Tổng hợp, nghiên cứu cấu trúc và tính chất của một số dị vòng imidazol 5 one, thiazolidin 2,4 dione và 1,3,4 oxadiazoline tt tieng anh

MINISTRY OF EDUCATION AND TRAINING VINH UNIVERSITY NGUYEN VAN THIN SYNTHESIS, STRUCTURE, AND PROPERTIES OF SOME IMIDAZOLE-5-ONE, THIAZOLIDINE-2,4-DIONE OR 1,3,4-OXADIAZOLINE HETEROCYCLES Specialization: Organic Chemistry Code: 9440114 SUMMARY OF DOCTORAL THESIS IN CHEMISTRY NGHE AN, 2020 The thesis was completed at Vinh University Scientific supervisors: Assoc Prof Dr Nguyen Tien Cong Assoc Prof Dr Le Duc Giang Reviewer 1.………………………………………… Reviewer ………………………………………… Reviewer 3………………………………………… The thesis is defended before the Ph.D Thesis Evaluation Council at the University level Location: Vinh University Time: At time , date month year 2020 The thesis can be found at: - National Library - Information Center - Library Nguyen Thuc Hao, Vinh University INTRODUCTION Reasons for the topic choice In recent years, the chemistry of heterocyclic compounds has developed dramatically The number of detected heterocyclic compounds as natural or synthetic compounds is increasing more and more, their properties and methods of synthesis have also been researched more and more fully and systematically Along with that, the biological activity of heterocyclic compounds also have been interested in research, so they have been increasingly applied Five-membered heterocycles with nitrogen heteroatom (azoles) such as pyrrole, imidazole, 1,3,4-oxadiazole, thiazolidine have received a lot of researchers’ interest because of their applications in different fields of life, especially in pharmaceutical chemistry Some aromatic heterocycles such as imidazole, thiazole, 1,3,4-oxadiazole are known to be biological active centers and they also are mediators in the preparation of bioactive compounds Many chemists have been interested in research and have discovered a relatively large number of compounds containing one of the above heterocycles with biological activities such as antibacterial, antiviral, antiinflammatory, anti-cancer, anti-diabetes, anticonvulsant, anti-oxidant A lot of compounds containing imidazole-5-one ring (a derivative of imidazole), thiazolidine2,4-dione ring (a derivative of thiazole) or 1,3,4-oxadiazoline ring (a derivative of 1,3,4-oxadiazole) were also detected as bioactive and pharmacological centers That has opened up new directions in research to synthesize, convert and apply these compounds in life fields, especially in the production of medicines Currently, in Vietnam, the number of studies on heterocyclic compounds containing imidazole-5-one; thiazolidine-2,4-dione or 1,3,4-oxadiazoline nucleus are modestly published compared to the abundance of directions for the synthesis of these compounds in the World According to our research, there is a small amount of research on 2-thiazolidine-4-one, thiazolidine-2,4-dione heterocycles from Vietnam and the number of published studies for 2-thiazolidine-4-one and 1,3,4-oxadiazoline heterocycles has been not much Today, in the World, many studies on azoles as imidazole, thiazolidine, and 1,3,4-oxadiazole have been published But the research on new derivatives of imidazoline-5-one; thiazolidine-2,4-dione and 1,3,4-oxadiazoline heterocycles with a few substituents are not much Recently published studies showed that the compounds containing these heterocycles also have biological activities such as antibacterial, antipruritic, anticancer, hypoglycemic, etc So they have attracted researchers’ interest, especially in the field of pharmaceutical chemistry Therefore the PhD student choose the topic: “Synthesis, structure, and properties of some imidazole-5-one, thiazolidine-2,4-dione or 1,3,4-oxadiazoline heterocycles” Goals and main research contents of the thesis 2.1 Goals of the study Synthesis of new organic compounds (target) containing imidazole-5-one heterocycle; thiazolidine-2,4-dione heterocycle or 1,3,4-oxadiazoline heterocycle with different substituents in experimental conditions of Vietnam Study on the properties, structures and biological activities of these compounds to contribute to the studies of both theory and application of heterocyclic compounds 2.2 Contents of the study * Synthesize series of new target compounds containing five-membered heterocycle: A-series consists of 14 compounds with imidazole-5-one nuclear of type 1-arylideneamino-4-(4-methoxybenzylidene)-2-methyl-1H-imidazolin-5 (4H)-one (8 substances) and 1-arylideneamino-4- (4-chlorobenzylidene)-2-methyl-1H-imidazolin5 (4H)-one (6 substances); B-series consists of 10 diesters which are derivatives of 5(2/3/4-hydroxybenzylidene)thiazolidine-2,4-dione; C-series consists of 12 compounds containing 1,3,4-oxadiazoline heterocycle of type 2- (4-acetyl-5-aryl-5methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl -4-bromophenyl acetate (3 substances) and 2-(4-acetyl-5-methyl-5-aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl) -4-iodophenyl acetate (9 substances) * Study the structures and properties of the synthesized compounds based on the methods of determining the melting point, determining the crystalization solvent; Infrared (IR) spectrum, high resolution mass spectrometry (HR-MS), nuclear magnetic resonance spectrum (NMR) Especially, some compounds belong to Cseries are determined by real structure by using X-ray monocrystalline diffraction * Test the biological activities: antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus; antifungal against Aspergillus niger, Fusarium oxysporum, Saccharomyces cerevisiae, Candida albicans; cytotoxicity with breast cancer MCF-7, carcinoma (KB), liver cancer (HepG2) cell lines of the synthesized target compounds Scientific significance, practicality and new contributions * Has studied, launched appropriate synthesis procedures and successfully synthesized 36 new heterocyclic compounds belong to series of compounds containing imidazole-5-one ring (A-series), thiazolidine-2,4-dione ring (B-series) and 1,3,4-oxadiazoline ring (C-series) Besides that, 32 intermediate compounds also were synthesized * Has provided scientific information and data on the structure (especially molecular crystal structure of compounds C5b3, C5b4 and C5b5), as well as properties, crystallization solvents and biological activities of 36 new target compounds (antibacterial and fungal activities of A4b1-6 compounds, anti-breast cancer MCF-7 of A4b1-6, B3a-e and B4a-e compounds, anticancer liver HepG2 and KB carcinoma of C5b1-9 compounds) Layout thesis The layout of thesis includes 154 pages, in which, introduction pages; overview 27 pages; experimental 32 pages; results and discussion 76 pages; conclusion pages The thesis has 56 diagrams, 49 figures and 27 tables; 12 pages of references with 139 Vietnamese and English documents In addition, there is also Appendix part consisting of 211 spectra and tables CHAPTER OVERVIEW The thesis has reviewed the literature on the synthesis and biological activities of heterocyclic compounds containing 1H-imidazol-5(4H)-one ring; thiazolidine-2,4dione ring or 1,3,4-oxadiazoline ring The kinds of literature were published both inside and outside of Vietnam The results of the review have shown the synthetic methods of the above heterocycles, as well as their biological activities such as antibacterial, antifungal, anti-tuberculosis, anticancer, anti-inflammatory, hypoglycemic, etc At the same time, it also pointed out that research on these heterocycles is a new trend with being of great interest and it is growing rapidly with a plentiful number of publications in the world, but not many in Vietnam CHAPTER EXPERIMENTS AND METHODS 2.1 Methods of studying the structure and properties The melting points were determined in open capillaries and are uncorrected The IR spectra were recorded on an FT-IR Shimadzu 8400-S NMR spectra were measured on a Bruker Avance 500 MHz in dimethyl sulfoxide (DMSO-d6) using tetramethylsilane (TMS) as an internal reference Mass spectra were recorded on a Bruker micrOTOF-Q 10187 mass spectrometer 2.2 Synthesis of compounds New organic compounds containing five-membered heterocycle with heteroatom of nitrogen are synthesized according to diagrams illustrated in Figures 2.1, 2.2, and 2.3 All chemicals were obtained from commercial sources and used without further purification O X (CH3CO)2O (A1a,b) N X X = Cl(a), CH3O(b) O O CH3CONHCH2COOH (A2a,b) NH2NH2 O CH3 N NH2 N X CH3 (A3a,b) X = Cl(a), CH3O(b) X = Cl(a), CH3O(b) R - C6H4-CHO (A4a1-8): X = Cl; R= 4-OCH3 (a1), 4-CH3 (a2), 2-F (a3), 4-F (a4), H (a5), 2-NO2 (a6), 3-NO2 (a7), 4-NO2 (a8) O N X (A4b1-6): X= OCH3 ; R= 4-Cl(b1), 2-NO2(b2), 3-NO2(b3), 4-NO2(b4), N N R CH3 3-CH3-4-OH (b5), 3,4-(-OCH2O-) (b6) (A4a1-8) & (A4b1-6) Figure 2.1: Synthetic pathway of targeted compounds (A4a1-8) and (A4b1-6) Cl O H2N HCl O NH2 R S O S OH R H (B1a-e) O NH O O O OH OH R O S H (B2a-e) N H S O N O H O O (B3a-e) 2-OCO2Et, R = H (3a); 2-OCO2Et, R = 5-Br (3b) 3-OCO2Et, R = H (3c); 4-OCO2Et, R = H (3b) 4-OCO2Et, R = 3-OMe (3e) O O O 2-OH, R = H (a); 2-OH, R = 5-Br (b); 3-OH, R = H (c); 4-OH, R = H (d); 4-OH, R = 3-OMe (e) R O S H O N O O O (B4a-e) 2-OCH2CO2Et, R = H (4a); 2-OCH2CO2Et, R = 5-Br (4b) 3-OCH2CO2Et, R = H (4c); 4-OCH2CO2Et, R = H (4d); 4-OCH2CO2Et, R = 3-OMe (4e) Figure 2.2: Synthetic pathway of targeted compounds (B3a-e) and (B4a-e) O O OH OH C4a/C5a OCH3 a) Br2/CCl4 CH3OH H2SO4 (C1) OH b) NaOCl, KI OCH3 N 2H OH (C2a-b): X = Br (a), I (b) O X = Br O O O X NHNH2 OH (C3a-b) X = Br (a), I (b) R-C6H4COCH3 CH3 N N CH3 R = 3-Br (a1), 3-OCH3 (a2),3-NO2 (a3) X X=I R = 3-NO2 (b1), 4-NO2 (b2), H(b3), 4-F (b4), C4b/C5b O X (CH3CO)2O X R 4-Cl (b5), 3-Br (b6), 4-Br (b7), 4-CH3 (b8), O CH3 4-NH2 (C4b9); 4-NH-CO-CH3 (C5b9) (C5a1-3) & (C5b1-9) O N OHH N CH3 (C4a1-3) &(C4b1-9) R Figure 2.3: Synthetic pathway of targeted compounds (C5a1-3) and (C5b1-9) 2.3 Biological activities 2.3.1 Antifungal and antibacterial activities Antimicrobial activity of tested samples was assayed using micro broth dilution methods of McKane, L., and Kandel for test microorganisms including Escherichia coli, Pseudomonas aureus, Bacillus subtilis, Staphylococcus aureus, Aspergillus niger, Fusarium oxysporum, Saccharomyces cerevisiae, and Candida albicans The positive controls were Ampicillin for Gram positive strains; Tetracycline for Gram negative strains and Nystatin for mycelium and yeast 2.3.2 Cytotoxic activity Tests for cytotoxic activity were conducted at the Biological Laboratory, Institute of Biotechnology, Vietnam Academy of Science and Technology The (A4b1-6) and (B3a-e, B4a-e) compounds were investigated for cytotoxic activity against the breast cancer cell line (MCF-7) by the Sulforhodamine B method (in vitro) with the positive control in the experiment is Camptothecin The (C5b1-9) compounds were tested for in vitro cytotoxic activity against carcinoma (KB) cell line, and hepatocellular cell line (HepG2) with Ellipticine as the positive control CHAPTER RESULTS AND DISCUSSION 3.1 The synthesis, structure and properties of the compounds belonging to A-series 3.1.1 Synthesis The (A4a1-8) and (A4b1-6) compounds were prepared from acetyl glycine and 4-chlorobenzaldehyde (A1a) or 4-methoxybenzaldehyde (A1b) according to the synthetic pathway illustrated in Figure 2.1 3.1.1.1 Synthetic procedures * The procedures to synthesize (A2a), (A2b), (A3a) and (A3b) compounds are presented in Section 2.2.1.2 and Section 2.2.1.3 of the thesis * The procedures to synthesize (A4a1-8) and (A4b1-6) compounds are presented in Section 2.2.1.4 of the thesis 3.1.1.2 Results * Synthetic results; IR, 1H-NMR spectral data of (A2a) and (A2b) compounds were mentioned in Section 2.2.1.2 of the thesis * Synthetic results; IR, MS, 1H-NMR, 13C-NMR spectral data of (A3a) and (A3b) compounds were mentioned in Section 2.2.1.3 of the thesis * Compounds (A4a1-8) and (A4b1-6): The (A3a) or (A3b) compound reacted with aromatic aldehydes in absolute ethanol to form azomethine derivatives (A4a1-8) and (A4b1-6), respectively The reactions occur according to the mechanism of a condensation reaction between an amine and a carbonyl compound Yields, physical properties, and IR, HR-MS spectral data of resulted azomethines (Schiff's bases) were shown in Table 3.1 Table 3.1: Physical properties and IR, MS spectral data of the Schiff's bases (A4a1-8) and (A4b1-6) Yiel IR (, cm-1) (M+H)+ Melting No Compound d C=C NO [Calc.] point (oC) C-H C=O (%) C=N 1678, 354.1051 3060 4-CH3O 1717 176-178 80 1605, 1561 [354.0931] 2930 (A4a1) - 360.0867 * 4-CH3 2924 1705 1651, 1589 182-184 66 2855 [360.0982] (A4a2) 342.0824 2-F (A4a3) 196-197 78 1717 1651, 1591 [342.0731] 342.0818 4-F (A4a4) 184-185 74 1713 1651, 1589 [342.0731] 6 H (A4a5) 173-174 68 2960 1713 1651, 1589 175-177 77 2847 1705 1643, 1582 181-182 81 3079 213-214 84 2924 4-Cl (A4b1) 192-193 64 2945 2-NO2 (A4a6) 3-NO2 (A4a7) 4-NO2 (A4a8) - 1520 1342 1536 1713 1589 1350 1538 1705 1643, 1582 1342 1708 1649, 1599 324.0928 [324.0825] 369.0751 [369.0676] 369.0746 [369.0676] 369.0783 [369.0676] 354.1002 [354.1009] 387.1077* [387.1069] 365.1235 [365.1250] 365.1245 [365.1250] 366.1452 [366.1454] 364.1264 [364.1297] 2-NO2 1544 234-235 74 1713 1643, 1597 1320 (A4b2) 3-NO2 1536 219-220 43 3018 1697 1643, 1597 11 1350 (A4b3) 1512 3001 4-NO2 245-246 58 1698 1667, 1597 12 1342 (A4b4) 2855 3-CH3O-42970 13 235-236 61 1688 1645, 1601 ** OH(A4b5) 2924 3,4-(CH2O2) 14 179-180 56 2918 1688 1649 1603 (A4b6) Note: * (A4a2), (A4b2): [M+Na]+; (A4b5)**: OH = 3441cm-1 3.1.2 The structures * The structure of (A3a) and (A3b) was confirmed by their IR, HR-MS, 1HNMR, 13C-NMR spectral data (see Section 2.2.1.3 of the thesis) * The structure of Schiff's bases (A4a1-8), (A4b1-6) was confirmed by their IR, HR-MS, 1H-NMR, 13C-NMR, HSQC, HMBC spectral data 1H-NMR and 13C-NMR were shown in Table 3.2, Table 3.3, Table 3.4, and Table 3.5 of the thesis 1H-NMR and 13C-NMR of the (A4a7) and (A4b3) compounds were chosen as representatives * (4Z)-1-(3-nitrobenzylideneamino)-4-(4-chlorobenzylidene) -2-methyl-1H-imidazol5(4H)-one (A4a7): 1H-NMR (δ, ppm J, Hz): 2.48 (3H, 10 singlet, H-2a, s); 7.06 (1H, singlet, H-6); 8.20 (2H, doublet, O Cl 11 17 16 J=8.5, H-8); 7,47 (2H, doublet, 3J=8.5, H-9); 9.70 (1H, N N 12 3N 15 14 13 2a CH3 singlet, H-11); 8.57 (1H, singlet, H-13); 8.29 (1H, doublet, (A4a7) NO2 J =8.0, H-15); 7,77 (1H, doublet-doublet, 3J 1=3J =8.0, H16); 8.23 (1H, doublet,3J =8.0, H-17) 13C-NMR (δ, ppm): 162.6 (C-2); 14.5 (C-2a); 136.6 (C-4); 165.4 (C-5); 125.0 (C-6); 132.1 (C-7); 133.3 (C-8); 128.3 (C-9); 134.8 (C-C-10); 151.1 (C-11); 135.2 (C-12); 121.3 (C-13); 148.1 (C-14); 124.9 (C-15); 130.1 (C-16); 133.2 (C-17) 10 Figure 3.1 The 1H-NMR spectrum of Hình 3.2 The 13C-NMR spectrum of (A4a7) (A4a7) 1-Amino-4-(4-chlorobenzylidene)-2-methyl-1H-imidazoline-5(4H)-one compound (A3a) reacted with 3-nitrobenzaldehyde in absolute ethanol to form azomethine derivative (A4a7) The IR spectrum of Schiff's base (A4a7) obtained from amine (A3a) showed not only a lack of stretching band at 3209 cm-1 (νNH2) but also an appearance of the absorption band of imine group (C=N) at 1589 cm-1; in addition, strong absorptions at 1536 cm-1 and 1350 cm-1 characterizing NO2 group also appeared in the spectrum The 1H-NMR spectrum of (A4a7) compound showed a new signal at 9.70 ppm assigned to the proton H-11 of the azomethine group (CH=N) Besides, one singlet signal with integral strength of 3H in the upfield (2.48 ppm) is attributed to protons H-2a of the 2-methyl group in the heterocycle In the aromatic region, there are singlet signals with an integral intensity of 1H at 7.06 ppm and 8.57 ppm are attributed to H-6 and H-13 Two doublet signals (3J = 8.5 Hz) with integral strength of 2H appear at 7.47 ppm and 8.20 ppm are attributed to the protons H-9, H-8 Proton H-9 is closer to the electron withdrawn group (Cl), so its resonance signal will appear at lower field Proton H-16 has spin-spin coupling with H-15 and H-17 so the doublet-doublet signal at 7.77ppm (3J1 = 3J2 = 8.0) corresponds to H-16 Two doublet signals (1H) at 8.23 ppm and 8.29 ppm correspond to protons H-17, H-15 Since H15 is in the ortho position of the -NO2 group, the local magnetic shielding must be reduced more than H-17 in the para position, so H-15 must give the resonance signal in the down field The 13C-NMR spectrum of (A4a7) showed enough 16 signals being accordant with the molecular structure In which, the signal of the aliphatic carbon C2a appears in the upfield (14.5 ppm); but the signal of carbon atoms such C-5 (C=O), C-2 (C=N in imidazoline heterocyclic), and C11 (-N=CH-) have to appear in the downfield that were at 165.4, 151.1 and 162.6 ppm respectively Besides, 12 signals of carbon on the benzene rings appear in the range of 121.3-148 ppm The HSQC spectrum shows that the signals of C-6, C-8, C-9, C-11, C-13, C-15, C-16, C-17 atoms make cross peaks with signals of the corresponding protons In the HMBC * The procedure to synthesize (B2a-e) compounds based on the reaction of hydroxybenzaldehydes with thiazolidine-2,4-dione using weakly basic amine (piperidine) as a catalyst and toluene as a solvent The procedure was presented in Section 2.2.2.2 of the thesis * The procedures to synthesize (B3a-e) and (B4a-e) compounds were presented in Section 2.2.2.3 of the thesis, where the mixture of the definite (B2a-e) compounds with ethyl chloroformate or ethyl chloroacetate (molar ratio of 1: 2) in acetone in the presence of K2CO3 was refluxed for about 10 hours 3.2.1.2 Results * Synthetic results and physical properties, IR spectral data of (B2a-e) compounds were summarized in Table 3.4 Table 3.4: Physical properties and IR spectral data of (B2a-e) compounds Comp IR (cm-1) Melting point (oC) Yield (%) O-H N-H C-H C=C C=O (B2a) 278 - 280 3426 3032 2810 1589 1728 1667 58.0 (B2b) 256 - 258 3449 3094 2905 1589 1728 1636 57.0 (B2c) 290 - 293 3302 3163 3063 1589 1751 1690 51.0 (B2d) 318 - 320 3403 3133 2903 1574 1728 1682 56.0 (B2e) 242-245 3464 3186 1574 1728 1682 54.0 * The reaction of (B2a-e) compounds with ethyl chloroformate follows the mechanism of SN2(CO) to form (B3a-e) compounds, while the reaction with ethyl chloroacetate follows the mechanism of SN2 to form (B4a-e) compounds In the conditions of the reactions, both OH and NH centers of the 5- (hydroxybenzylidene) thiazolidine-2,4-dione compounds reacted contemporaneously to afford the corresponding diesters Yields, physical properties, and IR, HR-MS spectral data of compounds (B3a-e), and (B4a-e) compounds were shown in Table 3.5 Table 3.5: Physical properties and IR, MS spectral data of (B3a-e) and (B4a-e) compounds No Melting Yieds point (0C) (%) C-H IR (, cm-1) C=C C=O C-O (B3a) 122- 123 63.0 2986 3032 1759, 1705 1319, 1249 (B3b) 126-127 73.0 2924 2986 1489 1759, 1705 1489, 1319 (B3c) 131-132 62.0 2986 3063 1613 1780, 1759 1312, 1235 (B3d) 139-140 66.0 2986 3090 1697 1751, 1705 1304, 1234 (B3e) 127-128 70.0 2986 3180 1605 1751, 1705 1312, 1257 11 [M+Na]+/ [Cacl.] 388.0426/ [388.046] 465.9566/ [465.957] 388.0448/ [388.046] 388.0451/ [388.046] 418.1560/ [418.057] (B4a) 111-112 50.0 2986, 2890 1597 1750, 1797 1372,1220 (B4b) 118-119 51.0 2986, 2924 1597 1736, 1690 1381, 1219 (B4c) 96-97 57.0 2986, 2916 1605 1744, 1697 1373, 1211 (B4d) 125-126 62.0 2978 1589 1744, 1690 1381, 1211 (B4e) 95-96 54.0 2986, 2909 1589 1728, 1690 1373, 1211 416.0757/ [416.078] 472.0065*/ [472.006] 416.0745/ [416.078] 416.0762/ [416.078] 446.0867/ [446.088] * (B4b): [M + H]+ 3.2.2 Structures * The structures of the (B2a-e) compounds were confirmed by IR spectroscopy, H-NMR as well as compared with the properties described in the references 1HNMR spectral data of compounds are shown in Table 3.10 of the thesis Compound (B2b) is a new compound with spectral features: IR (ν, cm-1): 3449 (O-H), 3094 (NH), 1728 (C=O), 1636 (C=O), 1589 (C=C), 1498, 1281, 602 (C-Br); 1H-NMR (δ, ppm J, Hz): 12.63 (1H, singlet, H-3), 10.89 (1H, singlet, -OH), 7.89 (1H, singlet, H-6), 7.49 (1H, doublet-doublet, 3J = 8.5, 4J = 2.5, H-10), 7.41 (1H, doublet, 4J = 2.5, H-12), 6.95 (1H, doublet, 3J = 8.5, H-9) (B2b) * The molecular structures of the (B3a-e) and (B4a-e) compounds were confirmed by their IR, HR-MS, 1H-NMR and 13C-NMR spectral data The results of analysing and attributing the 1H-NMR and 13C-NMR of the (B3ae), and (B4a-e) compounds were shown in Table 3.11, Table 3.12, Table 3.13, and Table 3.14 in the thesis The following are spectral data of (B3d) and (B4d) compounds that were selected as representative of the compounds belonging to the Bt series O H3C Oy O c O z * Ethyl 5-(4-((ethoxycarbonyl)oxy)benzylidene)-2,4x a b O d N CH O dioxothiazolidine-3-carboxylate (B3d): 1H-NMR (δ, (B4d) O S ppm J, Hz): 8.0 (1H, singlet, H-6); 7.72 (2H, doublet, 3J = 8.5, H-8), 7.45 (2H, doublet, 3J = 8.5, H-9); 4.46 (2H, quartet, 3J = 7.0, H-10b); 4.29 (2H, quartet, 3J = 7.0, H-3y); 1.33 (3H, triplet, 3J = 7.0, H-10c); 1.31 (3H, triplet, 3J = 7.0, H-3z); 13C-NMR (δ, ppm): 163.9 (C-2); 162.2 (C4); 120.2 (C-5); 133.3 (C-6); 130.6 (C-7); 131.8 (C-8); 122.4 (C-9); 147.2 (C-10); 122.4 (C-11); 131.8 (C-12); 152.2 (C-10a); 65.6 (C-10b); 13.9 (C-10c); 152.5 (C-3x); 65.0 (C-3y); 13.7 (C-3z) HN Br O O S 12 11 10 OH 12 11 10 12 Figure 3.5: A part of 1H-NMR spectrum of (B3d) Figure 3.6: The 13C-NMR spectrum of (B3d) * Ethyl 2-(5-(4-(2-ethoxy-2-oxoethoxy)benzylidene)-2,4dioxothiazolidin-3yl)acetate (B4d): 1H-NMR (δ, ppm J, Hz): 7.88 (1H, singlet, H-6), 7.49 (2H, O doublet, 3J = 9.0, H-8); 7,00 (2H, doublet, 3J =9.0, H-9), H3C O O O O CH3 4.67 (2H, singlet, H-10a), 4.46 (2H, singlet, H-3x), 4.28 N O O S (2H, quartet, 3J = 7,0, H-3z), 4.23 (2H, quartet, 3J = 7.0, (B3d) H-10c), 1.31 (6H, multiplet, H-3t, H-10d); 13C-NMR (δ, ppm): 168.2 (C-2); 165.7 (C-4); 118.8 (C-5); 134.1 (C-6); 132.3 (C-7); 126.8 (C-8); 115.4 (C-9); 159.7 (C-10); 115.4 (C-11); 126.8 (C-12); 65.2 (C-10a); 166.3 (C-10b); 62.2 (C-10c); 14.2 (C-10d); 42.1 (C-3x); 67.5 (C-3y); 61.6 (C-3z); 14.1 (C-3t) z y x 12 11 10 c a b Figure 3.7: The 1H-NMR spectrum of Figure 3.8: The 13C-NMR spectrum of (B4d) (B4d) The IR spectra of (B3d) and (B4d) were disappeared in some bands at 3403 -1 cm (OH) and 3133 cm-1(NH) and the presence of the carbonyl groups was recognized easily by the intense absorption bands at 1705, 1751, 1790 cm-1 (for B3d) or at 1744, 1690 cm-1(for B4d) 13 Comparing with the 1H-NMR spectrum of (B2d) compound, the 1H-NMR spectra of (B3d) and (B4d) did not appear any broad signal in the range of 9.80-12.70 ppm that characterized protons in the N-H and O-H groups The formation of the diesters (B3d) and (B4d) also was confirmed by the appearance of the signals of protons in two ethyl groups, which were assigned as two quartets (with the intensity of 2H for each signal, J=7.0Hz) around 4.29 - 4.47 ppm and two triplets (with the intensity of 3H for each signal, J=7.0Hz) around 1.20-1.40 ppm For (B3d) compound, these signals appeared at 4.46 ppm (2H, quartet, 3J = 7.0, H-10b), 4.29 (2H, quartet, 3J = 7.0, H-3y) and 1.33 (3H, triplet, 3J = 7.0, H-10c), 1.31 (3H, triplet, J = 7.0, H-3z) while for (B4d) compound, these signals appeared at 4.28 (2H, quartet, J = 7.0, H-3z), 4.23 (2H, quartet, 3J = 7.0, H-10c) and 1.31 ppm (6H, multiplet, H-3t, H-10d) The singlet signals for methylene groups between the heteroatom and carbonyl group of the (B4d) compounds appeared at 4.67 ppm (2H, singlet, H-10a) and 4.46 ppm (2H, singlet, H-3x) In the 13C-NMR spectra, signals appearing between 165.7- 168.2 ppm were assigned to carbonyl carbons including carbonyl carbons in the thiazolidine-2,4-dione ring and carbonyl carbons in the functional groups of diester; signals appearing in the aliphatic region of the spectrum of (B3d) compound were attributed to carbons of two ethyl groups while the spectrum of the (B4d) compound appeared more than signals in this region due to the presence of methylene groups, each of them was between heteroatom and carbonyl group The MS spectra of (B3d) and (B4d) compounds also showed molecular ion peaks being according to the assumed structures 3.2.3 The selective cytotoxicity on breast cancer cells (MCF-7) The synthesized compounds were tested for their selective cytotoxicity on breast cancer cells (MCF-7 cells) via SRB (sulforhodamine B) assay The selective cytotoxicity result on breast cancer cells of the diesters containing TZD ring (B3a-e, B4a-e) at a concentration of 100 µg/mL was shown in Table 3.6 (The B3d compound did not dissolve well in DMSO, so it was not tested the selective cytotoxicity on breast cancer cells) Table 3.6 Selective cytotoxicity on breast cancer cells of (B3a-e) and (B4a-e) compounds Percentage of cytotoxicity (%) No Comp 1st 2nd 3rd Avg ± SD (B3a) 24.43 10.58 16.77 17,26 ± 6,94 (B3b) 27.58 27.25 25.63 26,82 ± 1,04 (B3c) 18.39 13.36 14.57 15,44 ± 2,63 (B3d)* (B3e) 27.71 24.34 24.93 25,66 ± 1,80 (B4a) 7.18 1.98 -1.40 2,59 ± 4,32 (B4b) 5.54 5.69 -2.52 2,90 ± 4,70 (B4c) 2.90 5.16 -0.28 2,59 ± 2,73 (B4d) 4.03 5.16 -1.12 2,69 ± 3,35 10 (B4e) 1.13 -1.72 2.52 0,64 ± 2,16 53,84 50.64 54.46 52.98 ± 3.81 Camptothecin 14 (Note: Avg: average, SD: standard deviation) Although all tested compounds have not shown good cytotoxic activity on MCF-7 cells but ethyl 5-(((ethoxycarbonyl)oxy)benzylidene)-2,4-dioxothiazolidine3-carboxylate compounds (B3a-c, B3e) exhibit higher cytotoxic than ethyl 2-(5-(4(2-ethoxy-2-oxoethoxy)benzylidene)-2,4-dioxothiazolidin-3-yl)acetate compounds (B4a-c) 3.3 Synthesis, structure and properties of the compounds belonging to C-series 3.3.1.The synthesis 3.3.1.1 Synthetic procedures 12 new compounds (C5a1-3 and C5b1-9) that are derivatives of 5-bromo/iodo2-hydroxybenzoate were synthesized starting from methyl salicylate The synthesis pathway was described in Figure 2.3 * The procedures to synthesize methyl 5-bromo-2-hydroxy-5-iodobenzoate (C2a) and methyl 2-hydroxy-5-iodobenzoate (C2b) were presented in Section 2.2.3.1 of the thesis * The procedures to synthesize 5-bromo-2-hydroxybenzohydrazide (C3a) and 2hydroxy-5-iodobenzohydrazide (C3b) were presented in Section 2.2.3.2 of the thesis * The procedures to synthesize N’-(1-arylethylidene)-2-hydroxy-5-halobenzohydrazide compounds (C4a1-3 and 4b1-9) were presented in Section 2.2.3.3 of the thesis * Synthesis of 2-(4-acetyl-5-aryl-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4halophenyl acetate compounds (C5a1-3 and C5b1-9): A mixture of an appropriate Nsubstituted hydrazide (C4a1-3, C4b1-9) (5 mmol) and acetic anhydride (10 ml) was taken into a 100 ml round-bottomed flask The mixture was refluxed for hs After cooling to room temperature, the reaction mixture was poured into ice-cold water The precipitate obtained was filtered off and crystallized from a mixture of ethanol and water to give the corresponding products (C5a1-3 and C5b1-9) The crystals of compounds (C5b3, C5b4, and C5b5) were suitable for X-ray diffraction 3.3.1.2 Results * The synthetic results and physical characteristics of (C2a) and (C2b) were presented in Section 2.2.3.1 * The synthetic results, physical characteristics and IR, 1H-NMR spectra data of (C3a) and (C3b) were mentioned in Section 2.2.3.2 of the thesis * The synthetic results, physical properties and IR, HR-MS spectral data of compounds (C4a1-3) and (C4b1-9) were summarized in Table 3.7 Table 3.7: Yield, physical properties and IR, HR-MS spectral data of (C4a1-3) and (C4b1-9) compounds crystalliza Melting IR (, cm-1) Yield (M+H)+ tion point Comp O-H C=O (%) [Cacl.] NO2 solvent (oC) N-H C=N DMF: 3271 1641 434.9154* (C4a1) 247 64 H2O 3059 1599 [434.9163] DMF: 387.0176 3354 1622 (C4a2) 222.5 73 H2O 3256 1597 [387.0164] (C4a3) 258.3 69 dioxane 3283 1636 1520 399.9939* 15 3092 1599 1354 399.9909 3217 1636 1520 425.9924 (C4b1) 235-236 88 dioxane 3217 1599 1350 [425.9951] 3094 1643 1535 447.9718* (C4b2) 259-260 82 dioxane 3094 1600 1342 [447.9770] DMF: 3295 1643 380.9992 (C4b3) 179-180 84 H2O 3040 1566 381.0100 399.0007 3295 1643 DMF: (C4b4) 234-235 77 [399.0006] 3102 1605 H2O DMF: 414.9674 3287 1643 (C4b5) 269-270 85 H2O [414.9710] 3088 1550 480.9023* 3412 1644 DMF: (C4b6) 272-273 82 3034 1556 [480.9127] H2O 458.8999 3285 1647 DMF: (C4b7) 282-283 86 [458.9205] 3034 1593 H2O DMF: 3279 1645 395.0247 (C4b8) 228-229 76 H2O 3035 1606 [395.0256] 3440 396.0069 1634 (C4b9) 242-243 78 dioxane 3928 [396.0209] 1577 3201 * [M+Na]+ * The reaction mechanism to form the 1,3,4-oxadiazoline compounds (C5a1-3, C5b1-9) was described in Scheme 3.1 H X N N O OH R C -H+ R N N X O CH3 N N X CH3 OH (CH3CO)2O X O CH3 OCOCH3 O N N O +H+ CH3 R CH3 (CH3CO)2O SN(CO) OCOCH3 N N X O H R CH3 OCOCH3 Scheme 3.1: Reaction mechanism to form 1,3,4-oxadiazoline ring Synthetic results, physical properties and IR, HR-MS spectral data of (C5a1-3) and (C5b1-9) compounds were summarized in Table 3.8 Table 3.8: Yield, physical properties and IR, HR-MS spectral data of (C5a1-3) and (C5b1-9) compounds Melting Yiel MS IR ( cm-1) d point [M+Na]+ Comp C=N Csp -H NO2 C=O (%) Csp3-H (OC) [Cacl.] C=C 3078 1626 518.9360 (C5a1) 148-149 52 1765 2984 1568 [518.9375] 140.53072 1659 469.0379 (C5a2) 61 1765 141.5 2985 1580 [469.0375] 16 1661 1528 484.0123 3076 1765 1528 1347 [484.1120] 2950 3079 1659 1527 532.0008 (C5b1) 188-189 56 1751 2986 1589 1357 [531.9991] 3055 1667 1528 531.9991 (C5b2) 204-205 58 1759 2940 1605 1358 [531.9981] 3075 1667 487.0126* (C5b3) 153-154 53 1767 2950 1604 [487.0131] 3094 1659 505.0044 (C5b4) 158-160 54 1759 2940 1605 [505.0036] 3094 1667 520.9743 (C5b5) 198-199 58 1767 2930 1597 [520.9741] 3071 1651 564.9230 (C5b6) 202-203 53 1767 2932 1598 [564.9236] 3094 1620 564.9244 (C5b7) 201-202 55 1767 2928 1589 [564.9236] 3009 1667 501.0261 (C5b8) 199-200 62 1767 2924 1620 [501.0267] 544.0173 1655 3070 (C5b9) 1763 200-201 56 [544.0345] 1601 2934 ** + -1 Note: * (M+H) ** νNH = 3320 cm 3.3.2 Structures * The structure of the C4a1-3 and C4b1-9 compounds belonging to the Cseries was confirmed by their IR, HR-MS, 1H-NMR, and 13C-NMR spectra 1H-NMR and 13C-NMR spectral data of C4a1-3 and C4b1-9 compounds were presented in Table 3.18, Table 3.19, and Table 3.20 in the thesis * The structure of the (C5a1-3) and C5b1-9) compounds was confirmed by their IR, HR-MS, 1H-NMR, and 13C-NMR spectral data The results of analyzing and attributing 1H-NMR and 13C-NMR spectra of (C5a1-3) and (C5b1-9) compounds were showed in Table 3.21; Table 3.22 and Table 3.23 in the thesis The following is the spectral data of the two compounds (C5a3) and (C5b3) that was selected to represent the C-series * 2-(4-acetyl-5-methyl-5-(3-nitrophenyl)-4,5O CH dihydro-1,3,4-oxadiazol-2-yl)-4-bromophenyl acetate N N CH Br (C5a3): H-NMR (δ ppm and J, Hz): 8.32 (2H, multiplet, O H-12, H-10), 8.02 (1H, doublet, 3J=8.0 Hz, H-14), 7,96 O 11a ON (1H, doublet, 4J=2.5 Hz, H-2), 7.87 (1H, doublet-doublet, HC O (C5a3) J=8.5 Hz, 4J=2.0 Hz, H-6), 7.77 (1H, doublet-doublet, (C5a3) 121-122 51 19 18 17 16 3 14 13 10 15 11 12 17 J1=3J2=8.0 Hz, H-13), 7.32 (1H, doublet, 3J=8.5 Hz, H-5), 2.28 (3H, singlet, H-16), 2.27 (3H, singlet, H-19), 2.26 (3H, singlet, H-17); 13C-NMR δ ppm): 169.2 (C-15); 166.9 (C-18); 149.5 (C-7); 148.4 (C-4); 148.2 (C-11); 141.0 (C-9); 136.2 (C-3); 132.9 (C-6); 131.6 (C-2); 130.9 (C-12); 127.0 (C-13); 124.8 (C-5); 121.1 (C-10); 120.0 (C1); 119.2 (C-14); 99.5 (C-8); 22.7 (C-17); 22.6 (C-19); 21.1 (C-16) Figure 3.9: The 1H-NMR of (C5a3) Figure 3.10: The 13C-NMR of (C5a3 The 1H-NMR spectrum of (C5a3) compound (Fig 3.9) has enough signals corresponding to 16 protons In which, singlet signals with integral 3H of each at δ 2.28; δ 2.27 and δ 2.26 are assigned to three methyl groups at the positions of 16, 17 and 19 Four proton signals in the benzene ring (from number to number 14) appeared in the region 7.77-8.32 ppm and were attributed to H-13 (δ 7.77, 1H, doublet-doublet, 3J1 = 3J2 = 8.0 Hz), H-14 (δ 8.02, 1H, doublet, 3J = 8.0), H-10 (δ 8.32, 1H, 4J = 2.0 Hz) and H-12 (δ 8.31, 1H, doublet-doublet, 3J = 8.0 Hz, 4J = 2.0 Hz) Shape characteristics of the signals indicate that the benzene (C9-C14) ring contains two substituents at positions of and The 13C-NMR spectrum (Fig 3.10) of (C5a3) has all the signals of 19 carbon atoms The three signals in the alkane region correspond to the three-carbon of the three methyl groups at 22.7 ppm (C-17), 22.6 ppm (C-19), and 21.1 ppm (C-16), respectively Besides, the appearance of two signals of carbon in the C=O group at 169.2 ppm (C-15) and 166.9 ppm (C-18) is completely consistent with its structural characteristics The signals of C-7 (Csp2) and C-8 (Csp3) of the 1,3,4-oxadiazoline appear at 149.5 ppm and 99.5 ppm, respectively Since C-4 links to the oxygen atom while and C-11 links to the nitro group, their signals are shifted downfield and appear at 148.4 ppm and 148.2 ppm, respectively The signals of the other aromatic carbon atoms appear in the range 141.0 - 119.2 ppm 18 * 2-(4-Acetyl-5-methyl-5-phenyl-4,5-dihydro-1,3,4oxadiazol-2-yl)-4-iodophenyl acetate (C5b3): 1H-NMR (δ N N CH3 14 I O ppm J Hz) : 8.05 (1H, doublet, 4J = 2.0, H-2); 7.98 13 10 (1H, doublet-doublet, 3J = 8.5, 4J = 2.0, H-6); 7.51 (2H, O 12 11 15 16 doublet, 3J = 7.0, H-11, H-13), 7.44 (3H, multiplet, HH 3C O (C5b3) 10, H-12, H-14), 7.13 (1H, doublet, 3J = 8.5, H-5), 2.25 (3H, singlet, H-16), 2.24 (3H, singlet, H-19), 2.20 (3H, singlet, H-17); 13C-NMR (δ ppm): 169.2 (C-15); 166.5 (C-18); 149.3 (C-7); 148.7 (C-4); 141.9 (C-9); 139.1 (C-6); 137.2 (C-2); 129.8 (C-3); 129.0 (C-11,C-13); 126,9 (C-10, C-14); 126,1 (C-5); 120,3 (C-12); 100.4 (C-1); 91.7 (C-8); 22.8 (C-17); 22.7 (C-19); 21.1 (C-16) The spectra of (C5b3) compound were analyzed and attributed similarly to the compound (C5a3), thereby allowing confirmation of its molecular structure as well as the molecular structure of (C5b1-9) compounds in the C-series 3.3.3 Crystal structures of some compounds containing 1,3,4-oxadiazoline heterocycle (C5b3), (C5b4) and (C5b5) The crystals of (C5b3), (C5b4), and (C5b5) compounds are suitable for X-ray diffraction that belongs to the monoclinic space group P21/c Crystal data, data collection and structure refinement details for (C5b3), (C5b4), and (C5b5) were summarized in Table 3.9 Table 3.9: Crystal data and Data collection of Crystal data (C5b3) (C5b4) (C5b5) Chemycal formula C19H17IN2O4 C19H16FIN2O4 C19H16ClN2O4 Mr 464.24 482.24 498.69 Crystal system Monoclinic Monoclinic Monoclinic space group P21/c P21/c P21/c 8.8370 (1) 9.1241 (4) 11.703 (2) a (Å) b (Å) 20.0560 (1) 20.0980 (9) 22.037 (4) Crystalline c (Å) 11.0150 (1) 10.7456 7.4073 (12) cell β() 110.18 (1) 110.224 (2) 92.888 (8) parameters α=γ ( ) 90.0 90.0 90.0 V (Å ) 1832.4 (3) 1849.00 (15) 1907.9 (5) Radiation type Mo K Mo K Mo K -1 µ (mm ) 1.77 1.77 1.85 Crystal size (mm 0.42×0.20×0.16 0.60×0.37×0.29 0.22×0.12×0.12 Diffractometer Bruker APEXII Bruker APEXII Bruker APEXII CCD CCD CCD O 18 19 CH3 17 19 The fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2); Atomic displacement parameters (Å2); Geometric parameters (Å, º) were shown in the tables in the Appendix of the thesis * Crystal structures of (C5b3) compound The central 1,3,4-oxadiazoline ring in (C5b3) displays an envelope conformation (Fig.3.11) with the C8 atom as the flap [puckering parameters: Q = 0.1310 (14) Å and φ = 322.2(6)0] The best plane through the 1,3,4-oxadiazoline ring makes angles of 7.84(8)0 and 78.48(8)0 with the 4-iodophenyl ring (atoms C1-C6) and the phenyl ring (atoms C9-C14), respectively Both aromatic rings are inclined to each other by 82.11(8)0 In the crystal, molecules of (C5b3) are linked by C-H…O and C-H…π interactions, forming chains propagating along the b-axis direction (Fig 3.12 and Table 3.10) Molecules in parallel chains form inversion dimers by I…π interactions [Fig 3.12; I…Cg2iv = 3.7888 (8) Å; Cg2 is the centroid of the C1-C6 ring; symmetry code: (iv) x + 2, y + 1, z + 1] Figure 3.11: The molecular structure Figure 3.12: Packing diagram for of (C5b3) (C5b3) Cg2 is the centroid of the C1-C6 ring and Cg3 is the centroid of the C9-C14 ring [Symmetry codes: (i) -x + 1, y - 1/2, z + 1/2; (ii) -x + 2, y + 1, z + 1; (iii) x, - y + 3/2, z + 1/2.] Table 3.10: Hydrogen-bond geometry (Å, 0) for (C5b3) Hydrogen-bond Length (Å) Angle (0) D-H…A D-H H…A D…A D-H…A i C5-H5…O4 0.95 2.51 3.2828 (19) 139 ii C16-H16B…O4 0.98 2.55 3.529 (2) 177 iii C17-H17C…Cg3 0.98 2.70 3.5766 (17) 150 Note: Cg3 is the centroid of the C9-C14 ring; [Symmetry codes: (i) -x +1; y1/2; -z +1/2; (ii) x; -y+3/2; z-1/2; (iii) x; -y + 2; z + 1/2] 20 * Crystal structures of (C5b4) compound The crystal structures of (C5b3) and (C5b4) (Fig 3.13) are isomorphous; the r.m.s overlay fit is 0.0438 Å for the non-H atoms The puckering parameters of the 1,3,4-oxadiazoline ring of (C5b4) are Q = 0.1159(17) Å and φ = 325.4(8) The crystal packing is built up by C-H…O, C-H…π and C-I… π interactions, as for (C5b3) [Table 3.11: I…Cg2i = 3.7807 (8) Å ; Cg2 is the centroid of the C1-C6 ring; symmetry code: (i) x + 2, y + 1, z + 1] In addition, a C14- H14…O2 ii interaction (Table 3.11) is observed, which together with the C16-H16A…O4iii interaction, results in the formation of a dimer, generating an R22 loop (Fig 3.14) Table 3.11: Hydrogen-bond geometry (Å, 0) for (C5b4) Hydrogen-bond Length (Å) Angle (0) D-H…A D-H H…A D…A D-H…A i C5-H5…O4 0.95 2.53 3.331(2) 142 ii C14-H14…O2 0.95 2.51 3.335(2) 145 iii C16-H16A…O4 0.98 2.54 3.513(2) 174 ii C17-H17C…Cg3 0.98 2.50 3.407(2) 154 * Symmetry codes (i) -x + 1, y - 1/2, -z + 1/2; (ii) x, -y + 3/2, z + 1/2; (iii) x, -y + 3/2, z - 1/2 Cg3 is the centroid of the C9 - C14 ring Figure 3.13: The molecular structure of (C5b4) Figure 3.14 Partial packing diagram for (C5b4) [Symmetry code: (i) x, - y + 2, z + 1/2.] * Crystal structure of (C5b5) compound Compound (C5b5) is not isomorphous with analogues (C5b3) and (C5b4) The 1,3,4-oxadiazoline ring is almost planar (r.m.s deviation = 0.024 Å ) and is inclined to the planes of the aromatic rings by 11.95(8) (ring C1-C6) and 78.28(8) (ring C9C14) (Fig 3.15) The orientation of the acetate group in (C5b5) is different compared to compounds (C5b3) and (C5b4), as illustrated by the torsion angle C3-C4-O1-C15 [83.55(18)0 in (C5b5), 81.17(17)0 in (C5b3) and 81.5(2)0 in (C5b4)] As a result, in structures (C5b3) and (C5b4), the acetate group and the C8-aryl substituent are syn 21 with respect to one another, while in (C5b5) they are anti In all three cases, the carbonyl O atom (O-4) of acetate is close to being eclipsed with respect to atom C-4 of the aromatic ring, which may indicate a favourable interaction between a nonbonded pair of electrons on O4 and the π* orbital of the aromatic C1-C6 ring In the crystal, inversion dimers are formed by C11- H11…O1ii interactions (Table 3.12 and Fig 3.16) These dimers interact further by C6-H6…O2i and C19H19B…πiii interactions with the iodo-substituted phenyl ring (Table 3.12 and Fig 3.16), resulting in chains of molecules running in the c direction Parallel chains interact further by Cl…π contacts, again with the iodo-substituted phenyl ring (Table 3.12 and Fig 3.16) In contrast to the crystal packings of the two previous analogues, the packing of (C5b5) does not show I…π interactions The closest neighbour for atom I1 is H17B (I1…H17Bi = 3.13 Å) The shortest I…Cl distance in the crystal packing is I1…Cl1iv = 3.850(2) Å [symmetry code: (iv) x + 1, y + 1/2, z + 1/2] Figure 3.15: The molecular structure Figure 3.16: Partial packing diagram of (C5b5) for (C5b5) Table 3.12: Hydrogen-bond geometry (Å, 0) for (C5b5) Hydrogen-bond D-H…A C6-H6…O2i C11-H11…O1ii C19-H19B…Cg2iii Length (Å) D-H 0.95 0.95 0.98 H…A 2.47 2.55 2.75 D…A 3.258 (2) 3.435 (2) 3.649 (2) Angle (0) D-H…A 140 155 153 The crystal packings of compounds (C5b3), (C5b4) and (C5b5) contain no voids In summary, single-crystal X-ray diffraction studies were also carried out for (C5b3), (C5b4), and (C5b5) Compounds (C5b3), (C5b4) are isomorphous, with the 1,3,4-oxadiazoline ring having an envelope conformation, where the disubstituted C atom is the flap The packing is determined by C-H…O, C-H…π, and I…π interactions For (C5b5), the 1,3,4-oxadiazoline ring is almost planar In the packing, Cl…π interactions are observed, while the I atom is not involved in short interactions 22 3.3.4 In vitro cytotoxicity of (C5b1-9) compounds Table 13 Cytotoxic effects of the examined compounds (C5b1-9) (IC50 in µM) No Comp R KB (IC50 µM) HepG2 (IC50 µM) 3-NO2 C5b1 3.733  0.472 12.574  0.766 4-NO2 C5b2 9.214  0.884 14.735  0.727 H C5b3 5.280  0.819 12.284  0.625 C5b4 4-F 1.867  0.568 4.564  0.539 C5b5 4-Cl 4.012  0.622 3.811  0.822 C5b6 3-Br 0.921  0.360 3.315  0.552 4-Br C5b7 6.262  0.645 13.260  0.866 C5b8 4-CH3 3.166  0.398 3.983  0.482 4-NH-CO-CH3 C5b9 12.476  0.979 11.900  1.036 Ellipticine 1.260  0.528 2.358  0.407 The tested results in Table 3.13 indicate that most of the examined compounds possess at least moderate cytotoxic activity, and some compounds even display a promising activity profile Compounds (C5b4), (C5b5), (C5b6) and (C5b8) (IC50 values between 0.9 and 4.5 µM), showing a reasonable activity against two human cancer cell lines In particular, compound (C5b6) exhibits a strong anticancer effect against KB cells, with an IC50 value (0.9 µM) lower than Ellipticine (1.2 µM) Initially, it is possible to predict that the R substituent group in the meta position on the phenyl ring (from C-9 to C-14) increases the cytotoxic activity of the compound more than the para position Especially, compound (C5b6) with the Br substituent at the meta position on the benzene ring has the strongest activity and is capable of developing into cancer treatment drugs 23 CONCLUSION The 36 new target compounds including the A-series containing imidazole-5one heterocycle, the B-series containing thiazolidine-2,4-dione heterocycle and the Cseries containing 1,3,4-oxadiazoline heterocycle, and 32 intermediate compounds were successfully synthesized The number of new compounds in the A-series is 14, including substances (A4a1-8) type 1-arylideneamino-4- (4-methoxybenzylidene) -2-methyl-1Himidazolin-5-(4H)-one and substances (A4b1-6) type 1-arylideneamino-4 -(4chlorobenzylidene) -2-methyl-1H-imidazolin-5-(4H)-one B-series has 10 new compounds, including 05 compounds (B3a-e) in form ethyl 5-(4-((ethoxycarbonyl) oxygen)benzylidene)-2,4-dioxothiazolidine-3-carboxylate and 05 compounds (B4a-e) in form ethyl 2-(5-((2-ethoxy-2-oxoethoxy) benzylidene)-2,4-dioxothiazolidin-3-yl)acetates contains thiazolidine-2,4-dione heterocyclic C-series has 14 new compounds, including 03 substances (C5a1-3) of type 2-(4-acetyl-5-aryl-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2yl-4-bromophenyl acetate and 09 substances (C5b1-9) of category 2-(4-acetyl-5-methyl-5aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-iodophenyl acetate The structures and properties of 36 target compounds and 32 intermediates were studied by the methods of determining melting temperature, determining crystallization solvents; FT-IR, HR-MS, NMR spectrum Besides that, structures of compounds including (C5b3), (C5b4) and (C5b5) also studied by their X-ray single-crystal diffraction spectra The bioactivities of 33 target compounds were tested + Some compounds in the A-series including (A4a1-8) compounds were tested for antibacterial activity on strains of Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus; antifungal on strains of Aspergillus niger, Fusarium oxysporum, Saccharomyces cerevisiae, Candida albicans The results showed that compounds of that ((A4a1), (A4a2) and (A4a8)) possess antibacterial activity against S aureus with MIC values at a concentration of 100 μg / mL; the remaining compounds in the A-series exhibited low antimicrobial and antifungal activity against tested strains of bacteria and fungi + Some compounds in the A-series and B-series consisting of (A4b1-6), (B3a-e) and (B4a-e) were tested for MFC-7 cytotoxic activity As a result, (B3a-c) and (B3e) compounds exhibited cytotoxic activity against cancer cell lines MCF-7 much stronger than (B4a-e) compounds, but the level is still lower than the Camptothecine as the positive control + Some compounds (C5b1-9) belonging the C-series were tested for cytotoxic activity against carcinoma cell line (KB-CCL-17) and hepatocellular cell line (Hep G2HB-8065) The results indicate that most of the examined compounds possess at least moderate cytotoxic activity, and some compounds even display a promising activity profile In which, compounds being (C5b4), (C5b6), (C5b7), and (C5b8) have a good ability to inhibit tested human cancer cell lines (KB and HepG2) with IC50 in the range from 0.9 to 4, µM Initially, it can be seen that the R substituent group in the meta position on the phenyl ring (from C-9 to C-14) makes the activity of the compounds higher than that at the para position Especially, compound (C5b6) with the Br substituent in the meta position on the benzene ring has the strongest activity and is capable of developing into cancer treatment drugs 24 LIST OF PUBLISHED PAPERS Cong Tien Nguyen, Dao Thi Hong Dinh, Thin Van Nguyen, Giang Duc Le and Hien Cao Nguyen (2019), “Synthesis and Antimicrobial Activity of Some 1-arylideneamino-4-(4-chlorobenzylidene)-2-methyl-1H-imidazolin5(4H)-one Compounds,”Oriental Journal of Chemistry 35(2), 822-828 Cong Nguyen Tien, Thin Nguyen Van, Giang Le Duc, Manh Vu Quoc, Trung Vu Quoc, Thang Pham Chien, Hung Nguyen Huy, Anh Dang Thi Tuyet, Tuyen Nguyen Van and Luc Van Meervelt (2018), “Synthesis, structure and in vitro cytotoxicity testing of some 1,3,4-oxadiazoline derivatives from 2-hydroxy-5-iodobenzoic acid”, Acta Crystallographica, C74, 839-846 Hieu Quang Tran, Hien Cao Nguyen, Thin Van Nguyen, Thanh Thi Nguyen, Toan Ngoc Vo and Cong Tien Nguyen (2018), “Synthesis and evaluation of cytotoxic activity on MCF-7 cell line of some diesters derived from 5-(hydroxybenzylidene)thiazolidine-2,4-diones”, Acta Chemica Iasi, 26(2), 233-248 Nguyen Van Thin, Le Duc Giang, Nguyen Thi Hong Liên, To Nguyen Thuy Khuê, Dao Huynh Phuc, Nguyen Tien Cong (2018), “Synthesis of some 2-(4-acetyl-5-aryl-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-bromophenyl acetate compounds”, Vinh University Journal of Science, 47(4A), 63-70 Nguyen Van Thin, Dinh Thi Hong Dao, Nguyen Thị Thanh, Le Duc Giang, Nguyen Tien Cong (2017), “Synthesis and cytotoxic activity on breast cancer MCF-7 cells of 1-arylideneamino-4-(4-methoxybenzylidene)-2methyl-1h-imidazolin-5(4H)-one compounds”, Vietnam Jounal of Chemistry, 55(5E34), 58-62 Nguyen Tien Cong, Nguyen Van Thin, Tran Hoang Phuong (2017), “Synthesis and structure of some N’-(1-arylethylidene)-2-hydroxy-5idobenzohydrazide compounds,”Vietnam Jounal of Chemistry, 55(5E34), 464-468 25 ... 3 055 1667 152 8 53 1.9991 (C5b2) 204-2 05 58 1 759 2940 16 05 1 358 [53 1.9981] 30 75 1667 487.0126* (C5b3) 153 - 154 53 1767 2 950 1604 [487.0131] 3094 1 659 50 5.0044 (C5b4) 158 -160 54 1 759 2940 16 05 [50 5.0036]... 140 .53 072 1 659 469.0379 (C5a2) 61 17 65 141 .5 29 85 158 0 [469.03 75] 16 1661 152 8 484.0123 3076 17 65 152 8 1347 [484.1120] 2 950 3079 1 659 152 7 53 2.0008 (C5b1) 188-189 56 1 751 2986 158 9 1 357 [53 1.9991]... 1667 52 0.9743 (C5b5) 198-199 58 1767 2930 159 7 [52 0.9741] 3071 1 651 56 4.9230 (C5b6) 202-203 53 1767 2932 159 8 [56 4.9236] 3094 1620 56 4.9244 (C5b7) 201-202 55 1767 2928 158 9 [56 4.9236] 3009 1667 50 1.0261