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Article

Synthesis, In Vitro Evaluation and Molecular Docking Studies of Novel Thiophenyl Thiazolyl-Pyridine Hybrids as Potential Anticancer Agents

by
Fayza O. Ashmawy
1,
Sobhi M. Gomha
2,3,*,
Magda A. Abdallah
3,
Magdi E. A. Zaki
4,
Sami A. Al-Hussain
4 and
Mohamed A. El-desouky
1,*
1
Department of Chemistry, Biochemistry Division, Faculty of Science, Cairo University, Giza 12613, Egypt
2
Department of Chemistry, Faculty of Science, Islamic University of Madinah, Madinah 42351, Saudi Arabia
3
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
4
Department of Chemistry, Faculty of Science, Imam Mohammed Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(11), 4270; https://doi.org/10.3390/molecules28114270
Submission received: 9 March 2023 / Revised: 11 May 2023 / Accepted: 15 May 2023 / Published: 23 May 2023
(This article belongs to the Section Applied Chemistry)
Browse Figures
Versions Notes

Abstract

:
Many literature reports revealed the anticancer activity of pyridine and thiazole derivatives, especially in lung cancer. Therefore, a new series of thiazolyl pyridines linked with thiophene moiety via hydrazone group was prepared by one-pot multi-component reaction of (E)-1-(4-methyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)thiazol-5-yl)ethanone with benzaldehyde derivatives and malononitrile in a good yield. Then, compound 5 and the thiazolyl pyridines were investigated for their in vitro anticancer activity against lung cancer (A549) cell line using MTT assay compared to doxorubicin as a reference drug. The structure of all the newly synthesized compounds was established based on spectroscopic data and elemental analyses. For better insight to investigate their mechanism of action on A549 cell line, docking studies were performed, targeting epidermal growth factor receptor (EGFR) tyrosine kinase. The results obtained revealed that the tested compounds displayed excellent anticancer activities against lung cancer cell line except 8c and 8f compared to reference drug. Based on the data obtained, it can be inferred that the novel compounds, as well as their key intermediate, compound 5, demonstrated potent anticancer activity against lung carcinoma by inhibiting EGFR.

1. Introduction

The world’s most serious affliction, cancer, is the second leading reason for death worldwide. It is one of the life-threatening diseases that impair human health [1]. Globally, in 2020, 19.3 million new cancer cases and 9.9 million cancer-related deaths were recorded, according to the International Agency for Research on Cancer (IARC). By the end of 2030, these numbers are predicted to increase, reaching more than 24.1 million and 13.0 million [2]. Lung cancer, one of the most common types of cancer, is responsible for about 19% of cancer deaths globally, as compared to other types such as stomach, colorectal, hepatic and mammary gland cancers [3]. According to Hanahan and Weinberg, cancer is a diverse disease that displays characteristics associated with uncontrolled growth, proliferation and invasion into other organs and tissues. Cancer cells undergo significant biological changes that give rise to new cellular properties, which are established markers of cancer, including sustained proliferative signaling, growth suppressor inactivation, resistance to apoptosis, increased replicative capacity, promotion of angiogenesis, invasion of neighboring tissues and metastasis [4].
Although chemotherapy is commonly used to treat cancer, it can have significant adverse effects on healthy tissues, resulting in long-term damage to organs such as the heart, lungs, kidneys and reproductive system [5,6].
Numerous investigations have explored the use of diverse sulfur and nitrogen heterocycles, such as thiophene, thiazole, and pyridine, for the treatment of various diseases. Literature suggests that compounds featuring a thiophene core have generated significant attention in the field of drug discovery owing to their potential as anticancer agents, and they operate through multiple pathways implicated in cancer [7,8,9,10,11]. Thiazoles are important heterocyclic compounds due to their diversity of pharmacological properties and significant medicinal utility [12], including anti-bacterial, antimalarial, antiviral, antidiabetic and anticancer activities [13]. Additionally, drugs containing thiazole have been involved in several commercially available remedies for cancer, such as dasatinib [14], patellamide A [15], tiazofurin [16], ixabepilone [17], dabrafenib [18] and epothilone [19]. Moreover, anti-cancer drugs comprising a pyridine ring are streptonigrin, streptonigrone, and lavendamycin. As an attempt to develop a new anti-cancer drug, cytotoxicity and topoisomerase-inhibitory investigations were performed on some pyridine derivatives. Moreover, a large number of pyridine compounds have been recorded for their cardiotonic, antituberculosis, antibacterial and anti-hepatitis B virus activities [20,21].
Molecular hybridization of two or more heterocyclic rings enhances biological activity, such as antimalarial, tubulin inhibition, antibacterial, antidiabetic and anticancer activities [22,23,24,25,26,27]. Several studies have reported that thiazole-pyridine hybrids exhibit cytotoxicity towards cancer cells and can induce apoptosis in cancer cells (Figure 1) [28,29,30,31,32]. Ivasechko et al. reported the anticancer activity of newly synthesized thiazole-pyridine hybrids (Figure 1, I and II) against different cancer cells, with compound I being the most reactive and sensitive to lung, melanoma, colon and CNS cancer cell lines. Both compounds had shown their ability to affect DNA and cause nuclear morphology alteration that can induce genetic instability in tumor cells. Moreover, the anti-tumor activity of new series of pyridone-thiazole hybrid compounds (Figure 1, III) was estimated against colon, gastric and hepatocellular cancer, revealing the most potent one with chlorine atom in ortho position against gastric and hepatic cancer. Moreover, Vasu et al. screened nine imidazo[1,2-a]pyridine-thiazole derivatives for their anticancer activity and showed that hybrid (Figure 1, IV) was the most potent inhibitor of NF-ĸB activity. Combining pyridine with five-membered heterocycle containing nitrogen and sulfur (thiazole core) in a single hybrid structure via linker promotes interesting structural and biological characteristics, including anticancer effect on breast, liver and lung cancer (Figure 1, V). The pyridine-thiazole hybrid (shown in Figure 1, VI) was tested for its antiproliferative activity against various human carcinoma cell lines. It demonstrated notable anti-proliferative activity, specifically against the hepatocyte carcinoma (HEPG2) cell line.
Cancer is associated with the upregulation of epidermal growth factor receptors (EGFRs), potent mediators of normal cell growth and development, along with cell proliferation, apoptosis, angiogenesis and invasion for cancer cells [33]. In normal cells, low EGFR levels were recorded; on the contrary, higher levels were detected in many cancer types as lung, breast, esophagus and colon cancers. Since the amino thiazole derivatives have shown potent EGFR kinase inhibition property, the compounds containing this moiety could be potential EGFR inhibitors for anti-cancer therapy [34].
On the basis of these findings, and in continuation of our previous work on the synthesis of anticancer agents [9,20,35,36,37,38,39,40,41,42] from cheap laboratory-available starting materials with anticipated biological activities, here, hoping to obtain promising molecular candidates as anticancer agents (Figure 1), the aim of this study is to synthesize a novel series of heterocyclic compounds which are hybrids of all the mentioned bioactive heterocyclic moieties.

2. Results and Discussion

2.1. Chemistry

The required starting compound 5, namely, (E)-1-(4-methyl-2-(2-(1-(thiophen-2-yl) ethylidene)hydrazinyl)thiazol-5-yl)ethenone, was prepared as previously reported [43,44,45,46] (Scheme 1) and was used as a building block for preparing a new series of thiazolyl pyridines incorporating thiophene moiety 8a–f via one-pot three-component reaction. Thus, the reaction of compound 5 with benzaldehyde (or its derivatives) 6a–f and malononitrile 7 in the presence of ammonium acetate in glacial acetic acid under reflux led to the formation of products 8a–f (Scheme 2). The structure of the latter compounds, 8a–f, was confirmed by elemental analyses and spectral data. For example, the IR spectra revealed, in each case, two stretching absorption bands in the region ῡ 3148–3204 and 3353–3448 cm−1 attributed to the NH, NH2 groups, in addition to a sharp band in the region ῡ 2207–2222 cm−1 due to the nitrile group. The 1H-NMR spectra revealed three singlet signals in the region δ 6.87–6.94, 8.05–8.19 and 8.59–8.81 ppm assigned for the NH2, pyridyl-H and NH protons, respectively, in addition to the multiplet peaks in the aromatic region due to the aromatic protons. The mass spectra for all the new compounds 8a–f revealed, in each case, a molecular ion peak which is in accordance with the respective molecular weight.
The synthetic pathway of one-pot synthesis of amino cyanopyridine derivatives 8a–f [20,47] starts with the Claisen–Schimdt condensation reaction between the acetylthiazole derivative and substituted benzaldehyde derivatives 6 to form the α, β-unsaturated ketone intermediate. Then, the latter intermediate was reacted with malononitrile through the Michael addition reaction in the presence of ammonium acetate, followed by cyclization, auto-oxidation and finally tautomerization to afford the corresponding pyridine derivatives, 8a–f (Scheme 3).
The mass spectrum fragmentation of the newly synthesized compound 8b, taken as a representative example of series 8a–f, was investigated. The mass spectrum of 8b showed a molecular ion peak at m/z = 444 (1.76%), corresponding to its molecular formula C23H20N6S2. This molecular ion underwent fragmentation via homolytic and heterolytic α-cleavage, as shown in Scheme 4, to give the following fragment ions (molecular formula, m/z (%)): C17H14N5S; m/z = 320 (2.31%); C17H13N4S; m/z = 305 (1.53%); C10H12N3S2; m/z = 238 (2.58%); C13H10N3; m/z = 208 (1.67%); C6H7N2S; m/z = 139 (5.25%); C6H6NS; m/z = 124 (17%); C6H7S; m/z = 111 (19.76%); C6H6S; m/z = 110 (14.86%).

2.2. Cytotoxic Activity

The acetylthiazole derivative 5 and the newly synthesized compounds 8a–f were evaluated for their in vitro anticancer screening against human lung cancer (A549) cell line using MTT colorimetric assay with doxorubicin as a reference drug. Data obtained from MTT assay are depicted in Table 1 and show that generally, the tested compounds exert promising cytotoxic activities against A549 cell line except 8c and 8f when compared to doxorubicin that has IC50 of 0.460 µM. It was noticed that compound 5 has IC50 value of 0.452 µM. This potency may be due to the presence of both thiophene and thiazole rings in one hybrid molecule through hydrazone linkage exerting this action on A549 cell line in a good manner, which is reflected as an efficient anticancer agent.
This current result is in agreement with Rodríguez et al. [48] who reported an anticancer activity against the A549 cell line for a compound containing thiophene moiety after 24 h treatment. Similarly, a series of compounds comprising thiazole ring was noted to have anticancer activity after treatment of A549 cell line for 24 h [49].
Regarding compounds 8a–f, compounds 8e and 8f were identified as the most and least effective ones against the A549 cell line with IC50 of 0.302 and 0.788 µM, respectively, while the rest showed an intermediate activity. The anticancer activity of the newly synthesized products 8a–f can be attributed to the addition of a substituted pyridine ring to structure 5, elucidating that this addition has an influence on the cytotoxicity against human lung cancer cell line. This finding is in line with Suma et al. [50] who recorded an anticancer activity for a series of compounds containing both pyridine and thiazole rings with IC50 ranging from 0.66 to 16.03 µM with the most effective one having IC50 of 0.66 µM after 24 h treatment of A549 cell line.

2.3. Molecular Docking Studies

To investigate the binding mode of all the tested compounds, 5 and 8a–f, towards EGFR tyrosine kinase domain, molecular docking was conducted, where the results were compared with a known EGFR inhibitor as erlotinib, with binding energy S = −21.9889 Kcal/mol in addition to their corresponding binding energies, as shown in Table 2. It was found that compound 5, having energy E = 41.2253 Kcal/mol, interacts by the nitrogen atom of hydrazone linkage through hydrogen bond with key amino acid threonine (Thr830) with binding energy S = −20.1495 Kcal/mol and bond length of 2.16 Å, suggesting that threonine is the most reactive amino acid in the protein structure with compound 5 as compared to the series.
Based on the interaction of compounds 8a–f with EGFR, as shown in Figure 2, they can be divided into two groups: group A and group B. In group A, which comprises 8a,c,d and has mean energy E = 82.7210 Kcal/mol, it was observed that all of them interact via hydrogen bonding (via the hydrogen atom of the amine moiety attached to the pyridine ring) with amino acid Asp831 residue with mean binding energy S = −24.2234 Kcal/mol and mean bond length of 1.989 Å. Meanwhile, group B including 8b,e,f, with mean energy E = 75.8467 Kcal/mol and mean binding energy S = −24.4538 Kcal/mol, showed two arene–cation interactions, one between the substituted benzene ring attached to pyridine ring and lysine (Lys721) residue in three compounds and the other between thiophene ring and arginine (Arg817) residue in the case of 8b and 8e; except for 8f, the arene–cation interaction was between pyridine ring and amino acid arginine (Arg817). This change in the interaction may be due to the variance in the molecular weight since 8f has the highest molecular weight within this group. Concurrently, it was noticed that group B exhibits a slightly more stable interaction with the EGFR active site, which may be due to the difference in molecular weight among all the tested compounds.

3. Experimental Section

3.1. Reagents Used

2-Acetylthiophene and thiosemicarbazide were purchased from LOBA Chemie (Mumbai, India) and Research-Lab Fine Chem Industries (Mumbai, India), respectively, while both glacial acetic acid and sulfuryl chloride were purchased from Alpha Chemika (Mumbai, India). Ethanol, absolute (HPLC grade) and Acetylacetone were purchased from Fisher Scientific Co. (Loughborough, United Kingdom) and EL Nasr Pharmaceutical Chemical Co. (Cairo, Egypt), respectively. Malononitrile, Penicillin-Streptomycin, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and Trypan blue dye were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA), while Ammonium acetate was purchased from EL Nasr Pharmaceutical Chemical Co. (Egypt). Benzaldehyde, 4-methylbenzaldehyde, 4-chlorobenzaldehyde, 2,6-dichloro benzaldehyde and 4-nitrobenzaldehyde were purchased from Merck (Darmstadt, Germany), while 4-methoxybenzaldehyde and dimethyl sulfoxide (DMSO) and ethanol 70% were purchased from BDH (London, England). Both RPMI 1640 medium with L- glutamine and phosphate buffer saline (PBS) were purchased from Lonza BioWhittaker (Verviers, Belgium), while Fetal bovine serum (FBS) and Trypsin 0.25% were purchased from Gibco (Grand Island, NY, USA) and Amresco (Solon, OH, USA), respectively.

3.2. Chemistry

Melting points were measured using an Electrothermal Gallenkamp digital melting point apparatus and were reported uncorrected. IR spectra were recorded in potassium bromide discs using PyeՍnicam SP-1000 spectrometer. 1H-NMR spectra were recorded using deuterated dimethyl sulfoxide (DMSO-d6) solution on a Varian Mercury VX-300 MHz spectrometer, and 13C-NMR spectra were recorded at 75.46 MHz. Chemical shifts are quoted in δ and were reported related to that of solvents. Mass spectra were recorded using a Shimadzu GCMS-Qp-2010 Plus mass spectrometer (Tokyo, Japan) operating at 70 eV. Elemental analyses were carried out by the Microanalytical Centre of Cairo University, Giza, Egypt.
Synthesis of 2-(1-(thiophen-2-yl)ethylidene)hydrazine carbothioamide 3 [43,44,45,46]
Synthesis of (E)-1-(4-methyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)thiazol-5-yl) ethanone 5 [43,44,45,46].
General procedure for synthesis of products 8a–f
A mixture of compound 5, benzaldehyde or its derivatives 6a–f (2 mmol each) and malononitrile 7 in glacial acetic acid (5 mL) containing 0.5 g of ammonium acetate was refluxed for 4 h and then cooled. The solid formed was filtered and crystallized from acetic acid to give products 8a–f (see Supporting Information File).
(E)-2-Amino-6-(4-methyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)thiazol-5-yl)-4-phenylnicotinonitrile (8a)
Yellow color, yield 83%, m.p 117–119 °C, IR (KBr, cm−1): 3426, 3181 (NH2, NH), 3064 (Ar-H), 2927 (-C-H), 2212 (C≡N), 1625 (C=N), 1565 (C=CArom), 1313 (C–N), 885 (C–S). 1H-NMR (300 MHz, DMSO-d6) δ 2.36 (s, 3H, CH3), 2.39 (s, 3H, CH3), 6.89 (s, 2H, NH2), 7.04–7.05 (m, 1H, thienyl-H), 7.37–7.45 (m, 5H, Ar-H), 7.49–7.51 (d, 1H, thienyl-H), 7.64–7.66 (d, 1H, thienyl-H), 8.09 (s, 1H, pyridyl-H), 8.63 (s, 1H, NH) ppm. 13C-NMR (DMSO-d6): δ = 14.7, 21.2 (CH3), 112.3, 119.9, 122.1, 126.8, 127.1, 127.6, 128.3, 128.9, 129.3, 129.9, 134.1, 143.5, 144.9, 148.3, 152.3, 156.1, 168.4, 169.2 (Ar-C and C=N) ppm. MS, m/z (%): 431 (M+, 1), 327 (3), 279 (47), 236 (4.16), 141 (100), 139 (2), 124 (63.7), 111 (14.68), 110 (46.56), 97 (24), 77 (61), 67 (34), 57 (10). Analysis for C22H18N6S2 (430.56). Calcd: C, 61.37; H, 4.21; N, 19.52. Found: C, 61.20; H, 3.98; N, 19.30%.
(E)-2-Amino-6-(4-methyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)thiazol-5-yl)-4-(p-tolyl)nicotinonitrile (8b)
Orange color, yield 80%, m.p 116–118 °C, IR (KBr, cm−1): 3419, 3189 (NH2, NH), 3034 (Ar-H), 2918 (-C-H), 2221 (C≡N), 1605 (C=N), 1550 (C=CArom), 1369 (C–N), 814 (C–S). 1H-NMR (DMSO-d6) δ 2.30 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.45 (s, 3H, CH3), 6.94 (s, 2H, NH2), 7.06–7.08 (m, 1H, thienyl-H), 7.23–7.26 (d, J = 8 Hz, 2H, Ar-H), 7.36–7.44 (d, 1H, thienyl-H), 7.52–7.57 (d,1H, thienyl-H), 7.84–7.86 (d, J = 8 Hz, 2H, Ar-H), 8.08 (s, 1H, pyridyl-H), 8.64 (s, 1H, NH) ppm. 13C-NMR (DMSO-d6): δ = 14.9, 21.1, 21.6 (CH3), 113.5, 114.5, 122.0, 127.0, 127.4, 127.7, 129.5, 129.9, 30.2, 130.8, 140.1, 143.0, 145.7, 146.1, 148.8, 150.5, 161.3, 163.0 (Ar-C and C=N) ppm. MS, m/z (%): 444 (M+, 1.76), 423 (4), 367 (6), 320 (2.31), 313 (17), 305 (1.53), 239 (15), 238 (2.58), 208 (1.67), 141 (8), 139 (5.25), 124 (17), 111 (19.76), 110 (14.86), 97 (37), 83 (48), 71 (58), 57 (100). Analysis for C23H20N6S2 (444.59). Calcd: C, 62.14; H, 4.54; N, 18.90. Found: C, 61.92; H, 4.40; N, 18.60%.
(E)-2-Amino-4-(4-methoxyphenyl)-6-(4-methyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)thiazol-5-yl)nicotinonitrile (8c)
Orange color, yield 86%, m.p 121–123 °C, IR (KBr, cm−1): 3383, 3204 (NH2, NH), 3097 (Ar-H), 2928 (-C-H), 2208 (C≡N), 1605 (C=N), 1572 (C=CArom), 1299 (C–N), 828 (C–S). 1H-NMR (DMSO-d6) δ 2.31 (s, 3H, CH3), 2.46 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 6.87 (s, 2H, NH2), 7.07–7.10 (m, 1H, thienyl-H), 7.12–7.21 (d, J = 9 Hz, 2H, Ar-H), 7.58–7.62 (d, 1H, thienyl-H), 7.69–7.73 (d,1H, thienyl-H), 7.84–7.86 (d, J = 9 Hz, 2H, Ar-H), 8.05 (s, 1H, pyridyl-H), 8.59 (s, 1H, NH) ppm. MS, m/z (%): 460 (M+, 6), 441 (6), 374 (4), 349 (5), 336 (10), 306 (24), 265 (8), 236 (4.36), 209 (5), 160 (10), 139 (14), 134 (23), 124 (43.62), 121 (100), 111 (23.39), 110 (35.88), 97 (34), 83 (30), 77 (33), 57 (47). Analysis for C23H20N6S2O (460.59). Calcd: C, 59.98; H, 4.38; N, 18.25. Found: C, 59.62; H, 4.51; N, 17.82%.
(E)-2-Amino-6-(4-methyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)thiazol-5-yl)-4-(4-nitrophenyl)nicotinonitrile (8d)
Orange color, yield 85%, m.p 144–146 °C, IR (KBr, cm−1): 3430, 3177 (NH2, NH), 3079 (Ar-H), 2931 (-C-H), 2212 (C≡N), 1628 (C=N), 1563 (C=CArom), 1316 (C–N), 846 (C–S). 1H-NMR (DMSO-d6) δ 2.38 (s, 3H, CH3), 2.44 (s, 3H, CH3), 6.91 (s, 2H, NH2), 7.04–7.07 (m, 1H, thienyl-H), 7.38–7.40 (d, 1H, thienyl-H), 7.51–7.53 (d, 1H, thienyl-H), 7.88–7.92 (d, J = 9 Hz, 2H, Ar-H), 8.19 (s, 1H, pyridyl-H), 8.24–8.27 (d, J = 9 Hz, 2H, Ar-H), 8.81 (s, 1H, NH) ppm. 13C-NMR (DMSO-d6): δ = 14.6, 21.0 (CH3), 114.1, 119.9, 122.4, 123.7, 124.0, 127.1, 127.4, 127.6, 128.1, 128.3, 142.4, 143.4, 147.4, 148.2, 152.2, 155.1, 168.3, 169.0 (Ar-C and C=N) ppm. MS, m/z (%): 475.80 (M+, 0.35), 423 (1), 393 (1), 367 (2), 339 (3), 313 (6), 264 (6), 239 (8), 236 (2.99), 171 (4), 141 (14), 139 (6.29), 124 (18.43), 111 (24.32), 110 (21.03), 97 (50), 83 (69), 69 (71), 57 (100). Analysis for C22H17N7S2O2 (475.55). Calcd: C, 55.57; H, 3.60; N, 20.62. Found: C, 55.68; H, 3.51; N, 19.98%.
(E)-2-Amino-4-(4-chlorophenyl)-6-(4-methyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)thiazol-5-yl)nicotinonitrile (8e)
Yellow color, yield 84%, m.p 199–201 °C, IR (KBr, cm−1): 3448, 3148 (NH2, NH), 3028 (Ar-H), 2930 (-C-H), 2222 (C≡N), 1630 (C=N), 1563 (C=CArom), 1312 (C–N), 821 (C–S). 1H-NMR (DMSO-d6) δ 2.37 (s, 3H, CH3), 2.39 (s, 3H, CH3), 6.90 (s, 2H, NH2), 7.03–7.07 (m, 1H, thienyl-H), 7.32–7.35 (d, J = 9 Hz, 2H, Ar-H), 7.46–7.51 (d, 1H, thienyl-H), 7.66–7.69 (d,1H, thienyl-H), 7.85–7.88 (d, J = 9 Hz, 2H, Ar-H), 8.08 (s, 1H, pyridyl-H), 8.64 (s, 1H, NH) ppm. 13C-NMR (DMSO-d6): δ = 14.5, 20.9 (CH3), 115.0, 120.4, 121.9, 123.2, 125.8, 127.3, 127.4, 127.8, 128.0, 129.4, 141.5, 143.0, 146.8, 147.9, 150.5, 157.0, 167.4, 168.7 (Ar-C and C=N) ppm. MS, m/z (%): 467 (M++2, 1), 465 (M+, 3), 373 (8), 340 (7), 292 (16), 236 (5.59), 201 (8), 188 (10), 156 (36), 141 (100), 139 (35.85), 124 (60), 111 (66), 110 (42.35), 75 (72), 55 (94). Analysis for C22H17N6S2Cl (465.00). Calcd: C, 56.83; H, 3.69; N, 18.08. Found: C, 57.10; H, 3.52; N, 17.80%.
(E)-2-Amino-4-(2,6-dichlorophenyl)-6-(4-methyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)thiazol-5-yl)nicotinonitrile (8f)
Brownish red color, yield 82%, m.p 201–203 °C, IR (KBr, cm−1): 3353, 3194 (NH2, NH), 3096 (Ar-H), 2999, 2928 (-C-H), 2207 (C≡N), 1605 (C=N) 1548 (C=CArom), 1297 (C–N), 827 (C–S). 1H-NMR (DMSO-d6) δ 2.31 (s, 3H, CH3), 2.48 (s, 3H, CH3), 6.89 (s, 2H, NH2), 7.08–7.10 (m, 1H, thienyl-H), 7.11–7.22 (m, 3H, Ar-H), 7.59–7.68 (m, 2H, Ar-H), 8.13 (s, 1H, pyridyl-H), 8.68 (s, 1H, NH) ppm. MS, m/z (%): 499 (M+, 0.07), 467 (0.91), 418 (1), 379 (2), 349 (12), 325 (21), 308 (100), 265 (21), 237 (16), 236 (6.64), 139 (10.48), 134 (30), 124 (12.61), 121 (78), 111 (21.61), 110 (34), 77 (34), 57 (34). Analysis for C22H16N6S2Cl2 (499.45). Calcd: C, 52.91; H, 3.23; N, 16.83. Found: C, 52.71; H, 3.11; N, 16.62%.

3.3. Maintenance of Cell Line

Human lung adenocarcinoma (A549) cell line was obtained from Egyptian holding company for vaccines and sera (VACSERA) (Cell Culture lab., Cairo, Egypt). The cell line was maintained according to Esmail et al. [51].

3.4. Cytotoxicity Assay

MTT assay is a sensitive, quantitative and reliable colorimetric method that measures cells’ viability. It is based on the fact that the water-soluble substrate 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), utilized as 5 mg/mL, can be converted by mitochondrial lactate dehydrogenase enzymes (LDH) into a water-insoluble dark blue formazan in living cells. The insoluble purple formazan product is dissolved into a colored solution by the addition of a solubilization solution as dimethyl sulfoxide (DMSO). This colored solution’s absorbance can be measured using a spectrophotometer at a wavelength between 500 and 600 nm [52].
The cytotoxic effect of the synthesized compounds and the reference medication (doxorubicin) was evaluated using MTT assay. The tested compounds 8a–f were dissolved in DMSO and used at different concentrations to perform the assay. Precultured cell lines were exposed to the tested materials at 2-fold serial dilutions for 24 h at 37 °C following the decantation of growing media. Microscopically, the treated cell lines were inspected for morphological alterations and detached cells. Phosphate buffer saline (PBS), pH 7.2 ± 0.2, was used to remove dead cells. Residual live cells were treated with 0.5 % MTT stain as 25 µL/well. The plate was incubated for 3–4 h at 37 °C. A total of 0.05 mL of DMSO was used to dissolve formed intra-cytoplasmic MTT formazan crystals for 30 min on a plate shaker. Optical densities were determined using ELISA plate reader (Biotek—8000, USA). Data were reported for three independent experiments and represented as means [53]. The viability percentage was computed as follows: Cell viability percentage = (optical density of treated cells/optical density of untreated cells) × 100 [54]. IC50 of the tested compounds were determined using Master –plex-2010 program. Morphological changes were observed 24 h post-treatment using an inverted phase contrast microscope according to Zhang et al. [55].

3.5. Molecular Docking Study

Docking studies for the compounds were performed using Molecular Operating Environment (MOE) program, 2009.10 version, to examine ligand–protein interactions at the protein active site. The Protein Data Bank (PDB) was used to download the EGFR protein structure (www.rcsb.org (accessed on 8 March 2023), with PDB code: 4HJO). The grid box patterns were 30.077, 5.987 and 1.141. For preparation of the protein, the standard ligand molecules were removed from the protein’s active site; then, hydrogen atoms were added while maintaining all the heavy atoms in place. Partial charges were calculated using the MMFF94x force field. The program’s final structure was saved as a Pdb file and visualized using BIOVIA Discovery Studio V6.1.0.15350 program, where the target molecule seemed to fit into the protein’s active domain in 3D form.

4. Conclusions

Overall result, compound 5 and both groups A and B have nearly the same and higher binding energies than previously reported inhibitors as erlotinib, respectively, indicating that synthesized moieties have a greater binding ability with EGFR protein, and resulting in more effective blockage. Based on these findings, compound 5 and amino cyanopyridine derivatives 8a–f were observed to have promising chemotherapeutic effect on lung cancer cells. Compound 5 has the smallest molecular weight, while compounds 8a–f have higher molecular weight. The observed interactions may be accountable for the EGFR inhibition potency of all tested compounds that can vary according to the molecular weight. Also, the tested compounds record better anticancer activity except 8c and 8f as compared to the reference drug. As a result, the current investigation indicated that the described thiazolyl pyridines are promising EGFR inhibitors and pave the way for the synthesis of other libraries based on the reported scaffold, which may eventually result in the creation of an effective therapy for lung cancer.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28114270/s1, Some 1H-, 13C-NMR, IR, and Mass spectra of the synthesized compounds.

Author Contributions

Conceptualization, Methodology, Validation, Formal analysis, Data curation, Writing—original draft, Visualization: F.O.A., S.M.G., M.A.A. and M.A.E.-d.; Investigation: F.O.A.; Resources: F.O.A. and S.M.G.; Supervision, Writing—review and editing, Funding acquisition: F.O.A., S.M.G., M.A.A., M.E.A.Z., S.A.A.-H. and M.A.E.-d. 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

The data presented in this study are available on request.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of compounds 5 and 8a–f are available from the authors.

References

  1. Sanduja, M.; Gupta, J.; Virmani, T. Recent advancements in Uracil and 5-Fluorouracil hybrids as potential anticancer agents, A review. J. Appl. Pharm. Sci. 2020, 10, 129–146. [Google Scholar] [CrossRef]
  2. Teli, G.; Chawla, P.A. Hybridization of imidazole with various heterocycles in targeting cancer: A decade’s work. ChemistrySelect 2021, 6, 4803–4836. [Google Scholar] [CrossRef]
  3. Rajendran, P.; Maheshwari, U.; Muthukrishnan, A.; Muthuswamy, R.; Anand, K.; Ravindran, B.; Dhanaraj, P.; Balamuralikrishnan, B.; Chang, W.S.; Chung, W.J. Myricetin: Versatile plant based flavonoid for cancer treatment by inducing cell cycle arrest and ROS–reliant mitochondria-facilitated apoptosis in A549 lung cancer cells and in silico prediction. Mol. Cell. Biochem. 2021, 476, 57–68. [Google Scholar] [CrossRef]
  4. Ponte, L.G.S.; Pavan, I.C.B.; Mancini, M.C.S.; da Silva, L.G.S.; Morelli, A.P.; Severino, M.B.; Bezerra, R.M.N.; Simabuco, F.M. The hallmarks of flavonoids in cancer. Molecules 2021, 26, 2029. [Google Scholar] [CrossRef] [PubMed]
  5. Bukowski, K.; Kciuk, M.; Kontek, R. Mechanisms of multidrug resistance in cancer chemotherapy. Int. J. Mol. Sci. 2020, 21, 3233. [Google Scholar] [CrossRef]
  6. Véras Of Aguiar, A.C.; Olímpio of Moura, R.; Mendonça Junior, J.F.B.; de Oliveira Rocha, H.A.; Câmara, R.B.G.; Schiavon, M.D.S.C. Evaluation of the antiproliferative activity of 2-amino thiophene derivatives against human cancer cells lines. Biomed. Pharmacother. 2016, 84, 403–414. [Google Scholar] [CrossRef]
  7. Dos Santos, F.A.; Pereira, M.C.; de Oliveira, T.B.; Mendonça Junior, F.J.B.; de Lima, M.D.C.A.; Pitta, M.G.D.R.; Pitta, I.D.R.; de Melo Rêgo, M.J.B.; da Rocha Pitta, M.G. Anticancer properties of thiophene derivatives in breast cancer MCF-7 cells. Anti-Cancer Drugs 2018, 29, 157–166. [Google Scholar] [CrossRef] [PubMed]
  8. Shah, R.; Verma, P.K. Synthesis of thiophene derivatives and their anti-microbial, antioxidant, anticorrosion and anticancer activity. BMC Chem. 2019, 13, 54. [Google Scholar] [CrossRef] [PubMed]
  9. Gomha, S.M.; Riyadh, S.M.; Huwaimel, B.; Zayed, M.E.M.; Abdellattif, M.H. Synthesis, molecular docking study and cytotoxic activity on MCF cells of some new thiazole clubbed thiophene scaffolds. Molecules 2022, 27, 4639. [Google Scholar] [CrossRef]
  10. De Vasconcelos, A.; Campos, V.F.; Nedel, F.; Seixas, F.K.; Dellagostin, O.A.; Smith, K.R.; de Pereira, C.M.P.; Stefanello, F.M.; Collares, T.; Barschak, A.G. Cytotoxic and apoptotic effects of chalcone derivatives of 2-acetyl thiophene on human colon adenocarcinoma cells. Cell Biochem. Funct. 2013, 31, 289–297. [Google Scholar] [CrossRef]
  11. Gulipalli, K.C.; Bodige, S.; Ravula, P.; Endoori, S.; Vanaja, G.R.; Babu, G.S.; Chandra, J.N.N.; Seelam, N. Design, synthesis, in silico and in vitro evaluation of thiophene derivatives: A potent tyrosine phosphatase 1B inhibitor and anticancer activity. Bioorg. Med. Chem. Lett. 2017, 27, 3558–3564. [Google Scholar] [CrossRef] [PubMed]
  12. Bondock, S.; Albormani, O.; Fouda, A.M.; Abu Safieh, K.A. Progress in the chemistry of 5-acetylthiazoles. Synth. Commun. 2016, 46, 1081–1111. [Google Scholar] [CrossRef]
  13. Sharma, P.C.; Bansal, K.K.; Sharma, A.; Sharma, D.; Deep, A. Thiazole-containing compounds as therapeutic targets for cancer therapy. Eur. J. Med. Chem. 2020, 188, 112016–112062. [Google Scholar] [CrossRef] [PubMed]
  14. Li, X.; He, Y.; Ruiz, C.H.; Koenig, M.; Cameron, M.D. Characterization of dasatinib and its structural analogs as CYP3A4 mechanism-based inactivators and the proposed bioactivation pathway. Drug Metab. Dispos. 2009, 37, 1242–1250. [Google Scholar] [CrossRef]
  15. Rashid, M.A.; Gustafson, K.R.; Cardellina, J.H.; Boyd, M.R. Patellamide F, a new cytotoxic cyclic peptide from the colonial ascidian Lissoclinum patella. J. Nat. Prod. 1995, 58, 594–597. [Google Scholar] [CrossRef]
  16. Franchetti, P.; Cappellacci, L.; Grifantini, M.; Barzi, A.; Nocentini, G.; Yang, H.; O’Connor, A.; Jayaram, H.N.; Carrell, C.; Goldstein, B.M. Furanfurin and Thiophenfurin: Two Novel Tiazofurin Analogs. Synthesis, Structure, Antitumor Activity, and Interactions with Inosine Monophosphate Dehydrogenase. J. Med. Chem. 1995, 38, 3829–3837. [Google Scholar] [CrossRef]
  17. Yao, Y.; Chen, S.; Zhou, X.; Xie, L.; Chen, A. 5-FU and ixabepilone modify the microRNA expression profiles in MDA-MB-453 triple-negative breast cancer cells. Oncol. Lett. 2014, 7, 541–547. [Google Scholar] [CrossRef] [PubMed]
  18. Hu-Lieskovan, S.; Mok, S.; Homet Moreno, B.; Tsoi, J.; Robert, L.; Goedert, L.; Pinheiro, E.M.; Koya, R.C.; Graeber, T.; Comin-Anduix, B.; et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF V600E melanoma. Sci. Transl. Med. 2015, 7, 279ra41. [Google Scholar] [CrossRef]
  19. Altmann, K.H. Epothilone B and its analogs-a new family of anticancer agents. Mini Rev. Med. Chem. 2003, 3, 149–158. [Google Scholar] [CrossRef] [PubMed]
  20. Abdallah, M.A.; Gomha, S.M.; Abbas, I.M.; Kazem, M.S.H.; Alterary, S.S.; Mabkhot, Y.N. An Efficient synthesis of novel pyrazole-based heterocycles as potential antitumor agents. Appl. Sci. 2017, 7, 785. [Google Scholar] [CrossRef]
  21. Alqahtani, A.M.; Bayazeed, A.A. Synthesis and antiproliferative activity studies of new functionalized pyridine linked thiazole derivatives. Arab. J. Chem. 2021, 14, 102914–102927. [Google Scholar] [CrossRef]
  22. Singh, H.; Singh, J.V.; Gupta, M.K.; Saxena, A.K.; Sharma, S.; Nepali, K.; Bedi, P.M.S. Triazole tethered isatin-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies. BMCL 2017, 27, 3974–3979. [Google Scholar] [CrossRef] [PubMed]
  23. Hooshmand, S.E.; Ghadari, R.; Mohammadian, R.; Shaabani, A.; Khavasi, H.R. Rhodanine-Furan Bis-Heterocyclic Frameworks Synthesis via Green One-Pot Sequential Six-Component Reactions: A Synthetic and Computational Study. ChemistrySelect 2019, 4, 11893–11898. [Google Scholar] [CrossRef]
  24. Kumar, D.; Khan, S.I.; Ponnan, P.; Rawat, D.S. Triazine–pyrimidine based molecular hybrids: Synthesis, docking studies and evaluation of antimalarial activity. New J. Chem. 2014, 38, 5087–5095. [Google Scholar] [CrossRef]
  25. Gomha, S.M.; Abdel-aziz, H.M. Synthesis and antitumor activity of 1,3,4-thiadiazole derivatives bearing coumarine ring. Heterocycles 2015, 91, 583–592. [Google Scholar] [CrossRef]
  26. Kekeçmuhammed, H.; Tapera, M.; Tüzün, B.; Akkoç, S.; Zorlu, Y.; Sarıpınar, E. Synthesis, Molecular Docking and Antiproliferative Activity Studies of a Thiazole-Based Compound Linked to Hydrazone Moiety. ChemistrySelect 2022, 7, e202201502. [Google Scholar] [CrossRef]
  27. Bhavya, K.; Mantipally, M.; Roy, S.; Arora, L.; Badavath, V.N.; Gangireddy, M.; Dasgupta, S.; Gundla, R.; Pal, D. Novel imidazo [1, 2-a] pyridine derivatives induce apoptosis and cell cycle arrest in non-small cell lung cancer by activating NADPH oxidase mediated oxidative stress. Life Sci. 2022, 294, 120334–120346. [Google Scholar] [CrossRef]
  28. Ivasechko, I.; Yushyn, I.; Roszczenko, P.; Senkiv, J.; Finiuk, N.; Lesyk, D.; Holota, S.; Czarnomysy, R.; Klyuchivska, O.; Khyluk, D.; et al. Development of novel pyridine-thiazole hybrid molecules as potential anticancer agents. Molecules 2022, 27, 6219. [Google Scholar] [CrossRef]
  29. Xie, W.; Wu, Y.; Zhang, J.; Mei, Q.; Zhang, Y.; Zhu, N.; Liu, R.; Zhang, H. Design, synthesis and biological evaluations of novel pyridone-thiazole hybrid molecules as antitumor agents. Eur. J. Med. Chem. 2018, 145, 35–40. [Google Scholar] [CrossRef]
  30. Vasu, K.K.; Digwal, C.S.; Pandya, A.N.; Pandya, D.H.; Sharma, J.A.; Patel, S.; Agarwal, M. Imidazo[1,2-a]pyridines linked with thiazoles/thiophene motif through keto spacer as potential cytotoxic agents and NF-ĸB inhibitors. Bioorg. Med. Chem. Lett. 2017, 27, 5463–5466. [Google Scholar] [CrossRef]
  31. Dos Santos Silva, T.D.; Bomfim, L.M.; da Cruz Rodrigues, A.C.B.; Dias, R.B.; Sales, C.B.S.; Rocha, C.A.G.; Soares, M.B.P.; Bezerra, D.P.; de Oliveira Cardoso, M.V.; Leite, A.C.L.; et al. Anti-liver cancer activity in vitro and in vivo induced by 2-pyridyl 2,3-thiazole derivatives. Toxicol. Appl. Pharm. 2017, 329, 212–223. [Google Scholar] [CrossRef]
  32. Amin, H.K.; El-Araby, A.M.; Eid, S.; Nasr, T.; Bondock, S.; Leheta, O.; Dawoud, M.E. A thiazole analogue exhibits an antiproliferative effect in different human carcinoma cell lines and its mechanism based on molecular modeling. Adv. Biol. Chem. 2017, 7, 76–87. [Google Scholar] [CrossRef]
  33. Ayati, A.; Moghimi, S.; Salarinejad, S.; Safavi, M.; Pouramiri, B.; Foroumadi, A. A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy. Bioorg. Chem. 2020, 99, 103811–103826. [Google Scholar] [CrossRef]
  34. Palabindela, R.; Guda, R.; Ramesh, G.; Myadaraveni, P.; Banothu, D.; Ravi, G.; Korra, R.; Mekala, H.; Kasula, M. Novel tryptanthrin hybrids bearing aminothiazoles as potential EGFR inhibitors: Design, synthesis, biological screening, molecular docking studies, and ADME/T predictions. J. Heterocycl. Chem. 2022, 59, 1533–1550. [Google Scholar] [CrossRef]
  35. Abbas, I.M.; Gomha, S.M.; Elaasser, M.M.; Bauomi, M.A. Synthesis and biological evaluation of new pyridines containing imidazole moiety as antimicrobial and anticancer agents. Turk. J. Chem. 2015, 39, 334–346. [Google Scholar] [CrossRef]
  36. Gomha, S.M.; Muhammad, Z.A.; Abdel-aziz, M.R.; Abdel-aziz, H.M.; Gaber, H.M.; Elaasser, M.M. One-pot synthesis of new thiadiazolyl-pyridines as anticancer and antioxidant agents. J. Heterocycl. Chem. 2018, 55, 530–536. [Google Scholar] [CrossRef]
  37. Gomha, S.M.; Kheder, N.A.; Abdelaziz, M.R.; Mabkhot, Y.N.; Alhajoj, A.M. A facile synthesis and anticancer activity of some novel thiazoles carrying 1,3,4-thiadiazole moiety. Chem. Cent. J. 2017, 11, 25. [Google Scholar] [CrossRef]
  38. Gomha, S.M.; Edrees, M.M.; Muhammad, Z.A.; El-Reedy, A.A.M. 5-(Thiophen-2-yl)-1,3,4- thiadiazole derivatives: Synthesis, molecular docking and in-vitro cytotoxicity evaluation as potential anticancer agents. Drug Des. Devel. Ther. 2018, 12, 1511–1523. [Google Scholar] [CrossRef]
  39. Al-Mutabagani, L.A.; Abdelrazek, F.M.; Gomha, S.M.; Hebishy, A.S.; Abdelfattah, M.S.; Hassan, S.M.; Sayed, A.R.; Elaasser, M.M. Synthesis and Biological Evaluation of Thiazolyl-ethylidene hydrazino-thiazole Derivatives: A Novel Heterocyclic System. Appl. Sci. 2021, 11, 8908. [Google Scholar] [CrossRef]
  40. Edrees, M.M.; Abu-Melha, S.; Saad, A.M.; Kheder, N.A.; Gomha, S.M.; Muhammad, Z.A. Eco-friendly synthesis, characterization and biological evaluation of some novel pyrazolines containing thiazole moiety as potential anticancer and antimicrobial agents. Molecules 2018, 23, 2970. [Google Scholar] [CrossRef]
  41. Abu-Melha, S.; Edrees, M.M.; Salem, H.H.; Kheder, N.A.; Gomha, S.M.; Abdelaziz, M.R. Synthesis and biological evaluation of some novel thiazole-based heterocycles as potential anticancer and antimicrobial agents. Molecules 2019, 24, 539. [Google Scholar] [CrossRef]
  42. Gomha, S.M.; Muhammad, Z.A.; Abdel-aziz, H.M.; Matar, I.K.; El-Sayed, A.A. Green synthesis, molecular docking and anticancer activity of novel 1,4-dihydropyridine-3,5-Dicarbohydrazones under grind-stone chemistry. Green Chem. Lett. Rev. 2020, 13, 6–17. [Google Scholar] [CrossRef]
  43. Makam, P.; Kankanala, R.; Prakash, A.; Kannan, T. 2-(2-Hydrazinyl) thiazole derivatives: Design, synthesis and in vitro antimycobacterial studies. Eur. J. Med. Chem. 2013, 69, 564–576. [Google Scholar] [CrossRef]
  44. El-Naggar, A.M.; El-Hashash, M.A.; Elkaeed, E.B. Eco-friendly sequential one-pot synthesis, molecular docking, and anticancer evaluation of arylidene-hydrazinyl-thiazole derivatives as CDK2 inhibitors. Bioorg. Chem. 2021, 108, 104615–104629. [Google Scholar] [CrossRef]
  45. Makam, P.; Thakur, P.K.; Kannan, T. In vitro and in silico antimalarial activity of 2-(2-hydrazinyl)thiazole derivatives. Eur. J. Pharmaceut. Sci. 2014, 52, 138–145. [Google Scholar] [CrossRef]
  46. Mahmoud, H.K.; Abdelhady, H.A.; Elaasser, M.M.; Hassain, D.Z.H.; Gomha, S.M. Microwave-Assisted One-Pot Three Component Synthesis of Some Thiazolyl(Hydrazonoethyl)Thiazoles as Potential Anti-Breast Cancer Agents. Polycycl. Aromat. Comp. 2022, 42, 7232–7246. [Google Scholar] [CrossRef]
  47. El-Sayed, N.S.; Shirazi, A.N.; El-Meligy, M.G.; El-Ziaty, A.K.; Rowley, D.; Sun, J.; Nagib, Z.A.; Parang, K. Synthesis of 4-aryl-6-indolylpyridine-3-carbonitriles and evaluation of their antiproliferative activity. Tetrahedron Lett. 2014, 55, 1154–1158. [Google Scholar] [CrossRef]
  48. Rodríguez, M.R.; Balsa, L.M.; Piro, O.E.; Etcheverría, G.A.; García-Tojal, J.; Pis-Diez, R.; León, I.E.; Parajón-Costa, B.P.; González-Baró, A.C. Synthesis, Crystal Structure, Spectroscopic Characterization, DFT Calculations and Cytotoxicity Assays of a New Cu(II) Complex with an Acylhydrazone Ligand Derived from Thiophene. Inorganics 2021, 9, 9–23. [Google Scholar] [CrossRef]
  49. Yurttaş, L.; Temel, H.E.; Aksoy, M.O.; Bülbül, E.F.; Çiftçi, G.A. New chromanone derivatives containing thiazoles: Synthesis and antitumor activity evaluation on A549 lung cancer cell line. Drug Dev. Res. 2022, 83, 470–484. [Google Scholar] [CrossRef]
  50. Suma, V.R.; Sreenivasulu, R.; Rao, M.V.B.; Subramanyam, M.; Ahsan, M.J.; Alluri, R.; Rao, K.R.M. Design, synthesis, and biological evaluation of chalcone-linked thiazole-imidazopyridine derivatives as anticancer agents. Med. Chem. Res. 2020, 29, 1643–1654. [Google Scholar] [CrossRef]
  51. Esmail, E.A.; Fathy, H.M.; Sedik, M.Z.; Mohamed, A.F. Assessment The effect of prebiotics, probiotics and synbiotics on Hyperlipidemia. Egypt. J. Chem. 2022, 65, 421–432. [Google Scholar] [CrossRef]
  52. Cory, A.H.; Owen, T.C.; Barltrop, J.A.; Cory, J.G. Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun. 1991, 3, 207–212. [Google Scholar] [CrossRef] [PubMed]
  53. Berridge, M.V.; Herst, P.M.; Tan, A.S. Tetrazolium dyes as tools in cell biology: New insights into their cellular reduction. Biotechnol. Annu. Rev. 2005, 11, 127–152. [Google Scholar] [PubMed]
  54. Chen, X.; Lv, P.; Liu, J.; Xu, K. Apoptosis of human hepatocellular carcinoma cell (HepG2) induced by cardiotoxin III through S-phase arrest. Exp. Toxicol. Pathol. 2009, 61, 307–315. [Google Scholar] [CrossRef]
  55. Zhang, J.; Li, Y.; Liu, T.; He, W.; Chen, Y.; Chen, X.; Li, X.; Zhou, W.; Yi, J.; Ren, Z. Antitumor effect of matrine in human hepatoma G2 cells by inducing apoptosis and autophagy. World J. Gastroenterol. 2010, 16, 4281–4290. [Google Scholar] [CrossRef]
Molecules 28 04270 g001 550
Figure 1. Some thiazole-pyridine hybrids used as potent anticancer agents and the targeted compounds, 8a–f.
Figure 1. Some thiazole-pyridine hybrids used as potent anticancer agents and the targeted compounds, 8a–f.
Molecules 28 04270 g001
Molecules 28 04270 sch001 550
Scheme 1. Synthesis of acetylthiazole derivative 5.
Scheme 1. Synthesis of acetylthiazole derivative 5.
Molecules 28 04270 sch001
Molecules 28 04270 sch002 550
Scheme 2. Synthesis of amino cyanopyridine derivatives, 8a–f.
Scheme 2. Synthesis of amino cyanopyridine derivatives, 8a–f.
Molecules 28 04270 sch002
Molecules 28 04270 sch003 550
Scheme 3. Mechanism of the synthesis of amino cyanopyridine derivatives, 8a–f.
Scheme 3. Mechanism of the synthesis of amino cyanopyridine derivatives, 8a–f.
Molecules 28 04270 sch003
Molecules 28 04270 sch004 550
Scheme 4. Mass fragmentation pattern of compound 8b.
Scheme 4. Mass fragmentation pattern of compound 8b.
Molecules 28 04270 sch004
Molecules 28 04270 g002a 550Molecules 28 04270 g002b 550Molecules 28 04270 g002c 550
Figure 2. Two-dimensional and three-dimensional depictions of the binding model of EGFR (4HJO) with acetylthiazole derivative 5 and the new compounds, 8a–f. The figures are presented as (5): Compound 5, (8aA, 8cA, 8dA); Group A (8a,c,d) and (8bB, 8eB, 8fB); and Group B (8b,e,f), respectively.
Figure 2. Two-dimensional and three-dimensional depictions of the binding model of EGFR (4HJO) with acetylthiazole derivative 5 and the new compounds, 8a–f. The figures are presented as (5): Compound 5, (8aA, 8cA, 8dA); Group A (8a,c,d) and (8bB, 8eB, 8fB); and Group B (8b,e,f), respectively.
Molecules 28 04270 g002aMolecules 28 04270 g002bMolecules 28 04270 g002c
Table
Table 1. Evaluation of IC50 values (µM) for compounds 5 and 8a–f against A549 cell line.
Table 1. Evaluation of IC50 values (µM) for compounds 5 and 8a–f against A549 cell line.
CompoundIC50 (µM)
50.452
8a0.428
8b0.412
8c0.549
8d0.433
8e0.302
8f0.788
Doxorubicin0.460
Table
Table 2. Docking interaction with EGFR of all the tested compounds, 5 and 8a–f.
Table 2. Docking interaction with EGFR of all the tested compounds, 5 and 8a–f.
Compound(s)Compound 5Group A
(8a,c,d)		Group B
(8b,e,f)
Parameter
E (Kcal/mol) a41.225382.721075.8467
S (Kcal/mol) a−20.1495−24.2234−24.4538
Residues involved in interactionThr830 (H-bond)Asp831 (H-bond)Lys721, Arg817 (Arene-cation)
No. of hydrogen bonding11-
Bond length [Å]2.161.989-
a E: Energy of the compound (Kcal/mol); S: Binding energy of compound with EGFR (Kcal/mol). The results for the groups (A and B) are recorded as mean values.
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Ashmawy, F.O.; Gomha, S.M.; Abdallah, M.A.; Zaki, M.E.A.; Al-Hussain, S.A.; El-desouky, M.A. Synthesis, In Vitro Evaluation and Molecular Docking Studies of Novel Thiophenyl Thiazolyl-Pyridine Hybrids as Potential Anticancer Agents. Molecules 2023, 28, 4270. https://doi.org/10.3390/molecules28114270

AMA Style

Ashmawy FO, Gomha SM, Abdallah MA, Zaki MEA, Al-Hussain SA, El-desouky MA. Synthesis, In Vitro Evaluation and Molecular Docking Studies of Novel Thiophenyl Thiazolyl-Pyridine Hybrids as Potential Anticancer Agents. Molecules. 2023; 28(11):4270. https://doi.org/10.3390/molecules28114270

Chicago/Turabian Style

Ashmawy, Fayza O., Sobhi M. Gomha, Magda A. Abdallah, Magdi E. A. Zaki, Sami A. Al-Hussain, and Mohamed A. El-desouky. 2023. "Synthesis, In Vitro Evaluation and Molecular Docking Studies of Novel Thiophenyl Thiazolyl-Pyridine Hybrids as Potential Anticancer Agents" Molecules 28, no. 11: 4270. https://doi.org/10.3390/molecules28114270

APA Style

Ashmawy, F. O., Gomha, S. M., Abdallah, M. A., Zaki, M. E. A., Al-Hussain, S. A., & El-desouky, M. A. (2023). Synthesis, In Vitro Evaluation and Molecular Docking Studies of Novel Thiophenyl Thiazolyl-Pyridine Hybrids as Potential Anticancer Agents. Molecules, 28(11), 4270. https://doi.org/10.3390/molecules28114270

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