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Nghiên cứu tổng hợp, cấu trúc và khảo sát hoạt tính sinh học của một số hợp chất chứa dị vòng Benzothiaz.Nghiên cứu tổng hợp, cấu trúc và khảo sát hoạt tính sinh học của một số hợp chất chứa dị vòng Benzothiaz.Nghiên cứu tổng hợp, cấu trúc và khảo sát hoạt tính sinh học của một số hợp chất chứa dị vòng Benzothiaz.Nghiên cứu tổng hợp, cấu trúc và khảo sát hoạt tính sinh học của một số hợp chất chứa dị vòng Benzothiaz.Nghiên cứu tổng hợp, cấu trúc và khảo sát hoạt tính sinh học của một số hợp chất chứa dị vòng Benzothiaz.
MINISTRY OF EDUCATION AND TRAINING HANOI NATIONAL UNIVERSITY OF EDUCATION NGUYEN THI NGOC MAI STUDY ON SYNTHESIS, STRUCTURES AND BIOLOGICAL ACTIVITY EVALUATION OF SOME DERIVATIVES CONATING BENZOTHIAZOLE AND BENZOXAZOLE Major: ORGANIC CHEMISTRY Code: 9.44.01.14 ABSTRACT OF DOCTORAL THESIS IN CHEMISTRY Ha Noi, 12/2021 The Research Works is completed at: Hanoi National University of Education Supervisor: Dr Duong Quoc Hoan Dr Trinh Thi Huan Reviewer 1: Prof Pham Quoc Long Institute of Natural Products Chemistry Reviewer 2: Prof Nguyen Hai Nam Hanoi University of Pharmacy Reviewer 3: Assoc Prof Vu Quoc Trung Hanoi National University of Education The thesis is defended before Board of Thesis Examiners at Institutional level met in Hanoi National University of Education at ………on …………………… The thesis can be found at the library: National Library, Hanoi or the Library of Hanoi National University of Education INTRODUCTION Reasons for choosing the topic Benzothiazole heterocyclic derivatives have an important role in many fields, especially in synthetic chemistry, medicine and pharmaceuticals due to their diverse biological activities such as antibacterial, antifungal, anticancer etc Many benzothiazole heterocyclic compounds are used in drugs such as: Riluzole used in antidepressant, Zopolrestat used to treat diabetic complications and Ethoxazolamide used as treatment for glaucoma, diuretics, duodenal ulcers etc Many benzothiazole derivatives currently in clinical trials have shown the importance of this heterocycle Besides, benzoxazole is a heterocyclic compound commonly found in nature as well as in synthesis Benzoxazole is found in the chemical structure of several pharmaceutical products such as: anti-inflammatory drug Flunoxaprofen, antibiotic Calcimycin, analgesic, antipyretic and antiinflammatory Benoxaprofen etc Benoxaprofen heterocyclic derivatives have also received significant attention from scientists due to its diverse biological activities such as anticancer, antibacterial, anticonvulsant However, researches on these two heterocycles in Vietnam are few, unsystematic and just stop at synthesis without much attention to their biological activities The synthesis and study of benzothiazole derivatives containing both amino and hydroxyl functional groups not only increase the conversion capacity to form new derivatives but also increase the active resonance capacity Therefore, this research direction is still open, promising new, interesting and useful results in terms of theory and practice Thus I chose this topic: “Study on synthesis, structures and biological activity evaluation of some derivatives containing benzothiazole and benzoxazole” Objective of the thesis The study focuses on synthesis, structure udentification and oriented conversion to form some new derivatives containing benzothiazole and benzoxazole heterocycles with many substituents from the starting materials 4hydroxybenzaldehyde and vanillin, in order to search for compounds with high biological activity or other applications Mission of the thesis + Deriving from the first two substances, 4-hydroxybenzaldehyde and vanillin, synthesize some "key substances" of o-aminophenol type + Transforming the "key substance" into new sets of compounds containing benzothiazole and benzoxazole heterocycles + Studying the properties and determining the structures of new compounds by modern IR, NMR and MS spectroscopy methods + Exploring tested antimicrobial, antioxidant, anti-cancer and plant growth-stimulating activities of several new compounds to search for compounds with high biological activity Scientific and practical significance of the thesis - Completing 02 processes for synthesizing benzothiazole heterocyclic derivatives according to the principle of green chemistry from the two starting substances, 4-hydroxybenzaldehyde and vanillin, which are: i) close the benzothiazole heterocyclic ring containing the benzothiazole heterocycle, which occurs in both amino and hydroxyl functional groups; ii) N-formylation of the amine group, this reaction occurs only in the amine functional group During the synthesis process, there are several stages using microwave energy irradiation that shorten the reaction time, save solvents and increase the efficiency of the reaction - Providing accurate data on IR, NMR and MS spectra of complex heterocyclic compounds for scientific research and training high quality human resources for society - Some compounds containing the N-formamide-type benzothiazole heterocycle and hydroxamic acid exhibit good cytotoxicity comparable to the control, while the o-aminophenol-type compounds exhibit high antioxidant activity, which helps orienting the search for new compounds with potential for practical application CONTENTS OF THE THESIS CHAPTER OVERVIEW The overview covered the following: 1.1 Benzothiazole heterocycle overview 1.1.1 Benzothiazole heterocycle synthesis method 1.1.2 Biological activity of compounds containing benzothiazole heterocycle 1.2 Benzoxazole heterocycle overview 1.2.1 Benzoxazole heterocycle synthesis method 1.2.2 Biological activity of compounds containing benzoxazole heterocycle CHAPTER EXPERIMENT 2.1 Chemicals and equipment 2.1.1 Chemicals 2.1.2 Instruments and equipment in the laboratory 2.1.3 Methods for isolation of product 2.1.4 Equipment for studying properties and structures 2.2 Methods to detect biological activity 2.2.1 Antimicrobial activity 2.2.2 Antioxidant activity 2.2.3 Cytotoxic activity 2.2.4 Plant growth stimulant activity 2.3 Substance synthesis 2.3.1 General synthetic figure 2.3.2 Synthesis “key substances” OH HNO3 /AcOH SH OH NH2 1giê MW, 3-4 R R OHC OHC 1A,1B 2A,2B D·ym«i A: R=H o-aminothiophenol MW, 3-4 kh«ng dung R D·y B: R=OCH NO2 R S OH N 3A,3B NO2 Na S O /EtOH kh«ng dung m«i 224 giê R R S S OH N 7A,7B AcOH 8h OH O N S N 4A,4BNH2 6A,6B HN OH 2.3.3 Figure 2.4 Synthesis “key substances” 2.3.4 Synthesis of benzazole series R S R S OH Ar-CHO, AcOH, MW N 4A (R=H) 4B (R=OCH3) O N NH2 NAr Benzazole 4A1-4A6 (R=H); 4B1-4B13(R=OCH3) 2.3.5 Figure 2.5 Synthesis of benzazole series 2.3.6 Synthesis of N-formamide 5A, 5B R S OH N 4A: (R=H) 4B: (R=OCH3) R DMF MW NH2 S OH N 5A: (R=H) 5B: (R=OCH3) NH O H 2.3.7 Figure 2.6 Synthesis of N-formamide series 2.3.8 Synthesis of ester, carboxylic acid and hydroxamic acid series a Synthesis of ester series 6AE, 6BE, 7AE, 7BE R S N R1 6A (R=H, R1=NHCOCH3) 6B (R=OCH3, R1=NHCOCH3) 7A (R=H, R1=H) 7B (R=OCH3, R1=H) OH ClCH COOEt K2CO3/KI/DMF S N R O O O R1 6AE (R=H, R1=NHCOCH3) 6BE (R=OCH3, R1=NHCOCH3) 7AE (R=H, R1=H) 7BE (R=OCH3, R1=H) 2.3.9 Figure 2.7 Synthesis of ester series b Synthesis of carboxylic acid series 8A1, 8B1, 8B2 c R SS O N R O O NaOH/HCl O O N OH R1R1 6AE (R=H, R1=NHCOCH3)8A1 (R=H, R1=NHCOCH3) 6BE (R=OCH3, R1=NHCOCH3)8B1 (R=OCH3, R1=NHCOCH3) 7BE (R=OCH3, R1=H)8B2 (R=OCH3, R1=H) d Figure 2.8 Synthesis of carboxylic acid series e Synthesis of hydroxamic acid series 9B1, 9A2, 9B2 R O S N O O R H2N-OH.HCl MeOH/THF R1R1 6BE (R=OCH3, R1=NHCOCH3)9B1 (R=OCH3, R1=NHCOCH3) 7AE (R=H, R1=H)9A2 (R=H, R1=H) 7BE (R=OCH3, R1=H)9B2 (R=OCH3, R1=H) S O HN OH O N f Figure 2.9 Synthesis of hydroxamic acid series 2.3.10 Synthesis of hydrazide-hydrazone series a Synthesis of hydrazide series 10A, 10B, 11A, 11B R S N O O O R H2N-NH2.H2O C2H5OH R1 6AE (R=H, R1=NHCOCH3) 6BE (R=OCH3, R1=NHCOCH3) 7AE (R=H, R1=H) 7BE (R=OCH3, R1=H) O S O NH H2N N R1 10A (R=H, R1=NHCOCH3) 10B (R=OCH3, R1=NHCOCH3) 11A (R=H, R1=H) 11B (R=OCH3, R1=H) g Figure 2.10 Synthesis of hydrazide series b Synthesis of hydrazone series Hydrazone series 10A1-10A8 HN N S N 10A O CH2 C NH NH2 O NH C CH3 O ArCHO DMF, CH3COOH S N 10A1-10A8 HN OO O CH3 Ar h Figure 2.11 (a) Synthesis of hydrazone series 10A1-10A8 Hydrazone series 10B1-10B8 OCH3 S N OCH3 HN N O CH2 C NH NH2 O NH C CH3 O S ArCHO DMF, CH COOH N 10B1-10B8 10B HN Ar O O O CH3 Figure 2.11(b) Synthesis of hydrazone series 10B1-10B8 Hydrazone series 11A1-11A16 S OCH2CONHNH2 N Ar S ArCHO DMF, CH3COOH OHN N N 11A 11A1-11A16 O Figure 2.11(c) Synthesis of hydrazone series 11A1-11A16 Hydrazone series 11B1-11B8 OCH3 HN N OCH3 S O CH2 C NH NH2 O N 11B Ar S ArCHO DMF, CH3COOH N 11B1-11B8 O O Figure 2.11(d) Synthesis of hydrazone series 11B1-11B8 2.3.11 Synthesis of benzoxazoles from nitrovanillin a Synthesis of o-nitrophenols from nitrovanillin NO HO H3CO CHO nitrovanillin (2B) NO Ar - NH2 MW 4-10 phút; DMF NO2 HO HO H N NaBH4 H3CO 12B1-12B7 N Ar H3CO Ar 13B1-13B7 OO O NO2 HOOLiOHOO RN Ar 15B1-15B7 NO2 OR 14B1-14B7 N Ar Figure 2.12 Synthesis of o-nitrophenol series from nitrovanillin b Synthesis of o-aminophenol 16B1 c NO2 HOOHOO NH2 Na2S2O4 C2H5OH N H 3CO 15B1 N H 3CO 16B1 Cl Cl d Figure 2.13 Synthesis of o-aminophenol 16B1 e Synthesis of benzoxazole 18B1, 18B2 NH2 HO O O ArCHO/KCN/DMF N H 3CO 16B1 Cl Cl OCH3 O N N 18B1 (R=OCH3) 18B2 (R=OH) f Figure 2.14 Synthesis of benzoxazole 18B1, 18B2 g h CHAPTER RESULTS AND DISCUSSION i 3.1 Synthesis and structure of two key substances 4A and 4B R bst 3.49 Compound 10A1 has the predicted formula of C24H19O5N5S, corresponding to the molecular ion peak on the +HRMS spectrum of C24H20O5N5S+ calculated as 490.1174 au The measured value on the +HRMS spectrum of 10A1 (Figure 3.23) is 490.1178 au, which proves that compound 10A1 has a structure as originally expected For the remaining substances, the measured +HMRS or -HRMS spectra have a matching value of to decimal figures compared with the calculated value (see Table 3.48) Particularly, the HRMS spectrum of compound 11B1 is often accompanied by the M+Cl- value, according to calculations this molecular ion peak would have a value of 497.0697 au while the measured value is 497.0664 au 3.8 Synthesis and structure of benzoxazoles from nitrovanillin 3.8.1 Synthesis of o-nitrophenols 3.8.1.1 Synthesis bsu From nitrovanillin (2B), conducting condensation reaction with aromatic amines to obtain Schiff bases 12B1-12B7, the results of synthesizing this series have been published in the Journal of Science - Ho Chi Minh City University of Education [27] From the Schiff bases, conduct reduction to obtain secondary amines, 13B1-13B7, the results of synthesizing this series of substances have been published by the research team in the Journal of Chemistry [26] From the series of secondary amines, conducting acetylation reaction with Ac2O using microwave irradiation to obtain a series of compounds 14B1-14B7 Hydrolysis of 14B1-14B7 with LiOH yields a series of N-acetyl (o-nitrophenol type) 15B1-15B7 3.8.1.2 Structure identification bsv NMR spectra of substances 15B1-15B7 are presented in the appendix, the results of spectral analysis are included in Table 3.51 and Table 3.52 A special feature on the 1H NMR spectrum of the o-nitrophenol series is that the two H8 protons of 15B2 have completely different chemical shifts at δ = 5.5 ppm and at δ bsw = 4.2 ppm respectively (denoted as H8a and H8b) with separation constant J = 14 Hz characterizes the spin-spin interaction of the gem-hydrogen In the remaining substances (15B1, 15B3, 15B4, 15B5, 15B6 and 15B7), the signal of protons H8 is shown as a single fringe, intensity 2H (Figure 3.24) 15B2 15B1 15B4 15B3 15B6 15B5 15B7 bsx Figure 3.24 Signals of H8 protons of substances bsy The above "strange" phenomenon can be explained by two reasons: (i) Pyramidal inversion of the nitrogen configuration in tetrahedral form when the amide group has an electron-withdrawing group such as a halogen, O, N, S on the nitrogen atom [27] (ii) restricted rotation around the Ar-N bond bsz In the case of compound 15B2, on the N atom that does not contain an electron-absorbing group, it does not reduce the resonance nature of N with C= bta O in the amide group, leading to the nitrogen atom not carrying a tetrahedral nature, so the N atom does not exist in a pyramidal form Therefore, the appearance of two non-equivalent proton signals of H-8 is not related to the pyramidal transition Besides, the naphthyl group directs the aromatic ring towards H-8 causing anisotropy effect, the anti form is preferred [57] Furthermore, Shvo et al established two systems to separate the two phenomena of pyramidal inversion and limited rotation around the Ar-N bond and confirmed the nonequivalence of the diastereotopic protons of the benzyl methylene group in N -benzyl-N-(o-tolyl)acetamide is due to limited rotation around the Ar-N bond In addition, one more demonstration of the chemical shift disequivalence of the methylene protons (H-8) of 15B2 is that their signals are always sharp, sharp fringes even when measured at room temperature (298K) ) or measured at high temperature (373K) (Figure 3.25) [86] btb HO H C NO2 10 H3CO 15B2 19 O N 11 12 15 16 18 298K 13 20 14 17 373K btc Figure 3.25 H8's signal in 15B2 at two temperatures btd The spectral analysis results of 15B1-15B7 presented in Tables 3.513.54 bte have shown that their structure is consistent with the predicted formula 3.8.2 Series of o-aminophenols and derivatives 3.8.2.1 Synthesis btf Applying the method of reducing o-nitrophenol compounds with Na2S2O4/C2H5OH agent similar to when synthesizing compounds 4A and 4B (section 3.1.1), 15B1 has been reduced to obtain o-aminophenol-type compound 16B1 (the structure of 16B1 was identified through IR, NMR, MS spectroscopy) The spectral analysis results of 16B1 presented in Table 3.57 have shown that their structure is consistent with the predicted formula btg Conducting the benzoxazole ring-closing reaction from 16B1 with aromatic aldehydes, two benzoxazole derivatives 18B1 and 18B2 were obtained The mechanism of the benzoxazole ring-closing reaction is Figure bth.3.4 The spectral analysis results of 18B1 and 18B2 are presented in Table 3.59 bti and Table 3.60 below btj Table 3.59 Spectral analysis results of compound 18B1 btk btl btn bto btm btp btq bts.btr btt btu btv 13C btw HMBC H NMR NMR btx x: has mixed spectrum btz δ (ppm), J bua bub.δ with OCH3 10 13 14 Cl bty P roton bud - bui H (Hz) bue buj 1H) - Carbon buf C1 6.82 (s, buk C2 bun - buo - bup bus - but - buu bux - buy - C4 buz.C5 C3 bvc bvd 7.09 (s, bve C6 bvh bvi 3.94 (s, bvj C7 bvn 4.95 (s, bvo.C8 H6 1H) H7 3H) bvm 2H) H8 bvs - bvx bvy H10 bwc bvt 3H) 11 O N 24 182 21 O 12 17 5N 16 18B1 (ppm) bug 13 5.1 bul 10 8.1 buq.14 3.9 buv 13 8.1 bva 14 3.2 bvf 11 1.0 bvk 56 bvp 51 bvu bvv 16 1.87 (s, bvz C1 bwa 23.9 bwf 14 1.3 bwe bwh bwi 7.26 (d, J = bwj bwk bwm bwn bwo bwp bwt bwu 7.40 (d, J = 8.5, 1H) bxc 7.26 (d, J = 8.5, 1H) bxh - bwy bwz bxm - bxn H12 H13 bwr - bww H15 bxb H16 bxg H17 bxl H 18 8.5, 1H) 7.40 (d, J = 8.5, 1H) bws - bwx bxq bxr 8.07 (d, J = bxv bxw H19 H20 bya H21 byf H 22 8.5, 1H) 7.13 (d, J = 8.5, 1H) byb - byg 7.13 (d, J = 8.5, 1H) C11 C12 C13 C14 C15 bxd C16 bxi C1 C18 bxs C1 bxx.C2 byc C2 byh C11 bum 129.9 129.3 131.9 129.3 bxe 12 9.9 bxj 16 2.5 bxo 11 8.6 bxt 12 9.3 bxy 11 4.7 byd 16 2.1 byi 11 4.7 - H2xC8; H2xC6; H2xC4;H2xC3 bur - buw - bvb - bvg H6xC8; H6xC2; H6xC4 bvl H7xC3 bvq H8xC2; H8xC6; H8xC1; H8xC11; bvr H8xC9 bvw - 9.3 bwd - - buh .5 - C9 20 OCH 23 22 86 15 19 bwb bwg - bwl H12xC16; H12xC14; bwq H12xC11 H13xC15; H13xC11; H15xC14 bwv - bxa H15xC13; H15xC11; bxf H15xC14 H16x C12; H14xC14; H14xC11 bxk - bxp - bxu H19xC21; H19xC23; bxz byj H19xC20 H20xC18; H20xC22; H20xC21 bye H22xC18; H22xC20; H22xC21 byk byl 8.07 (d, J = H23 8.5, 1H) byq 3.85 (s, 3H) byp H24 bym byn 12 C23 byr C2 byo H23xC19; H23xC21; 9.3 H23xC20 byt H24xC21 bys 55 3.9 Biological activities of substances 3.9.1 Tested antimicrobial activity byu Table 3.61 Results of tested antimicrobial activity of some substances bzc Minimum inhibitory concentration byv byz ( MIC, µg/ml) bza bzf B bzg byw bzb bzh bzi acteriu Bacterium Mold Yeast byx Sample m Gr(-) Gr(+) symbol No bzn P bzp B bzr bzv F bzx S bzz C bzl bzt S byy bzo aer bzw bzy ce E A uginos a bzq s bzs oxyspo vevisia e caa a bzm bzu ubtili arue lbican r um coli s cab cac cad cae - caf cal can cao - cap cax cay - caz cbh cbi cbr cbs ccb cav cbf cbp cbz ccj 4B5 (T6f) cam 5A (H19.1) caw 5B (H19.3) cbg 8B1 (La) cbq 9B1 (Lb) cca 9A2 (Lb1) cck 10A - - - ccc - caj - cak car cas - cat - cau cbb cbc - cbd - cbe - cbj cbk cbl cbm cbt - cbu cbv cbw - cbn cbx - cbo cby - ccd ccn cct ccu 10B ccv 200 ccw 200 cdd cde 11A cdf cdg 200 cdh cdn cdo 11B 10 - ccx cdp cdq 200 cdr 200 - cag - caq - cba - s cah cai ccl ccm 200 niger us - - - - - - cce ccf ccg - cco ccp ccq - ccy ccz cda - cdi cdj cdk - cds - cdt - cdu - cch - cci - ccr 20 ccs - cdb - cdc - cdl - cdm - cdv - cdw - cdx cdy 10A1 cdz cea - ceb - cec - ced - cee - cef - ceg ceh cei 10A3 cej cek - cel - cem - cen - ceo - cep 20 ceq cer ces 10A5 cet ceu - cey - cez 20 cfa cfb cfc 10A7 cfi - cfj - cfk cfl cfm 11A3 cfn cfv cfw 11 12 13 14 15 16 cgf 17 (H19.11) 11A11 (H19.8) cgg 11A12 (H19.12) - cfd cfe cev cew - cex 00 - - 200 cff - cfg cfo - cfp - cfq - cfr - cfs - cft - cfu cfx cfy - cfz - cga - cgb - cgc - cgd - cge cgh cgi - cgj - cgm - cgn - 200 - cgk - - cfh - 200 cgl - - cgo - cgp 18 cgq cgr - cgz 11A14 (H19.10A) cha 15B1 chj chk 16B1 chl 19 20 cgs - cgt - cgu - cgv - cgw - cgx - cgy - chb chc 200 chd che chf 200 - chm 200 50 150 chn - cho - chp - chg - chh - chi - chq - chr - chs - cht Test results have shown that: chu - Samples 4B5, 5A, 5B, 8B1, 9B1, 9A2, 10A1, 11A3, 11A11, 11A12, chv.11A14 did not exhibit any antimicrobial activity against tested bacterial and fungal strains chw - The remaining samples exhibited tested antimicrobial activity against at least bacterial strain or fungal strain with MIC values between 150-200 chx.µg/mL 3.9.2 Antioxidant activity chy.Among the synthesized substances, 10 samples were selected to test the antioxidant activity by DPPH method, including the following samples: samples of o-nitrophenol and o-aminophenol (4A, 4B, 15B1, 16B1); samples of N-formamide (5A, 5B) samples of benzazole (4A1, 4A2, 4A6) and sample of benzoxazole 18B2 The test results are presented in Table 3.62 chz Table 3.62 Test results of antioxidant activity of some substances cia cid cif Fre cih S e radical cie Sample symbol C50 neutralization cib cii ( cig capacity cic No cir civ Prototype (+) / [acid ascorbic] cim Prototype (-) / [DPPH/EtOH+DMSO] cis 4A cip 0±0 cit 83.92±0.7 ciq ciu 4B cix 88.52±0.2 ciy cik cio µg/ml) (SC, %)* cil 87.53±0.3 ciw 1.5 2.23 2.96 ciz cja 15B1 cjb 69.49±0.5 cjc cjd cje 16B1 cjf 80.69±0.6 cjg cjh cji 5A cjj 36.38±0.8 cjk ≥ cjl cjm 5B cjn 36.85±1.4 cjo ≥ cjr 45.77±0.8 cjs cjv 80.78 ± 0.91 cjw cjz 78.87 ± 1.02 cka cjp cjq 18B2 cjt cju 4A1 cjx cjy 4A2 4.01 4.81 50 50 7.26 16.85 ckb 10 ckc 4A6 ckd 82.21 ± 0.77 09.87 cke 04.32 ckf Maximum sample test concentration 50 µg/ml The results of antioxidant activity test have shown that: - Five samples 4A1, 4A2, 4A6, 5A and 5B did not exhibit any antioxidant activity in vitro when tested for free radical neutralization by the DPPH method within the test concentration range - The remaining five samples including 4A, 4B, 15B1, 16B1 and 18B2 all showed antioxidant activity in vitro when testing the capacity to neutralize free radicals by DPPH method with SC50 from 12,23-47,26 µg/mL 3.9.3 Cytotoxic activity of substances Among the synthesized substances, seven samples were selected for cytotoxicity testing, including: 04 samples of substance 8B1, 9A2, 9B1, 9B2 to test the activity on KB cell line (carcinoma cells), test results on KB cell line are presented in Table 3.63 and 03 samples 5A, 5B and 9B2 were tested for activity on cell lines Hep-G2 (liver cancer cells), MCF-7 (breast cancer cells), A549 (lung cancer cells), HGC 27 (gastric cancer cells), the test results are presented in Table 3.64 Table 3.63 Anticancer activity of 8B1, 9A2, 9B1 and 9B2 on KB line - N - Sample - IC50 value, - o symbol -8B1 (La) µg/mL - >128 - - 9A2 (L1b) - - - 9B1 (Lb) - - - 9B2 (L2b) - - Ellipticine (ĐC) - 13.12 71.86 80.69 - 45 - Table 3.63 has shown that: - Sample 8B1 (La) showed no activity against the KB cancer cell line at the test concentrations - Samples 9A2, 9B1 and 9B2 exhibited activity against the KB cell line with IC50 values of 13.12; 71.86 and 80.69 µg/mL, respectively Table 3.64 Anticancer activity of substances 5A, 5B, 9B2 - Cell line (IC50 value, µg/mL) - Sample - A549 - HepG - MCF7 - HGC- symbol No - - >100 - >100 - 18.18 - 27 >100 - - >100 - 25.82 - 24.81 - 30.65 - - - 15.09 -5.5 - 99.04 - 42.01 - 37.91 - 61.23 A - B - B2 Paclit axel (ĐC) 23 - 49.13 - Table 3.64 has shown that all samples showed high activity against to tested cell lines Specifically: - Compound 5A showed activity on 01 MCF7 cell line with IC50 value = - 18.18 µg/mL - Compound 5B showed activity on 02 cell lines MCF7, HepG2 and HGC- 27 with IC50 values of 24.81 µg/mL, 25.82 µg/mL and 30.65 µg/mL - Compound 9B2 showed activity on 04 cell lines MCF7, HepG2, A549 and HGC-27 with IC50 values of 5.51 µg/mL; 15.09 µg/mL 3.23 - µg/mL; 99.04 µg/mL 3.9.4 Plant growth stimulant activity a Plant growth stimulant activities of 9A2 and 9B2 on some maize varieties The plant growth stimulant activity of compounds 9A2 and 9B2 was tested on maize varieties LVN092, LVN17, VN556, VN5885, DL668 The test b results are shown through the average stem length and average root length of the maize varieties when stimulated with compounds 9A2 and 9B2 after 10 and 15 days of growing in the growth chamber compared with the tested, presented in Table 3.65 c Based on Table 3.65, we can see that increasing the concentration of derivative 9A2 will reduce the growth of maize varieties Especially, at the concentration of 10-3M, the young plants of LVN092 variety showed difficulties in growing and gradually dying, yellowing, poor root development because the plants had difficulty absorbing water at this concentration At the tested concentrations, maize varieties LVN17, VN556, VN5885 not had much difference in stem height, but the DL668 variety had a much lower stem height than the other varieties However, the DL668 had better root length than the other varieties d At all concentrations of derivative 9B2, maize varieties LVN092, LVN17, VN556, VN5885, DL668 showed growth inhibition Although variation was not as pronounced as that of derivative 9A2, at all concentrations the stem and root heights were lower than that of the control samples (Table 3.66) Increasing the concentration of derivative 9B2 reduced the growth ability of maize varieties, all had better developed roots than the stem e Plant growth stimulant activities of 9A2 and 9B2 on some rice varieties f The growth stimulant activity of compounds 9A2 on BACTHOM7 variety and 9B2 on OM18 variety has been tested, the test results are presented in Table 3.67 and Table 3.68 g Table 3.67 shows that at the test concentrations 10-3 M and 10-4 M of compound 9A2, both exhibited growth inhibition against BACTHOM7 variety, but at lower concentrations (10-5, 10-6, 10-7 M) growth stimulation for plants and roots was exhibited, especially at the concentration of 10 -6 M after 15 days, the length of the stem was significantly higher than that of the control (145.79%) h Table 3.68 shows that, at all tested concentrations of 9B2, after 10 days, the root length of the OM18 rice variety was more developed than that of the control, especially at the concentration of 10 -7M-10-5 M Most of the stem lengths showed a decrease in growth rate compared to the control (except at the concentration of 10-5M) After 15 days of testing, most of the stem and root length were reduced compared to the control (except at the concentration of 105 M), especially at concentration 10-3M, starting from day onwards, the plants gradually withered and died after 10 days of testing i CONCLUSION j After a period of conducting the thesis, we have obtained the following results: i From the two starting substances, 4-hydroxybenzaldehyde and vanillin, using the combination of various reactions, some of which were supported by microwave irradiation, "key substances" have been synthesized: 2-amino-4(benzo[d]thiazol-2-yl)phenol (4A); 2-amino-4-(benzo[d]thiazol-2- yl)-6methoxyphenol (4B); 4-(benzo[d]thiazol-2-yl)phenol (7A); 2-amino-4(benzo[d]thiazol-2-yl)phenol (7B) and N-(3-amino-4-hydroxy-5methoxybenzyl)-N-(4-chlorophenyl)acetamide (16B1) In which compounds 4A, 4B, 16B1 are o-aminophenol-type compounds with high reactivity and good antioxidant activity ii From the "key substances" mentioned in conclusion 1, 06 series of substances containing benzothiazole and benzoxazole heterocycles have been synthesized, specifically as follows: benzazole series 4A1-4A6 and 4B1-4B13 (19 substances); N-formamide series 5A, 5B (2 substances); Carboxylic acid series 8A1, 8B1, 8B2 (3 substances); Hydroxamic acid series 9B1, 9A2, 9B2 (3 substances); Hydrazide series 10A, 10B, 11A, 11B (4 substances); Hydrazide hydrazone series 10A1-10A8; 10B1-10B8; 11A1-11A16 and 11B1-11B8 (40 substances) iii From nitrovanillin (2B), were synthesized the "key substance" 16B1 of oaminophenol-type was obtained and two benzoxazoles 18B1-18B2 Structures of the 83 new compounds have been identified by IR, 1H NMR, 13C NMR, 2D NMR, HRMS and MS spectra By using HSQC spectroscopy, HMBC has accurately attributed each signal on the 1H NMR and 13C NMR spectra of the synthesized compounds, as well as showing the dependence between the spectral properties and the chemical structure of the substances in the hydrazide-hydrazone series 10A1-10A8; 10B1-10B8, 11A1- 11A16; 11B111B8 and o-nitrophenol series 15B1-15B7 i The antimicrobial activity of 20 compounds has been tested, the results showed that, there are 09 compounds showing moderate and weak activity against some bacterial and fungal strains with IC50 =150-200 µg/mL ii Antioxidant activity of 10 compounds 4A, 4B, 4A1, 4A2, 4A6, 5A, 5B, 15B1, 16B1, 18B1 has been tested by DPPH method The results showed that 05 compounds 5A, 5B, 4A1, 4A2, 4A6 did not show any antioxidant activity at the test concentrations, 01 compound 18B1 showed weak antioxidant activity with IC50 of 47.26 µg/mL, 04 compounds 4A, 4B, 15B1 and 16B1 showed moderate and high antioxidant activity at test concentrations with IC50 of 12.23; 22.96; 14.81 and 24.01 g/mL iii.Cytotoxic activity of 07 compounds has been tested, including: 04 compounds (8B1, 9A2, 9B1, 9B2) on KB cancer line, 03 compounds (5A, 5B, 9B2) on lines: Hep-G2 (liver cancer cells), MCF-7 (breast cancer cells), A549 iv (lung cancer cells), HGC-27 (gastric cancer cells) Test results showed that compounds 9A2, 9B1 and 9B2 exhibited cytotoxic activity on KB cancer line at test concentrations with IC50 values of 13.12, 71.86 and 80.59 µg/mL; compounds 5A, 5B, 9B2 exhibited cytotoxic activity on cancer line MCF7 at test concentrations with IC50 value of 18.18; 24.81 and 5.57 µg/mL; compounds 5B, 9B2 exhibited cytotoxic activity on HepG2 cancer line at test concentrations with IC50 values of 25.82 and 15.09 µg/mL; compound 9B2 exhibited cytotoxic activity on A459 cancer line at test concentration with IC 50 value of 3.23 µg/mL Compound 5B and 9B2 exhibited cytotoxic activity on HGC-27 cancer line at test concentrations with IC50 values of 30.65 and 99.04 v µg/mL vi.Plant growth stimulant activity of compounds 9A2 and 9B2 has been tested on maize varieties and rice varietie., The test results showed that both compounds 9A2, 9B2 exhibited growth inhibitory activity on young plants and roots of maize varieties, while stimulating the growth of rice varieties at low concentration vii LIST OF PUBLISHED RESEARCH WORKS viii There are 06 articles published in specialized journals: Duong Quoc Hoan, Nguyen Thi Ngoc Mai, Nguyen Thi Lan, Trinh Thi Huan (2019), Preparation of some new N-acetyl derivatives from 5nitrovanillin, Vietnam journal of chemistry, 57, 2AB, pp 248-253 Nguyen Thi Ngoc Mai, Tran Thi Phuong Anh, Pham Thi Thu May, Pham Phuong Thao, Nguyen Van Trang, Duong Quoc Hoan (2019), Preparation of some benzo[d]thiazole-containing acetohydrazide derivatives, J Sci HNUE, 64 (6), 3-10 Nguyen Thi Ngoc Mai, Duong Quoc Hoan (2019), Research on nuclear magnetic resonance spectra of some N-acetyl synthesized from 5nitrovanillin, Journal of Analytical Physics - Chemistry - Biology, 24(4), 9095 Nguyen Thi Ngoc Mai, Duong Quoc Hoan, Vu Thi Anh Tuyet, Tran Thi Thu Trang, Duong Khanh Linh, Trinh Thi Huan (2020), An Effective Assembling of Novel Derivatives Containing Both Benzo[d]thiazole and Benzo[d]oxazole Rings, Letters in Organic Chemistry, Q4 (IF=0779), 17(11), 815–822 Nguyen Thi Ngoc Mai, Trinh Thi Huan, Nguyen Thi Dung, Duong Quoc Hoan (2020), Research on nuclear magnetic resonance spectra of hydrazidehydrazone series containing benzo[d]thiazole heterocyclic compound from 4hydroxybenzaldehyde, Journal of Analytical Physics - Chemistry - Biology, 25 (4), 131-137 Nguyen Thi Ngoc Mai, Nguyen Van Dat, Trinh Thi Huan, Duong Quoc Hoan (2021), N-Formylation of Amines Using A Domestic Microwave Oven And Bioactivities of Some N-Formamides, Vietnam journal of chemistry, Scopus, 59(3), 389-394