Synthesis, Spectral Characteristics, and Molecular Docking Studies of 2,4-Dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide. Chemistry Proceedings. 2022; 12(1):8. https://doi.org/10.3390/ecsoc-26-13642

Chicago/Turabian Style

Pavlova, Valeriia V., Pavlo V. Zadorozhnii, Vadym V. Kiselev, and Aleksandr V. Kharchenko. 2022. "Synthesis, Spectral Characteristics, and Molecular Docking Studies of 2,4-Dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide" Chemistry Proceedings 12, no. 1: 8. https://doi.org/10.3390/ecsoc-26-13642

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