Synthesis, Computational study, Solvatochromism and Biological Studies of Thiazoles-Hydrazones Derivatives published by Ural Federal University eISSN 2411-1414 chimicatechnoacta.ru ARTICLE 2023, vol. 10(1), No. 202310110 DOI: 10.15826/chimtech.2023.10.1.10 1 of 13 Synthesis, computational study, solvatochromism and biological studies of thiazole-owing hydrazone derivatives C. Kiran Yadav a, B.P. Nandeshwarappa a * , K.M. Mussuvir Pasha b a: Department of Studies in Chemistry, Shivagangotri, Davangere University, Davanagere, Karnataka 577007, India b: Department of P.G. studies and research in chemistry/Industrial chemistry, Vijayanagara Sri Krishnadevaraya University, Ballari 583105, Karnataka, India * Corresponding author: belakatte@gmail.com This paper belongs to a Regular Issue. Abstract In the present work, we have synthesized thiazole-hydrazone conjugates 5(a–h) and characterized them using various analytical techniques such as UV, IR, NMR, and mass spectrometry. Solvatochromic properties were eval- uated in ten solvents with different polarity and quantum chemical param- eters using a DFT study. The antibacterial activity results revealed that com- pounds 5c, 5d and 5g exhibited good efficacy and that the remaining com- pounds displayed significant activity. The synthesized compounds were screened for their cytotoxic activity against HepG2 and MCF-7 cell lines, and all the synthesized compounds exhibited significant potency towards the screened cancer cell lines. The anti-inflammatory efficacy of the synthesized thiazole derivatives was determined against MMP-2 and MMP-9, and some of the compounds showed significant activity. Furthermore, the in silico mo- lecular docking was performed with the COX-2 receptor. Keywords biological activity DFT solvatochromic study thiazole-hydrazone conjugates Received: 18.01.23 Revised: 05.02.23 Accepted: 10.02.23 Available online: 20.02.23 Key findings ● Thiazole-hydrazone conjugates were synthesized. Biological efficacy of the synthesized compounds was determined. ● Solvatochromic properties were evaluated in ten different solvents. Structures were characterized by using vari- ous analytical techniques. ● Quantum chemical parameters were evaluated using a DFT study. © 2023, the Authors. This article is published in open access under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction Heterocyclic compounds are important for medicinal chem- istry because they serve as key building blocks for active pharmaceutical ingredients. Compounds with heterocyclic ring systems are extremely useful in both medicine and ma- terial science [1–5]. Thiazoles, for example, are five-mem- bered ring heterocycles with three carbon atoms, one nitro- gen atom, and one sulfur atom. These heterocycles are of great interest in medicinal and pesticide chemistry, as well as polymer and material science [6]. Thiazoles are one of the most important classes of heterocyclic moieties which possess a wide range of therapeutic and pharmacological applications. Compounds containing thiazole ring have chemotherapeutic, fungicidal, and pesticidal properties [7– 11]. Thiazole derivatives have broad biological activities such as antimicrobial [12], anti-inflammatory [13], antitubercular [14], antihypertensive [15], anticancer [16], and analgesic [17]. Natural compounds such as thiamine, thiamine pyrophosphate, bacitracin, penicillin antibiotics, and most of the drugs contain thiazole moiety. From the re- cent literature survey, thiazole and its derivatives were used as antimicrobial additives in polyurethane coating, and their corrosion behavior was also investigated [18, 19]. An asymmetric thiazole core exhibits fascinating behavior such as nonlinear optical properties and ferroelectricity with a lateral π-conjugated system [20]. Thiazole-based fluoro- phores are used as blue light-emitting polymers in organic light-emitting diodes (OLEDs); thiazoles are also used in dye synthesized solar cells [21]. Hydrazones and their derivatives are organic compounds with a wide range of applications. The biological properties of these compounds are intriguing. Hydrazones are useful as potential ligands for metal com- plexes, organocatalysis, and the synthesis of heterocyclic http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2023.10.1.10 mailto:belakatte@gmail.com http://creativecommons.org/licenses/by/4.0/ https://orcid.org/0000-0003-0559-7240 https://crossmark.crossref.org/dialog/?doi=https://doi.org/10.15826/chimtech.2023.10.1.10&domain=pdf&date_stamp=2023-02-20 https://journals.urfu.ru/index.php/chimtech/rt/suppFiles/6537/0 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 2 of 13 DOI: 10.15826/chimtech.2023.10.1.10 compounds [22–25]. The complex study of hydrazones has piqued interest due to their biological activity and potential as enzyme inhibitors. Hydrazones' rings are crucial in deter- mining the magnitude of their pharmacological properties [26, 27]. Hydrazones can act as neutral or anionic ligands for metal ions, resulting in stable metal complexes. These hydra- zones have revealed themselves to be important optical phe- nomena materials [28]. 2. Experimental details 2.1. Materials and methods All the chemicals and solvents were purchased from Sigma- Aldrich and Spectrochem. The FT-IR spectra were recorded on a Perkin Elmer spectrometer (Spectrum 100). The elec- tronic absorption spectra were recorded on a Shimadzu spectrophotometer (UV-1800). The 1H NMR and 13C NMR spectra were recorded with the aid of an Agilent NMR at 400 MHz and 100 MHz, respectively. The HR-MS spectra were recorded on a Sciex API 3200 mass spectrometer. Melting points were determined in open capillary and are uncorrected. Silica-gel GF-254 was used for thin-layer chro- matography (TLC). Purity of the compounds was checked by TLC on silica gel. All extracted solvents were dried with anhydrous Na2SO4 and evaporated with a BUCHI rotary evaporator. 2.2. Computational studies All computational calculations were performed using the Gaussian 09 software [29], and B3LYP was used for the DFT calculations with a 6-31G (d, p) basis set [30, 31]. Output files of the Gaussian software were visualized by using Gaussview 05 [32]. MEP and RDG calculations were done using Multi- wfn 3.7 [32] and visualized using Visual Molecular Dynamics (VMD) software [33]. 2.3. General procedure for the synthesis of thiazole hydrazones 5(a–h) 2.3.1. Step 1: synthesis of thiosemicarbazones 3(a–h) 2 mmol of various carbonyl compounds 1(a–h) and 2 mmol of thiosemicarbazide 2 were taken in 10 mL of ethanol and stirred with reflux at 70–80 °C in oil bath for about 1–2 hrs, employing 2–3 drops of AcOH catalyst. After the complete formation of the product identified by TLC (Mobile phase: n-Hexane:Ethyl acetate 8:2), the obtained solid was fil- tered, washed with ethanol, dried and recrystallised using ethanol solvent. 2.3.2. Step 2: synthesis of thiazole hydrazones 5(a–h) 1 mmol of the obtained thiosemicarbazones 3(a–h) from step 1, and phenacyl bromide(1 mmol) were taken together in 50 mL RB; to that, 10–15 mL of isopropanol was added, and the mixture was stirred at room temperature for about 2–3 hrs. The formation of the product was monitored by TLC (Mobile phase: n-Hexane:Ethyl acetate 8:2). After the completion of the reaction, the obtained colorant was fil- tered, dried, and recrystallized using ethanol. 2.3.3. 2-{(2E)-2-[4-fluoro-3-(trifluoromethyl)benzyli- dene]hydrazinyl}-4-phenyl-1,3-thiazole (5a) C17H11F4N3S, m.p: 187–189 °C. FT-IR (KBr) νmax: 3066 (N– H), 1582 (C=N), 1484 (C=N), 1278 (C–F), 709 (C–S). 1H NMR (400 MHz, DMSO-d6) δ in ppm 7.31 (t, 1H, ArH, J = 7.6 Hz), 7.36 (s, 1H, ArH), 7.41 (d, 2H, ArH, J = 8 Hz), 7.58 (t, 1H, ArH, J = 8 Hz), 7.85 (d, 2H, ArH, J = 8 Hz), 8.04 (t, 2H, ArH, J = 8 Hz), 8.11 (s, 1H, ArH), 12.40 (s, 1H, N–NH). 13C NMR (100 MHz, DMSO-d6): δ 103.97, 117.81, 121.10, 123.80, 124.65, 125.51, 127.56, 128.59, 131.77, 132.29, 134.57, 138.43, 150.61, 157.60, 160.14, 168.01. HRMS: m/z = 365.8 [M+]. Anal. Calcd (%): C (55.89%), H (3.03%), N (11.50%), Found: C (55.35), H (2.98), N (11.12). 2.3.4. 2-[(2E)-2-(2,6-dibromobenzylidene)hydrazinyl]- 4-phenyl-1,3-thiazole (5b) C16H11Br2N3S, m.p: 192–193 °C. FT-IR (KBr) νmax: 3317 (N–H), 1633 (C=N), 1546 (C=N), 725 (C–S), 608 (C– Br). 1H NMR (400MHz, DMSO-d6) δ in ppm 7.23 (t, 1H, ArH, J = 8 Hz), 7.33 (t, 2H, ArH, J = 7.2Hz), 7.41 (t, 2H, ArH, J = 8 Hz), 7.81 (d, 2H, ArH, J = 8 Hz), 7.86 (t, 2H, ArH, J = 7.6 Hz), 8.15 (s, 1H, ArH), 12.30 (s, 1H, N–NH). 13C NMR (100 MHz, DMSO-d6): δ 104.31, 123.20, 125.65, 127.76, 127.91, 128.37, 128.62, 131.33, 132.74, 133.09, 134.16, 139.70, 149.83, 168.16. HRMS: m/z = 436.0 [M-1]. Anal. Calcd (%): C (43.96%), H (2.54%), N (9.61%), Found: C (43.45), H (2.24), N (9.27). 2.3.5. 4-{(E)-[2-(4-phenyl-1,3-thiazol-2-yl)hydrazinyli- dene]methyl}benzaldehyde (5c) C17H13N3OS, m.p: 171–173 °C. FT-IR (KBr) νmax: 3299 (N– H), 1689 (C=N), 1569 (C=N), 712 (C–S). 1H NMR (400MHz, DMSO-d6) δ in ppm 7.1 (s, 1H, ArH), 7.26 (m, 2H ArH, J = 7.2 Hz), 7.38 (m, 2H, ArH, J = 8 Hz), 7.72 (s, 1H, ArH), 7.75 (m, 1H, ArH, J = 8 Hz), 7.83 (m, 3H, ArH, J = 4 Hz), 8.03 (s, 1H, ArH), 9.94 (s, 1H, –CHO). 13C NMR (100 MHz, DMSO-d6): δ 38.87, 40.12, 104.11, 125.68, 126.77, 128.03, 128.79, 130.20, 134.78, 135.22, 139.44, 140.83, 150.72, 168.42, 192.63. HRMS: m/z = 308.1 [M+1]. Anal. Calcd (%): C (66.43%), H (4.26%), N (13.67%), Found: C (66.12), H (4.06), N (13.16). 2.3.6. 2-{(2E)-2-[4-(methylsulfanyl)benzylidene]hydra- zinyl}-4-phenyl-1,3-thiazole (5d) C17H15N3S2, m.p: 189–191 °C. FT-IR (KBr) νmax: 3054 (N– H), 1595 (C=N), 1494 (C=N), 712 (C–S). 1H NMR (400MHz, DMSO-d6) δ in ppm: 2.50 (t, 3H,–CH3), 7.30 (t, 4H, ArH, J = 1.2 Hz), 7.41 (t, 2H, ArH, J = 8 Hz), 7.60 (d, 2H, ArH, J = 4.4 Hz), 7.86 (d, 2H, ArH, J = 7.2 Hz), 7.99 (s, 1H, ArH), 12.01 (s, 1H, N–NH). 13C NMR (100 MHz, DMSO-d6): δ 14.35, 40.12, 103.54, 125.48, 126.64, 127.46, 128.56, 130.90, 134.62, 139.82, 140.89, 150.43, 168.16. HRMS: m/z =Anal. Calcd (%): C (62.74%), H (4.65%), N (12.91%), Found: C (62.41), H (4.35), N (12.62). https://doi.org/10.15826/chimtech.2023.10.1.10 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 3 of 13 DOI: 10.15826/chimtech.2023.10.1.10 2.3.7. 2-{2-[1-(furan-2-yl)ethylidene]hydrazinyl}-4- phenyl-1,3-thiazole (5e) C15H13N3OS, m.p: 135–136 °C. FT-IR (KBr) νmax: 3088 (N– H), 1612 (C=N), 1496 (C=N), 719(C–S). 1H NMR (400 MHz, DMSO-d6) δ in ppm 2.25 (s, 3H, –CH3), 6.58 (m, 2H, ArH, J = 1.6 Hz), 6.84 (d, 1H, ArH, J = 3.2 Hz), 7.31 (d, 2H, ArH, J = 5.6 Hz), 7.41 (t, 2H, ArH, J = 8 Hz), 7.77 (d, 1H, ArH, J = 1.2 Hz), 7.88 (t, 2H, ArH, J = 7.2 Hz), 11.30 (s, 1H, N–NH). 13C NMR (100 MHz, DMSO-d6): δ 13.85, 40.12, 104.17, 110.17, 111.89, 125.59, 127.68, 128.06, 128.64, 134.18, 139.66, 144.13, 151.66, 169.41. HRMS: m/z = 283.80 [M+]. Anal. Calcd (%): C (63.58%), H (4.62%), N (14.83%), Found: C (63.37), H (4.28), N (14.57). 2.3.8. 4-phenyl-2-[(2E)-2-(1-phenylpropylidene)hydra- zinyl]-1,3-thiazole (5f) C18H17N3S, m.p: 159–160 °C. FT-IR (KBr) νmax: 3062 (N– H), 1617 (C=N), 1494 (C=N), 769 (C–S). 1H NMR (400 MHz, DMSO-d6) δ in ppm 1.09 (t, 3H, –CH3), 2.88 (m, 2H, –CH2), 7.32 (d, 2H, ArH, J = 7.2 Hz), 7.42 (m, 5H, ArH, J = 7.6 Hz), 7.80 (d, 2H, ArH, J = 7.2 Hz), 7.89 (d, 2H, ArH, J = 7.2 Hz), 11.30 (s, 1H, N– NH). 13C NMR (100 MHz, DMSO-d6): δ 8.08, 19.74, 31.20, 104.15, 125.59, 127.48, 128.11, 128.53, 128.65, 128.73, 129.03, 130.54, 132.96, 133.62, 136.35, 136.59, 168.63, 169.83. HRMS: m/z = 309.10 [M+2]. Anal. Calcd (%): C (70.33%), H (5.57%), N (13.67%), Found: C (70.10), H (5.38), N (13.52). 2.3.9. 2-{(2E)-2-[1-(4-ethylphenyl)ethylidene]hydrazi- nyl}-4-phenyl-1,3-thiazole (5g) C19H19N3S, m.p: 201–203 °C. FT-IR (KBr) νmax: 3061 (N– H), 1614 (C=N), 1508 (C=N), 717 (C–S). 1H NMR (400 MHz, DMSO-d6) δ in ppm 1.19 (m, 3H, –CH3), 2.32 (s, 3H, –CH3), 2.65 (m, 2H, –CH2), 7.27 (t, 2H, ArH, J = 8 Hz), 7.32 (m, 2H, ArH, J = 5.2 Hz), 7.42 (t, 2H, ArH, J = 8 Hz), 7.70 (m, 2H, ArH, J = 6 Hz), 7.89 (d, 2H, ArH, J = 7.2 Hz), 11.10 (s, 1H, N–NH). 13C NMR (100 MHz, DMSO-d6): δ 14.61, 15.87, 39.30, 104.57, 126.27, 128.23, 128.77, 129.06, 134.44, 135.67, 145.16, 157.98, 170.28, 189.43, 215.73. HRMS: m/z = 321.80 [M+]. Anal. Calcd (%): C (70.99%), H (5.96%), N (13.07%), Found: C (70.84), H (5.81), N (12.96). 2.3.10. 2-{(2E)-2-[1-(1,3-benzodioxol-5-yl)ethyli- dene]hydrazinyl}-4-phenyl-1,3-thiazole (5h) C18H15N3O2S, m.p: 123–124 °C. FT-IR (KBr) νmax: 3022 (N– H), 1599 (N–H), 1489 (N–H), 706 (C–S). 1H NMR (400 MHz, DMSO-d6) δ in ppm 2.82 (s, 3H, –CH3), 6.06 (s, 2H, –CH2), 6.96 (d, 1H, ArH, J = 8.4 Hz), 7.27 (m, 1H, ArH, J = 1.6 Hz), 7.31 (d, 2H, ArH, J = 7.6 Hz), 7.35 (d, 2H, ArH, J = 1.6 Hz), 7.40 (m, 2H, ArH, J = 8 Hz), 7.88 (d, 2H, ArH, J = 7.2 Hz), 11.15 (s, 1H, N–NH). 13C NMR (100 MHz, DMSO-d6): δ 14.53, 39.30, 101.73, 104.33, 105.84, 108.35, 120.59, 125.94, 127.89, 129.01, 132.71, 135.16, 146.66, 148.37, 170.32, 223.72. HRMS: m/z =338.10 [M+1]. Anal. Calcd (%):C (64.08%), H (4.48%), N (12.45%), Found: C (59.97), H (4.36), N (12.32). 2.4. Biological activity 2.4.1. Antimicrobial activity The antibacterial activity screening for synthesized com- pounds 5(a–h) was done by the disc diffusion method [34–36]. The tubes were inoculated with 1ml lag phase culture of gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and gram-positive bacte- ria such as Staphylococcus aureus and Bacillus Subtilis. Fungal strains such as Candida albicans and Aspergillus flavus were used. The sterile nutrient agar media was used for bacteria growth, and potato dextrose agar media was used for fungi. In the respective labeled discs, dif- ferent concentrations (10–100 mg) of synthesized conju- gates 5(a–h) were added and mixed with DMSO. Then the bacterial plate was incubated at 37 °C for 24 hours and the fungal plate – at 27 °C for 48 hours. The zone of in- hibition was measured for each compound. 2.4.2. Cytotoxic activity Gibco Dulbecco's Modified Eagle Medium (DMEM) with 10% Fetal Bovine Serum was used to culture the cell line. The cytotoxic activity of the synthesized compounds was evaluated against MCF-7 and HePG2 cell lines using a modified micro-titration colorimetric MTT reduction method [37]. For 24 hours, cells were seeded at a density of 1·104 cells per well in 96-well plates. The cells were then exposed to various concentrations of synthesized compounds 5(a–h) for 24 hours, ranging from 15.625 M to 1000 M. 10 μL of MTT solution (5 mg/mL) was pipet- ted into each well and incubated for another 4h. The me- dium was discarded after the formazan precipitate was formed and dissolved in DMSO. The absorbance of the mixtures was measured at 570 nm with a microfilter plate reader, and cell viability was calculated. % inhibition = [Atest / Acontrol · 100], (1) where Atest is the absorbance of the test sample, Acontrol is the absorbance of control. The IC50 value of the synthesized compounds was cal- culated using linear aggression equation, viz., Y = Mx+C. Here Y = 50 and M and C values were derived from the viability graph. 2.4.3. Anti-inflammatory activity Gel electrophoresis was used to determine the anti-inflam- matory efficacy of the prepared compounds against two ma- trix metalloproteinases, MMP-2 and MMP-9, as described in the published methodology [38]. Electrophoresis gels were prepared, and 50 liters of test compounds and 50 liters of MMP sample were thoroughly mixed before being incu- bated for one hour. Furthermore, the non-reducing buffer was thoroughly mixed in an equal-volume tank with the positive control (MMP) and negative control (tetracycline hydrochloride) (MMP). The tank was then closed and https://doi.org/10.15826/chimtech.2023.10.1.10 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 4 of 13 DOI: 10.15826/chimtech.2023.10.1.10 plugged into a 50 V power supply for 15 minutes before in- creasing the voltage to 100 V until bromophenol blue reached the plate's bottom. The instrument was discon- nected after completion, and the gel was gently removed, washed with a zymogram renaturing buffer solution for about 1 hour to remove SDS (sodium dodecyl sulfate), and allowed the proteins to denature. The zymogram renaturing buffer was decanted, and the gel was incubated overnight at 37 °C in the zymogram incubation buffer. Furthermore, the background stains blue with Coomassie stain where the Gelatin is degraded, and the gels are stained with Coo- massie blue R-250. The presence of gelatinases is indicated by the development of white bands, with the lower bands being gelatinases-A (MMP-2) at 72 KD and the upper bands being gelatinases-B (MMP-9) at 95 KD. 2.4.4. In silico Molecular docking The 2D structures of synthesized derivatives were drawn using ChemDraw. The energy was minimized using the Dundee prodrug server and then converted into PDBQT using the graphical interface program ‘MGL tools’ [39]. 3KCY is a crystal structure of Factor Inhibiting HIF-1 (FIH-1) with quinol family inhibitors at a resolution of 2.59 Å [40]. ‘MGL tools’ were used to adjust the grid box for docking simulations. The grid was adjusted so that it encompasses the region of the active site of the protein which comprised of Ile 281, Phe 207, His 279, Asp 201, Trp 296, His 199, Leu 186, Leu 188, Gln 147. The docking algo- rithm provided with AutodockVina was used to search for the best-docked conformation between ligand and protein, and the binding energy was determined. LigPlot and PyMol were used to infer the pictorial depiction of the interaction between the ligands and the target protein [41]. 3. Results and Discussion 3.1. Chemistry and characterization The main aim of this work was to synthesize the novel thi- azole hydrazones and explore their biological potency. Herein, we prepared a novel thiazole hydrazones 5(a–h) ex- cept 5e [42, 43], by a simple two-step reaction. The synthetic route is shown in Scheme 1, and the physical data summarized in Table 1 were obtained using various analyt- ical techniques. The compounds' efficacy towards cytotoxi- city and anti-inflammatory activity were determined. In the IR spectrum of compound 5a, the signal at 3066 cm–1 was observed due to the presence of –NH func- tionality, the Ar–CH stretching occurs at 2939 cm–1, the –C=N of hydrazone and thiazole resonated respectively at 1529 cm–1 and 1484 cm–1, the peak at 1278 cm–1 is related to C–F stretching, and the C–S group resonated at 709 cm–1. In the 1H NMR spectra of conjugate 5a, the –NH proton resonated at δ 12.40 ppm as a broad singlet, the aromatic proton of –CH–N= functionality appeared at δ 8.01 ppm as a singlet, the signal at δ 7.36 ppm is related to the proton of thiazole ring and the aromatic protons were observed in the region 7.29–8.06 ppm as a multiplet. In the proton de- coupled 13C NMR spectra, the thiazole ring carbon resonated at δ 168.01 ppm, the aromatic carbons resonated in the re- gion 117–160 ppm, and the azomethine carbon resonated at δ 105 ppm. The mass spectra of compound 5a confirmed the for- mation of the product by demonstrating a M+ signal at m/z 365.8, which corresponds to a calculated molecular weight of the compound. The IR, 1H NMR, 13C NMR and mass spectra of all the synthesized thiazole derivatives 5(a–h) are shown in the supplementary material (Figure S1–Figure S32). 3.2. Solvatochromic UV-Vis absorption Figure 1 and Figure 2 show the UV-Vis absorption spectra of the synthesized conjugates, and Table 2 lists the specific spectral data. The maximum absorption of these com- pounds was found in the range of 326–366 nm in the UV- visible spectra. The π–π* transition of electrons in aromatic rings present in all derivatives may account for this absorp- tion [44]. On conjugation with aromatic rings, there is an abundance of electrons, resulting in a bathochromic shift. The compounds 5a and 5d exhibited bathochromic shift, as compared to the other synthesized compounds, and the compounds 5f and 5g showed a blue shift related to the other synthesized conjugates. Scheme 1 Synthesis of thiazole hydrazone conjugates 5(a–h). https://doi.org/10.15826/chimtech.2023.10.1.10 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 5 of 13 DOI: 10.15826/chimtech.2023.10.1.10 Table 1 Analytical data of the synthesized thiazole derivatives 5(a–h). Compound Structure Molecular formula Molecular weight Yield (%) m.p. (°C) 5a F N N N S H FF F C17H11F4N3S 365.3479 88 187–189 5b N N N S HBr Br C16H11Br2N3S 437.1516 90 192–193 5c N N N S H O C17H13N3OS 307.3692 86 171–173 5d N NH N S S CH3 C17H15N3S2 325.4511 92 189–191 5e N N N S HCH3 O C15H13N3OS 283.3482 89 135–136 5f N N N S H CH3 C18H17N3S 307.4126 91 159–160 5g N N N S HCH3 CH3 C19H19N3S 321.4392 88 201–203 5h N N N S HCH3 O O C18H15N3O2S 337.3956 92 123–124 The values of λmax for the synthesized thiazole compounds vary depending on the nature of the solvents and change with changing solvent polarity; among the ten solvents, the largest λmax was observed for any given compound in DMF and DMSO solvents with high polarity. This demonstrates that synthesized compounds are exhibiting solvatochromic behavior, which is attributed to the interaction of the sol- vent and lone pair electrons of azo dyes. 3.3. Computational studies The optimized structures of the synthesized thiazole-conju- gates are shown in the supplementary material (Figure S33–Figure S40). Figure 3 and Figure 4 display the energy gap and electronic distribution of HOMO-LUMO of the syn- thesized thiazole hydrazones 5(a–h). As can be seen from the figures, compound 5a has less energy gap, viz., 3.512 eV; soft molecule and the compound 5g was found to have a large energy gap, viz., 4.38 eV. With the help of the energy of frontier molecular orbitals, some of the quantum chemical parameters were calculated using the following equations, and the values are listed in Table 3. Electronegativity (χ) = –1/2(ELUMO + EHOMO). Chemical potential (μ) = –χ = 1/2(ELUMO + EHOMO). Global hardness (η) =1/2 (ELUMO – EHOMO). Global softness (S) = 1/2η. Electrophilicity index (ω) = μ2/2η. https://doi.org/10.15826/chimtech.2023.10.1.10 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 6 of 13 DOI: 10.15826/chimtech.2023.10.1.10 Figure 1 Solvatochromic absorption spectra of compounds 5(a–d). Figure 2 Solvatochromic absorption spectra of compounds 5(e–h). https://doi.org/10.15826/chimtech.2023.10.1.10 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 7 of 13 DOI: 10.15826/chimtech.2023.10.1.10 Table 2 UV-Visible data of the synthesized compounds 5(a–h). Compounds λmax, nm DMF DMSO ACN n-Hexane MeOH Benzene Ethyl acetate Toluene EtOH 1,4- dioxane 5a 353.63 355.29 342.83 348.63 346.42 349.75 348.09 348.92 349.18 353.63 5b 349.75 352.51 346.97 347.25 338.96 346.13 342.00 345.59 346.42 336.17 5c 350.59 356.96 343.92 343.09 346.97 347.25 344.75 346.42 346.97 348.92 5d 358.34 366.38 353.08 350.84 351.67 355.84 355.29 354.46 349.18 357.22 5e 341.23 346.90 334.49 332.75 336.00 339.70 337.31 338.19 337.31 339.04 5f 338.58 341.37 326.31 336.97 335.42 334.23 330.66 334.23 331.85 331.07 5g 338.71 340.50 330.41 333.08 328.35 334.29 331.88 334.56 330.72 334.29 5h 345.04 344.47 334.76 330.08 335.05 338.96 337.29 337.00 337.55 338.67 Compounds Logε DMF DMSO ACN n-Hexane MeOH Benzene Ethyl acetate Toluene EtOH 1,4- dioxane 5a 3.58 3.72 4.17 3.36 3.98 4.10 4.24 3.89 3.85 3.39 5b 4.36 3.74 2.93 3.15 4.23 3.83 3.36 3.45 3.57 3.91 5c 3.32 3.36 3.77 2.80 3.43 3.67 4.15 4.22 3.99 3.83 5d 3.14 3.18 3.11 3.20 3.53 3.97 3.53 3.77 4.17 3.86 5e 3.96 3.46 3.73 4.18 3.89 4.19 3.77 4.03 4.07 3.47 5f 3.36 3.78 3.57 3.58 2.97 3.99 3.24 3.62 3.77 3.99 5g 3.81 3.84 3.82 3.41 4.34 3.78 3.97 4.10 4.03 4.26 5h 3.72 4.13 3.79 3.30 4.07 3.35 3.77 3.57 3.58 3.87 Figure 3 Calculated FMO orbitals plot of the synthesized compounds 5(a–d). Figure 4 Calculated FMO orbitals plot of the synthesized compounds 5(e–h). 5a 5b 5c 5d LUMO HOMO 3.512 eV 3.960 eV 3.776 eV 3.674 eV LUMO HOMO 5e 5f 5g 5h 3.776 eV 3.823 eV 4.388 eV 3.860 eV https://doi.org/10.15826/chimtech.2023.10.1.10 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 8 of 13 DOI: 10.15826/chimtech.2023.10.1.10 Table 3 Quantum chemical parameters calculated for synthesized compounds 5(a–h). Parameters 5a 5b 5c 5d 5e 5f 5g 5h EHOMO (eV) –5.918 –5.680 –5.839 –5.623 –5.418 –5.517 –5.552 –5.429 ELUMO (eV) –2.406 –1.720 –2.063 –1.984 –1.642 –1.693 –1.163 –1.568 Energy gap (Δ) (eV) 3.512 3.960 3.776 3.674 3.776 3.823 4.388 3.860 Ionization energy (I) (eV) 5.918 5.680 5.839 5.623 5.418 5.517 5.552 5.429 Electron affinity (A) (eV) 2.406 1.720 2.063 1.984 1.642 1.693 1.163 1.568 Electronegativity (χ) (eV) 4.162 3.70 3.951 3.803 3.530 2.758 3.357 3.498 Chemical potential (μ) (eV) –4.162 –3.70 –3.951 –3.803 –3.530 –2.758 –3.357 –3.498 Global hardness (η) (eV) 1.756 1.98 1.888 1.819 1.888 1.065 2.194 1.930 Global softness (S) (eV–1) 0.284 0.252 0.264 0.274 0.264 0.469 0.227 0.259 Electrophilicity index (ω) (eV) 4.932 3.457 4.134 3.974 3.30 3.571 2.567 3.169 Molecular electrostatic potential map (MEP) helps to pre- dict the charge distribution in the molecule. In the MEP, the electrophilic nature of the molecule is represented by the positive regions (blue), and the nucleophilic nature of the molecule is represented by the negative regions (red). The MEP map was displayed in Figure 5, which reveals that the blue region was found at –NH of the hydrazone in the syn- thesized compounds 5(a–h), and the red region was ob- served in compounds 5(c–f). 3.4. Biological activity 3.4.1. Antimicrobial activity The inhibition efficacy of the synthesized compounds 5(a–h) towards both gram-positive and gram-negative bacterial strains was determined by the disc diffusion method using DMSO, even though DMSO is toxic to antimicrobial strains, but to a lesser extent [44], and the results were appended in Table 4. The compounds 5c, 5d, and 5g showed excellent ac- tivity compared to Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus Subtilis compared to streptomycin, and the remaining compounds showed moder- ate to good activity. The antifungal activities of the titled compounds 5(a–h) towards fungal strains such as Aspergillus flavus, Candida al- bicans and Aspergillussterreus are shown in Table 4. From the results, it was found that compounds 5a and 5c display a good activity against Aspergillus flavus and Candida albicans. Furthermore, the remaining derivatives also show signifi- cant activity. 3.4.2. Cytotoxic activity All the synthesized thiazole derivatives were screened for their cytotoxic activity against MCF-7 and HePG2 cell lines. The IC50 values for cytotoxic activity of the synthesized compounds are listed in Table 5, and the % cell viability against the treated compounds is shown in Figure 6 and Figure 7. Compounds 5c and 5f inhibited MCF-7 cell lines to a good extent with IC50 values 58.13 µg/mL and 60.88 µg/mL, respectively; compounds 5h and 5d displayed excellent activity against HePG2 cells with IC50 values 55.8 µg/mL and 57.47 µg/mL, respectively, and the remain- ing compounds exhibited moderate activity against both MCF-7 and HePG2 cells with the IC50 values ranging from 61.80 to 70.08 µg/mL. 3.4.3. Anti-inflammatory activity The anti-inflammatory efficacy of the synthesized deriva- tives 5(a–h) was determined against MMP-2 and MMP-9, and results were interpreted in terms of % inhibition. The % inhibition of the synthesized compounds is shown in Table 6. Gelatin Zymography image is shown in Figure 8. From Table 6, it can be noticed that compound 5c indicates very good ef- ficacy, viz., inhibited MMP-2 and MMP-9 to 70% and 55% respectively. Compound 5f exhibits lower activity against both MMP-2 and MMP-9 compared to the other compounds. The remaining compounds exhibit moderate activity. Figure 5 MEP map of the synthesized compounds 5(a–h). Figure 6 MCF-7 Cell viability % against the synthesized thiazole conjugates 5(a–h). https://doi.org/10.15826/chimtech.2023.10.1.10 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 9 of 13 DOI: 10.15826/chimtech.2023.10.1.10 Table 4 Antimicrobial activity results of synthesized compounds 5(a–h). Compounds Concentration, mg/mL Zone of inhibition in mm (mean ± S.D.) Bacterial strains Fungal strains P. a. B. s. S. t. E. c. A. f. C. a. M. g. A.t. 5a 1 18±0.4 19±0.3 15±0.2 17±0.4 20±0.45 16±0.7 19±0.2 21±0.53 0.5 12±0.2 11±0.4 16±0.5 14±0.6 15±0.2 15±0.9 16±0.2 17±0.3 5b 1 16±0.36 17±0.25 20±0.4 19±0.2 19±0.43 20±0.4 21±0.4 18±0.5 0.5 14±0.23 13±0.5 17±0.34 16±0.24 15±0.32 14±0.5 16±0.3 13±0.53 5c 1 23±0.4 21±0.3 19±0.6 20±0.5 21±0.3 17±0.4 19±0.6 18±0.4 0.5 14±0.52 13±0.3 11±0.5 12±0.6 11±0.32 13±0.4 11±0.6 12±0.6 5d 1 20±0.4 19±0.6 17±0.4 18±0.4 19±0.25 18±0.36 17±0.4 18±0.6 0.5 13±0.1 16±0.54 14±0.24 15±0.45 12±0.5 11±0.23 15±0.4 14±0.3 5e 1 17±0.5 15±0.4 14±0.4 19±0.7 18±0.5 15±0.23 19±06 18±0.4 0.5 12±0.3 13±0.1 12±0.4 11±0.7 14±0.35 11±0.5 13±0.1 12±0.5 5f 1 12±0.4 11±0.31 13±0.5 11±0.6 13±0.32 10±0.3 15±0.6 14±0.4 0.5 09±0.6 10±0.3 12±0.4 10±0.4 10±0.5 12±0.3 08±0.25 12±0.6 5g 1 20±0.25 21±0.16 19±0.44 20±0.6 17±0.5 20±0.1 19±0.25 20±0.26 0.5 14±0.36 17±0.3 11±0.5 23±0.4 12±0.4 20±0.2 15±0.4 16±0.22 5h 1 16±0.4 17±0.5 19±0.4 15±0.41 16±0.4 21±0.46 19±0.51 17±0.3 0.5 10±0.1 15±0.21 13±0.5 10±0.24 12±0.4 15±0.4 12±0.6 13±0.5 Standarda 23±0.6 22±0.3 21±0.4 20±0.3 – – – – Standardb – – – – 22±0.3 21±0.5 20±0.4 22±0.2 P.a – Pseudomonas aeruginosa, B.s – Bacillus Subtilis, E.s – Escherichia coli, S.a – Staphylococcus aureus, A.f – Aspergillus flavus, C.a – Candida albicans, A.s – Aspergillusterreus, A.t – Aspergillus terreus. Standarda – Streptomycin, Standardb – Fluconazole. Table 5 IC50 values of the synthesized compounds against MCF-7 and HePG2 cell lines. Compounds IC50 in µg/mL against MCF-7 cells IC50 in µg/mL against HePG2 cells 5a 62.35 61.02 5b 65.43 70.02 5c 58.13 62.6 5d 63.36 57.47 5e 64.48 67.31 5f 60.88 64.57 5g 64.54 61.8 5h 63.03 55.8 Table 6 Anti-inflammatory activity of the synthesized compounds 5(a–h). S.NO. Name of the compound MMP-2 (% Inhibition) MMP-9 (% Inhibition) 1 5a 55 15 2 5b 50 30 3 5c 70 55 4 5d 60 20 5 5e 65 15 6 5f 20 15 7 5g 70 30 8 5h 30 10 9 PC (positive control) 100 95 10 NC (negative control) 0(NIL) 0(NIL) Figure 7 HePG2 Cell viability % against the synthesized thiazole conjugates 5(a–h). Figure 8 Gelatin Zymography showing MMP-2 and MMP-9 treated with synthesized derivatives 5(a–h). https://doi.org/10.15826/chimtech.2023.10.1.10 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 10 of 13 DOI: 10.15826/chimtech.2023.10.1.10 3.4.4. In silico Molecular docking study To support the in vitro biological activity of the synthe- sized thiazole-hydrazone conjugates, in silico molecular docking study was carried out with COX-2 receptor (PDB:1PXX). The binding energy, number of hydrogen bonds and the hydrophobic interaction of the compounds with receptors are tabulated in Table 7. The 2D and 3D view of the interaction of synthesized compounds with COX-2 is given in Figure 9. From the in silico study results, it was found that all the compounds showed excellent binding affinity in the range of –6.9 to –8.4 kcal/mol compared to standard drug diclofenac (–8.4 kcal/mol). Compounds 5d, 5f, and 5g exhibited hy- drogen bonds, but the remaining compounds did not show hydrogen bond. All compounds displayed hydrophobic in- teractions with the COX-2 receptor. 4. Limitations The authors did not find any difficulties and limitations during this research work. 5. Conclusions Herein we reported the synthesis of thiazole-hydrazone conju- gates 5(a–h), and their structure was identified with the help of analytical techniques such as UV, IR NMR and mass spec- trometry. In addition, global and reactive parameters were calculated via the computational study. All the synthesized compounds exhibit positive solvatochromic behaviour, signif- icant potency towards antibacterial activity, excellent efficacy toward cytotoxins and anti-inflammatory activity. Further- more, the synthesized compounds showed a good docking score with the COX-2 receptor. ● Supplementary materials This manuscript contains supplementary materials, which are available on the corresponding online page. ● Funding This research had no external funding. Table 7 Molecular docking results of synthesized thiazole-conjugates 5(a–h) and diclofenac with COX-2 receptor. Ligand Hydrogen bonds Bond length (Å) H-Bond With Hydrophobic interactions Binding energy (kcal/mol) 5a 0 Met 113, Arg 120, Ile 345, Leu 531, Phe 518, Val 349, Met 522, Leu 352, Val 523, Gly 526, Tyr 385, Phe 381, Leu 384, Trp 387, Tyr 355, Ser 353, Leu 359, Val 116, Met 113 –8.4 5b 0 Leu 359, Val 116, Met 113, Val 349, Ser 353, Val 523, Phe 381, Gly 526, Tyr 385, Met 522, Leu 384, Trp 387, Ala 527, Leu 531, Ile 345 –8.0 5c 0 Phe 518, Val 253, Gln 192, Ala 516, Ala 527, Ser 253, His 90, Val 116, Val 349, Arg 120, Leu 531, Ser 530, Leu 352 –6.9 5d 1 3.1 Drg:N2:Tyr 355OB Ala 516, Ser 353, His 90, Arg 513, Leu 352, Val 523, Phe 518, Ser 530, Tyr 385, Tyr 348, Gly 526, Ala 527, Val 349, Leu 531 –7.5 5e 0 Tyr 385, Leu 384, Trp 387, Gly 526, Val 523, Ala 527, Leu 531, Met 113, Leu 359, Tyr 385, Val 349, Tyr 355, Val 116, Ser 353, Phe 518, Leu 352, Trp 387, Met 522 –7.9 5f 2 3.12 Drg:E:Tyr 355OB Phe 518, Leu 352, Trp 387, Gly 526, Val 523, Ala 527, Phe 381, Leu 384, Tyr 385, Met 522, Ile 345, Met 113, Val 349, Leu 531, Leu 359, Ser 353 –7.6 2.91 Drg:E:Arg 120 NB1 5g 1 2.88 Drg:N1:Tyr 385 OH Val 349, Leu 352, Tyr 348, Ser 530, Leu 534, Phe 205, Ile 377, Val 228, Phe 381, Phe 381, Phe 209, Gly 533, Val 344, Ala 527, Leu 531 –6.9 5h 0 Phe 369, Trp 194, Leu 209, Tyr 489 –7.9 Diclofenac 2 2.87 Drg:N1:Tyr 385 OH Leu 384, Gly 526, Phe 518, Trp 387, Ser 353,Val 523, Met 522, Tyr 355, Ala 527, Leu 352, Val 349, Tyr 348, –8.4 2.82 Drg:N1:Tyr 385 OH https://doi.org/10.15826/chimtech.2023.10.1.10 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 11 of 13 DOI: 10.15826/chimtech.2023.10.1.10 Figure 9 2D and 3D docked view of compounds 5(a–h) and diclofenac with COX-2 receptor. https://doi.org/10.15826/chimtech.2023.10.1.10 Chimica Techno Acta 2023, vol. 10(1), No. 202310110 ARTICLE 12 of 13 DOI: 10.15826/chimtech.2023.10.1.10 ● Author contributions Conceptualization: N.B.P. Data curation: K.Y.C. Formal Analysis: K.Y.C., N.B.P., M.P.K. Funding acquisition: N.B.P., M.P.K. Investigation: K.Y.C., M.P.K. Methodology: K.Y.C., N.B.P., M.P.K. Project administration: M.P.K. Resources: K. K.Y.C., Y.C., N.B.P. Software: K.Y.C., M.P.K. Supervision: M.P.K. Validation: K.Y.C., M.P.K. Visualization: M.P.K. Writing – original draft: K.Y.C., N.B.P. Writing – review & editing: M.P.K. ● Conflict of interest The authors declare no conflict of interest. ● Additional information Author IDs: BP Nandeshwarappa, Scopus ID 11839628200; KM Mussuvir Pasha, Scopus ID 57416747400. Websites: Davangere University, https://vskub.ac.in; Vijayanagara Sri Krishnadevaraya University, https://davangereuniversity.ac.in. References 1. Mallikarjuna SM, Padmashali MSMB, Chandrashekharappa S, Sandeep C. Synthesis, anticancer and antituberculosis studies for [1-(4-chlorophenyl) Cyclopropyl](Piperazine-yl) Meth- anone derivates. Int J Pharm Sci Res. 2014;6(7):423–427. 2. 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