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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 Benzothiazol.Nghiên cứu tổng hợp, cấu trúc và khảo sát hoạt tính sinh học của một số hợp chất chứa dị vòng Benzothiazol.Nghiên cứu tổng hợp, cấu trúc và khảo sát hoạt tính sinh học của một số hợp chất chứa dị vòng Benzothiazol.Nghiên cứu tổng hợp, cấu trúc và khảo sát hoạt tính sinh học của một số hợp chất chứa dị vòng Benzothiazol.Nghiên cứu tổng hợp, cấu trúc và khảo sát hoạt tính sinh học của một số hợp chất chứa dị vòng Benzothiazol.
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” R SH R OH OH HNO3 /AcOH 1giê OHC OHC NO2 1A,1B 2A,2B o-aminothiophenol MW, 3-4 kh«ng dung m«i R S NH2 OH MW, 3-4 kh«ng dung m«i N D·y A: R=H D·y B: R=OCH3 R Na2S2O4/EtOH giê R S R S OH N S AcOH OH O N OH 8h N 4A,4B 6A,6B HN 7A,7B NO2 3A,3B NH2 Figure 2.4 Synthesis “key substances” 2.3.3 Synthesis of benzazole series R R S S OH Ar-CHO, AcOH, MW N O N 4A (R=H) 4B (R=OCH3) N NH2 Ar Benzazole 4A1-4A6 (R=H); 4B1-4B13(R=OCH3) Figure 2.5 Synthesis of benzazole series 2.3.4 Synthesis of N-formamide 5A, 5B R R S OH N 4A: (R=H) 4B: (R=OCH3) DMF S MW N OH NH2 5A: (R=H) 5B: (R=OCH3) NH O H Figure 2.6 Synthesis of N-formamide series 2.3.5 Synthesis of ester, carboxylic acid and hydroxamic acid series a Synthesis of ester series 6AE, 6BE, 7AE, 7BE R S OH R ClCH2COOEt K2CO3/KI/DMF O N 6A 6B 7A 7B O S O N R1 (R=H, R1=NHCOCH3) (R=OCH3, R1=NHCOCH3) (R=H, R1=H) (R=OCH3, R1=H) 6AE 6BE 7AE 7BE R1 (R=H, R1=NHCOCH3) (R=OCH3, R1=NHCOCH3) (R=H, R1=H) (R=OCH3, R1=H) Figure 2.7 Synthesis of ester series b Synthesis of carboxylic acid series 8A1, 8B1, 8B2 R R O S O S NaOH/HCl O O O N OH N R1 6AE (R=H, R1=NHCOCH3) 6BE (R=OCH3, R1=NHCOCH3) 7BE (R=OCH3, R1=H) R1 8A1 (R=H, R1=NHCOCH3) 8B1 (R=OCH3, R1=NHCOCH3) 8B2 (R=OCH3, R1=H) Figure 2.8 Synthesis of carboxylic acid series c Synthesis of hydroxamic acid series 9B1, 9A2, 9B2 R O S O O N R S H2N-OH.HCl HN OH O MeOH/THF R1 O N R1 9B1 (R=OCH3, R1=NHCOCH3) 9A2 (R=H, R1=H) 9B2 (R=OCH3, R1=H) 6BE (R=OCH3, R1=NHCOCH3) 7AE (R=H, R1=H) 7BE (R=OCH3, R1=H) Figure 2.9 Synthesis of hydroxamic acid series 2.3.6 Synthesis of hydrazide-hydrazone series a Synthesis of hydrazide series 10A, 10B, 11A, 11B R O S O O R H2N-NH2.H2O C2H5OH N O S O N R1 NH H2N R1 6AE (R=H, R1=NHCOCH3) 6BE (R=OCH3, R1=NHCOCH3) 7AE (R=H, R1=H) 7BE (R=OCH3, R1=H) 10A (R=H, R1=NHCOCH3) 10B (R=OCH3, R1=NHCOCH3) 11A (R=H, R1=H) 11B (R=OCH3, R1=H) Figure 2.10 Synthesis of hydrazide series b Synthesis of hydrazone series Hydrazone series 10A1-10A8 HN N S N 10A ArCHO O CH2 C NH NH2 O NH C CH3 O DMF, CH3COOH Ar S N 10A1-10A8 HN O O CH3 Figure 2.11 (a) Synthesis of hydrazone series 10A1-10A8 Hydrazone series 10B1-10B8 O OCH3 OCH3 HN N S O CH2 C NH NH2 O NH C CH3 O N 10B Ar S ArCHO DMF, CH3COOH O O N O HN 10B1-10B8 CH3 Figure 2.11(b) Synthesis of hydrazone series 10B1-10B8 Hydrazone series 11A1-11A16 S OCH2CONHNH2 N Ar S ArCHO HN N O DMF, CH3COOH N 11A O 11A1-11A16 Figure 2.11(c) Synthesis of hydrazone series 11A1-11A16 Hydrazone series 11B1-11B8 OCH3 OCH3 S ArCHO O CH2 C NH NH2 O N 11B HN N Ar S O DMF, CH3COOH O N 11B1-11B8 Figure 2.11(d) Synthesis of hydrazone series 11B1-11B8 2.3.7 Synthesis of benzoxazoles from nitrovanillin a Synthesis of o-nitrophenols from nitrovanillin HO H3CO CHO nitrovanillin (2B) NO2 NO2 NO2 Ar - NH2 MW 4-10 phút; DMF HO HO H N NaBH4 H3CO 12B1-12B7 N H3CO Ar Ar 13B1-13B7 O O O NO2 NO2 HO O N R 15B1-15B7 Ar O LiOH O R 14B1-14B7 O N Ar Figure 2.12 Synthesis of o-nitrophenol series from nitrovanillin b Synthesis of o-aminophenol 16B1 NO2 NH2 HO O HO O Na2S2O4 N H3CO C2H5OH 15B1 N H3CO 16B1 Cl Cl Figure 2.13 Synthesis of o-aminophenol 16B1 c Synthesis of benzoxazole 18B1, 18B2 OCH3 NH2 HO O O O ArCHO/KCN/DMF R N N H3CO 16B1 18B1 (R=OCH3) 18B2 (R=OH) Cl Cl N Figure 2.14 Synthesis of benzoxazole 18B1, 18B2 CHAPTER RESULTS AND DISCUSSION 3.1 Synthesis and structure of two key substances 4A and 4B To synthesize the two key substances 4A and 4B from the two starting substances, 4-hydroxybenzaldehyde and vanillin, three stages are required, including the closing of the benzothiazole ring to form compounds 3A and 3B Benzothiazole cyclization reaction to form substances 3A, 3B is carried out by condensing aromatic aldehydes with 2-aminothiophenol with household microwave irradiation This synthesis method has many outstanding advantages such as: i) no solvent nor catalyst is required; ii) the reaction occurs in a very short time, only about 4-6 minutes; iii) very high efficiency, above 95% The absence of solvents and catalysts for the reaction partially saves cost and limits waste to the environment, so it meets the requirements of green chemical synthesis [5] The mechanism of the benzothiazole ring-closing reaction is Figure 3.1 [61, 80] + O H N Ar H (III) (II) (VI) SH OH chuyÓn H+ H N H2 Ar Ar NH2 (I) SH O H SH H S H N Ar (VII) S H [O] N H Ar -H2O H -H2O (IV) chuyÓn proton SH toC N Ar (V) S Ar N (VIII) Figure 3.1 Benzothiazole ring-closing mechanism There are many agents used to reduce the –NO2 group to –NH2 group such as Fe/HCl; Zn/NH4Cl; Na2S2O4/NaOH etc and usually done in acidic or base environment However, compounds 3A and 3B have both the –OH group and – NO2 group at ortho position, so when performing the reduction reaction in the base medium, the result is obtained in the form of phenolate salt and when reducing in acid medium, the obtained result exists in the form of ammonium salt of the amine, which is difficult to separate and derive Through literature review, Siddiqui et al successfully reduced 4-carbomethoxy-2-nitrophenol to 4carbomethoxy-2-aminophenol by reducing agent Na2S2O4/C2H5OH [88] Compounds 3A, 3B have similar structure to 4-carbomethoxy-2-nitrophenol, so when applying similar reaction conditions, the desired products 4A and 4B were obtained with high efficiency (> 80%), Na2S2O4 is pretty cheap and easy to find In particular, compound 4A was isolated for the first time in pure form, and compound 4B, although isolated by Vu Thi Anh Tuyet's group as a free oaminophenol, the procedure is complicated and has more stage (3 stages): reduction with HCl/Fe agent to obtain the product as ammonium salt, acetylation and hydrolysis [8] This shows that the reduction method in neutral medium applied above is more efficient compared to the reduction method of previous authors: simple procedure, few stages, high reaction efficiency, and cheap reducing agent The results of 4A and 4B synthesis are presented in Table 3.1, the results of spectral analysis to determine their structures are presented in Table 3.2 – Table 3.5, below are the results of 1H NMR and 13C NMR spectral data of 4A and 4B Table 3.3 1H NMR signal of 4A and 4B (δ (ppm), J (Hz)) Symbol H2 H3 H4 H5 H9 H10 H13 H14 OH NH2 4A 8.04 (dd, J = 0.5; 7.5, 1H) 7.37 (td, J = 1.5; 7.5, 1H) 7.56 (t, J = 1.5; 7.5, 1H) 7.94 (d, J = 8.0, 1H) 7.39 (d, J = 7.5, 1H) 6.77 (d; J = 8.0; 1H) 7.18 (dd, J = 2.0; 8.0, 1H) 10.10 (s, 1H) 4.84 (s, 2H) 4B 8.06 (d, J = 8.0, 1H) 7.49 (t, J = 8.5; 1.5, 1H) 7.39 (t, J = 8.5; 1.5, 1H) 7.96 (d, J = 8.0, 1H) 7.09 (d, J = 2.0, 1H) 7.02 (d, J = 2.0, 1H) 3.87 (s, 3H) 8.95 (s, 1H) 4.99 (s, 2H) Table 3.4 13C NMR signal of 4A and 4B, δ (ppm) Symbol 4A 4B C1 C2 134.0 121.9 135.7 122.7 C3 C4 124.6 126.2 125.6 127.5 C5 C6 122.0 153.7 122.9 154.9 C7 C8 168.3 124.5 171.3 137.5 C9 C10 116.4 114.4 102.2 149.2 C11 C12 147.3 137.3 138.4 126.0 C13 C14 112.3 110.1 56.6 3.2 Synthesis and structure identification of benzazole series 4A1-4A6 and 4B1-4B13 The synthesis of compounds 4A1-4A6 and 4B1-4B13 (these are compounds containing both benzothiazole and benzoxazole heterocycles, collectively referred to as benzazoles) was carried out under microwave irradiation from starting amines 4A and 4B The influence of home microwave energy level on the reaction efficiency was investigated during the synthesis of compound 4B1 In 150 watt mode, the reaction took 26 minutes but was unfinished and the efficiency was only 46% When the power level was set at 280 watts, after refining the efficiency reached 80% after 19 minutes of irradiation At 400 watts, the reaction ended quickly in just minutes and the desired product efficiency is 92% Both 600 watts and 800 watts reduce efficiency due to overheating (Table 3.6) Table 3.6 Optimizing the energy of home microwave oven No Power level (watts) Time (minutes) Efficiency (%)* 150 26 46 280 19 80 400 92 600 26 800 burnt * after refining; reaction conditions: 4B1 (308 mg, mmol), benzaldehyde (116 mg, 1,1 mmol) and HOAc (2 ml) irradiated with a microwave oven at different power levels Applying the above optimization process, 19 benzazoles including 4A14A6 and 4B1-4B13 were synthesized with the maximum efficiency of 92% The results were published in the journal Letters in Organic Chemistry Thus, the process of performing the reaction to synthesize benzazoles has many advantages: (i) easy to implement, (ii) environmentally friendly due to minimal use of solvent, (iii) energy- and time-saving since it is fast and clean, (iv) easy experimental handling: irradiation of the reaction mixture, adding ethanol to the post-reaction mixture to form crystals, filtering and drying, (v) using laboratory equipment readily available and cheap The mechanism of benzazole formation consists of two stages: Stage 1: H H O H O H H Ar C O H Ar Ar Stage 2: OH OH H H H O C NH2 Ar (A) H O (C) Ar C N H H (D) H O Ar C N H H N H2 OH H ChuyÓn proton Ar OH (B) O Ar [O] O H -H2O N C + N -H (E) N H t0 Ar -H2O OH2 Ar H Figure 3.2 Mechanism of benzazole formation The data on appearance, color, crystallization solvent, melting point and 4B3 135.2 121.6 125.3 126.4 123.2 154.1 167.8 133.7 107.5 145.2 141.7 143.8 112.9 161.8 125.7 132.5 131.5 132.2 126.9 131.9 56.8 - 4B4 135.2 121.6 125.3 126.4 123.2 154.1 167.7 131.5 107.1 145.1 141.8 144.1 112.4 163.1 125.1 129.3 129.1 138.2 129.1 129.3 56.6 - 4B5 135.2 121.7 125.4 126.5 123.3 154.1 167.5 131.9 107.6 145.3 142.0 143.8 112.6 161.6 128.5 122.7 148.8, 126.1 130.2 133.2 56.7 - No spectral data available due to poor solubility in DMSO at 373 K 4B6 134.5 122.2 125.4 130.4 122.7 153.4 167.1 130.4 106.4 144.6 140.9 143.9 110.9 163.8 116.5 116.1 129.5 161.2 129.5 116.1 56.4 - 134.6 122.3 125.6 126.7 122.8 153.4 167.0 130.6 106.9 144.8 141.2 143.6 111.4, 163.4 126.9 113.8 157.9 119.5 130.7 118.2 56.5 - 4B9 135.2 121.6 125.2 126.3 123.2 154.1 168.0, 131.2 106.7 145.0 141.7 144.4 112.2 164.2 114.4 129.7 119.2 162.6 119.2 129.7 56.6 55.5 4B10 135.2 121.8 125.1 126.3 122.5 153.2 166.5, 130.7 107.5 143.4 141.1 144.6 111.1 162.3 124.9 129.0 132.1 125.6 132.1 129.0 56.5 - 4B11 135.2 121.6 125.1 126.4 123.2 154.1 167.8 131.5 106.9 145.1 141.8 144.1 112.2 162.9 119.5 109.0 147.5 146.6 108.7 125.3 58.5 56.8 4B12 134.3 121.6 125.0 126.1 122.4 153.1 166.5 130.5 107.3 144.5 140.9 143.3 111.0 162.8 126.8 111.9 159.4 118.0 130.0 119.4 56.3 55.1 4B13 134.5 122.2 125.1 126.6 122.4 153.4 167.2 130.5 106.4 148.6 140.5 143.6 111.5 154.3 124.0 131.5 154.3 124.5 136.3 56.2 - 4B7 4B8 3.3 Synthesis and structure of N-formamides 5A and 5B N-formylation plays an important role in organic synthesis such as protecting amine functional groups and in pharmaceutical chemistry, so many methods of formamide synthesis have been researched and developed In which one interesting method is to use N,N-dimethylformamide (DMF) in combination with suitable agent for N-formyl synthesis such as imidazole and DMF [95]; P2O5 and DMF[17]; POCl3 and DMF [18]; [Ni(quin)2], DMF and imidazole [93] Microwave irradiation also has the effect of supporting the N-formylation process such as using ester, DMF under microwave irradiation to create Nformyl from amine in minutes [110]; using HCOOH/SiO2 heterogeneous catalyst in solvent-free conditions, or using HCOOH under the effect of microwaves, can also create N-formamides from amines or alcohols [13, 25] With the above basis, use amine 4A to react with DMF using common catalysts such as HCl, AcOH, TsOH or silica gel The reaction mixture was microwave irradiated at 380W for an appropriate time The progress of the reaction was monitored by TLC in the n-hexane/ethyl acetate solvent system (1:1) The experiments show that, when using HCl as a catalyst, the obtained products are only shown as traces on TLC, when using TsOH as a catalyst, although the efficiency may reach 70%, the refining is more complicated, a base solution is required to wash off TsOH, after washing off the excess amine with an acid solution Experimental results are presented in Table 3.14 11 Table 3.14 Experimental conditions for N-formamide creation NO Reaction Catalyst 4A + DMF 4A + DMF 4A + DMF 4A + DMF AcOH HCl TsOH Silica gel Time Efficiency (minutes) 92% 20 5% 20 70% 20 22% The above table has shown that the optimal conditions for the reaction to create N-formamide from compound 4A were selected using amine + DMF + AcOH, the mixture was microwave irradiated in medium level (380W-450W) To verify this experimental procedure, amine 4B is also processed in the same way as amine 4A, yielding N-formamide 5B The structures of 5A and 5B were identified by IR, NMR and MS spectra This procedure opens up a new method to generate N-formamide from free amine in a simple, efficient and effective way using home microwave irradiation, which has been successfully applied and synthesized a series of twenty N-formamide and the results were published in the Journal of Chemistry The advantage of this method is that it is selectively formylated to the amine group but not to the –OH phenol phenol functional group, especially selective to weak nucleophilic amine groups such as p-nitroaniline The reaction mechanism to generate N-formamide: H O O H Het: N N H -OAc R Het S O H O N R R OH NH2 Het H3C O H H H3C N CH3 R -NH(CH3)2 R OH Het OH H N H O H H N H3C CH3 H2N N H3C Het OH OH -AcOH Het OH O H N H H AcO HN CHO 5A (R=H); 5B (R=OCH3) Figure 3.3 Mechanism of N-formamide 5A and 5B formation The spectral analysis results of 5A and 5B are presented in Table 3.17 and Table 3.18 Below is the resonance signal of the protons and carbon of 5A and 5B 12 Table 3.17 Proton and carbon resonance data of compounds 5A and 5B H H2 H3 H4 H5 H9 H10 H13 H14 OH NH H15 5A δ (ppm), J (Hz) 8.08 (d, J = 8.0, 1H) 7.40 (td, J = 8.0; J = 1.0, 1H) 7.50 (td, J = 8.0; J = 1.0, 1H) 8.00 (d, J = 8.0, 1H) 7.69 (dd, J = 8.5, J = 2.0, 1H) 7.04 (d, J = 8.5, 1H) 8.94 (d, J = 2.0, 1H) 8.37 (d, J = 1.5, 1H) 10.84 (s, 1H) 9.76 (s, 1H) - C C1 C2 C3 δ (ppm) 134.1 122.1 124.9 H H2 H3 C4 126.4 H4 C5 C6 C7 C8 C9 122.3 153.6 167.4 123.6 123.9 H5 H9 5B δ (ppm), J (Hz) 8.08 (d, J = 8.0,1H) 7.40 (td, J = 8.0, 1.0, 1H) 7.50 (td, J = 8.0, 1.0, 1H) 8.02 (d, J = 8.0, 1H) 7.46 (d, J = 2.0, 1H) C10 C11 C12 C13 C14 C15 115.3 149.6 126.6 119.0 160.3 - H10 H13 H14 OH NH H15 8.59 (d, J = 2.0, 1H) 8.37 (d, J = 2.0, 1H) 10.08 (s, 1H) 9.31 (s, 1H) 3.95 (s, 3H) C C1 C2 C3 δ (ppm) 134.2 122.1 123.5 C4 126.4 C5 C6 C7 C8 C9 122.2 153.6 167.6 125 105.6 C10 C11 C12 C13 C14 C15 147.8 138.8 126.9 112.8 160.4 56.1 3.4 Synthesis and structure of the carboxylic acid series 3.4.1 Synthesis of carboxylic acid series a Acetylation of the amine group of 4A and 4B According to the authors Vu Thi Anh Tuyet and Nguyen My Linh, to acetylate the NH2 group of compound 4B to form compound 6B, two steps are required Step 1: acetylation of both –OH group and –NH2 group by Ac2O agent in DMF solvent and Et3N catalyst Step 2: hydrolyze the ester functional group with LiOH (in MeOH:H2O = 4:1), leaving the amide functional group [5, 9] In this thesis, the method of synthesizing 6B from 4B has been improved, shortened to one stage by refluxing amine 4B in the residual acetic acid for hours, the reaction efficiency reached 87% Using the same procedure with amine 4A, we obtained amide 6A (light brown needle-shaped crystals) with 85% efficiency b Synthesis of esters Using Finkelstein reaction to perform etherification with NaI and K2CO3 catalysts, instead of using acetone solvent, we use DMF Since the boiling point of acetone is lower than that of DMF, the reaction is easier to occur and with higher efficiency NaI has the role of providing I- for the halogen exchange reaction to form a C-I bond, in which I- is more easily replaced than Cl-, so the reaction also occurs more easily c Hydrolyzed ester form acid carboxylic Conducting the hydrolysis reaction of the esters will obtain the corresponding carboxylic acid series 8A1, 8B1, 8B2 The synthesis results are presented in Table 3.19 The spectrum analysis results presented in Table 3.20 13 to Table 3.22 have shown that their structure is consistent with the predicted formula 3.5 Synthesis and structure identification of hydroxamic acid series Hydroxamic acids are obtained when the corresponding esters react with hydroxyamine Synthesis results of hydroxamic acid series 9B1, 9A2, 9B2 are presented in Table 3.23 The spectral analysis results presented in Tables 3.24 to Table 3.27 have shown that the hydroxamics’ structure is consistent with the predicted formula 3.6 Synthesis and structure identification of hydrazide series A series of four hydrazides 10A, 10B, 11A and 11B is formed when the corresponding esters react with hydrazine hydrate This reaction is fast with simple procedure, the product is easy to refine, and high yield Synthetic results of hydrazide series are presented in Table 3.28 The spectrum analysis results are presented in Table 3.29-3.32 Table 3.30 1H NMR spectral data of 10A, 10B, 11A 11B (δ (ppm); J (Hz)) H H2 H3 H4 H5 H9 H10 H12 H13 H14 H10a H12b NHa NHb NH2 10A 8.11 d, J = 8.0, 1H 7.43 td, J = 1.0, 8.0, 1H 7.52 td, J= 1, J=8.5, 1H 8.03 d, J = 8.0, 1H 7.78 dd, J = 2.0, 8.5, 1H 7.21 d, J = 9.0, 1H - 10B 8.13 d, J = 8.0, 1H 7.45 t, J = 7.5, 1H 7.52 t, J = 7.5, 1H 8.01 d, J = 8.0, 1H 8.57 s, 1H - 8.79 (s, 1H) 7.47 (s, 1H) 4.70 (s, 2H) 2.18 (s, 3H) 9.55 (s, 1H) 9.62 (s, 1H) 4.41 (s, 2H) 4.56 (s, 2H) 3.95 (s, 3H) 2.19 (s, 3H) 9.45 (s, 1H) 10.43 (s, 1H) 4.34 (s, 2H) - 11A 8.11 dd, J = 8.0, 0.5, 1H 7.43 td, J = 8.5; 1.5, 1H 7.52 td, J = 8.5; 1.5, 1H 8.01 d, J = 8.0, 1H 8.03 d, J = 9.0, 1H 7.14 td, J = 9.0, 2.0, 1H 7.14 td, J = 9.0, 2.0, 1H 8.03 d, J = 9.0, 1H 4.60 (s, 2H) 9.39 (s, 1H) 4.34 (s, 2H) 11B 8.10 d, J = 8.0, 1H 7.44 td, J = 1.5, 8.0, 1H 7.52 td, J = 1.0, 8.5, 1H 8.02 d, J = 8.0, 1H 7.67 d, J = 2.0, 1H 7.08 d, J = 8.5, 1H 7.59 dd, J = 2.0, 8.0 1H 4.57 (s, 2H) 3.91 (s, 3H) 9.24 (s, 1H) 4.34 (s, 2H) Table 3.31 1H NMR spectral data of 10A, 10B, 11A 11B δ (ppm); C C1 C2 C3 C4 C5 C6 C7 10A 134.3 122.2 125.1 126.5 122.5 153.6 166.1 10B 134.4 122.2 125.4 126.6 122.7 153.4 167.0 14 11A 134.2 122.1 125.0 126.4 122.4 153.5 166.8 11B 134.4 122.2 125.3 126.6 122.6 153.6 166.4 125.9 123.4 112.9 149.9 128.1 120.7 67.1 168.7 166.9 23.9 C8 C9 C10 C11 C12 C13 C14 C15 C10a C12a C12b 128.8 112.0 152.3 139.3 133.3 105.4 70.9 168.6 56.1 168.6 24.1 126.0 128.7 115.4 160.2 115.4 128.7 66.2 166.1 - 126.6 109.9 150.0 149.5 120.7 113.9 67.1 167.1 55.8 - 3.7 Synthesis and structure of hydrazide - hydrazone series To synthesize the hydrazide - hydrazone series 10A1-10A8; 10B1-10B8; 11A1-11A16 and 11B1-11B8 a condensation reaction must be conducted between corresponding hydrazides 10A, 10B, 11A and 11B with aromatic aldehydes, in the presence of the catalyst AcOH The reaction is carried out by microwave irradiation in a short time from only 5-30 minutes (compared with the conventional reflux heating method which requires 2-3 hours) and the efficiency is very high (>90%) The results of hydrazide - hydrazone synthesis are presented in Table 3.33 – 3.36 The 1H NMR spectra of all these hydrazide - hydrazones are quite complex, consisting of sets of signals, one with strong intensity and one with weak intensity, sometimes separate and sometimes intertwined, which makes it difficult to analyze (Figure 3.20) NHa S N 18 17 HN N 10 14 15 11 O O 12 O 13 HN NHb 12a CH3 H19,H21 20 NO 16 22 21 H12b H18,H22 H14 12b H12b' NHa H14' NHa' H16 H5 H16' 19 NHb NHb' H13 H13' H4 H2 H9 H10 H3 H10' H9' Figure 3.20 1H NMR spectrum of 10A1 Hydrazide - hydrazone 10A1 in solution may be exit isomer, E/Z imine isomers (-N=CH-) and cis/trans (-N-C(O) amide When studying the hydrazides - hydrazones formed from the condensation reaction between substituent hydrazides and aromatic aldehydes Wyrzykiewicz et al demonstrated that in solution the hydrazides - hydrazones usually exist in the geometrical form E imine [106] 15 H H O Ar' C H2 N C C N Ar Ar H ChËm O Ar' O C H2 Nhanh Ar' O O Nhanh C N C H2 Cis, E Ar= NO2 N H N C H Trans, Z Trans, E Ar N C C N H H O ChËm Ar' O C N C H2 Ar N C H Ar'= O C NH H3C S O Cis, Z Besides, compound 10A1 was spectroscopically measured in d6-dimethyl sulfoxide solvent, the E imine isomer undergoes a rapid conversion of the cis/trans amide equilibrium in which the cis amide conformation is preferred [68] Therefore, it can be confirmed that the form of hydrazide - hydrazone 10A1 in DMSO-d6 measuring solution is cis amide E imine corresponding to the strong signal set, while the weaker signal set is trans amide Z imine [21] The results of NMR, HRMS and MS spectral analysis of the hydrazide hydrazones presented in Table 3.38 – Table 3.49 have shown that their structure is consistent with the predicted formula The four series of hydrazide - hydrazone synthesized above are all very insoluble in common organic solvents, so the product is not recrystallized, but only washed several times with hot alcohol until the impurities are gone, thus the most effective method to verify the structure is based on HRMS highresolution mass spectrometry In the above four series of hydrazide hydrazones, a representative substance is selected in each series to measure HRMS, the samples are 10A1, 10B2, 11A2 and 11B1, the remaining substances in the series are measured MS normally Spectral measurement results are listed in the appendix, the results of HRMS analysis of the four hydrazones selected to represent each series are presented in Table 3.48 and the normal MS results of the remaining substances are presented in Table 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+Clvalue, according to calculations this molecular ion peak would have a value of 497.0697 au while the measured value is 497.0664 au 16 3.8 Synthesis and structure of benzoxazoles from nitrovanillin 3.8.1 Synthesis of o-nitrophenols 3.8.1.1 Synthesis 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 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 = 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) 15B4 15B2 15B3 15B1 15B6 15B5 15B7 Figure 3.24 Signals of H8 protons of substances 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 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 = 17 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] HO NO2 10 H3C H3CO N O 15B2 11 12 13 20 19 14 15 18 16 17 298K 373K Figure 3.25 H8's signal in 15B2 at two temperatures The spectral analysis results of 15B1-15B7 presented in Tables 3.51-3.54 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 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 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 3.4 The spectral analysis results of 18B1 and 18B2 are presented in Table 3.59 and Table 3.60 below 18 Table 3.59 Spectral analysis results of compound 18B1 OCH3 10 12 13 11 O2 N 14 Cl Proton H2 H6 H7 19 18 O N 20 24 OCH3 23 22 18B1 16 15 13 H NMR δ (ppm), J (Hz) 6.82 (s, 1H) 7.09 (s, 1H) 3.94 (s, 3H) 21 17 C NMR Carbon δ (ppm) 135.1 C1 108.1 C2 143.9 C3 138.1 C4 143.2 C5 111.0 C6 56.1 C7 H8 4.95 (s, 2H) C8 51.5 H10 H12 H13 H15 H16 H17 H18 H19 H20 H21 H22 H23 H24 1.87 (s, 3H) 7.26 (d, J = 8.5, 1H) 7.40 (d, J = 8.5, 1H) 7.40 (d, J = 8.5, 1H) 7.26 (d, J = 8.5, 1H) 8.07 (d, J = 8.5, 1H) 7.13 (d, J = 8.5, 1H) 7.13 (d, J = 8.5, 1H) 8.07 (d, J = 8.5, 1H) 3.85 (s, 3H) C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C11 C23 C24 169.3 23.9 141.3 129.9 129.3 131.9 129.3 129.9 162.5 118.6 129.3 114.7 162.1 114.7 129.3 55.4 HMBC x: has mixed spectrum with H2xC8; H2xC6; H2xC4;H2xC3 H6xC8; H6xC2; H6xC4 H7xC3 H8xC2; H8xC6; H8xC1; H8xC11; H8xC9 H12xC16; H12xC14; H12xC11 H13xC15; H13xC11; H15xC14 H15xC13; H15xC11; H15xC14 H16x C12; H14xC14; H14xC11 H19xC21; H19xC23; H19xC20 H20xC18; H20xC22; H20xC21 H22xC18; H22xC20; H22xC21 H23xC19; H23xC21; H23xC20 H24xC21 3.9 Biological activities of substances 3.9.1 Tested antimicrobial activity Table 3.61 Results of tested antimicrobial activity of some substances No Sample symbol 4B5 (T6f) 5A (H19.1) 5B (H19.3) 8B1 (La) 9B1 (Lb) 9A2 (Lb1) 10A 10B 11A Minimum inhibitory concentration ( MIC, µg/ml) Bacterium Bacterium Mold Yeast Gr(-) Gr(+) P B S F S C E A aeruginos subtili arueu oxyspor cevevisia albican coli niger a s s um e s 200 - 200 200 200 - - 19 - - 200 - - 10 11 12 13 14 15 16 17 18 19 20 11B 10A1 10A3 10A5 10A7 11A3 (H19.11) 11A11 (H19.8) 11A12 (H19.12) 11A14 (H19.10A) 15B1 16B1 200 200 - 200 200 - 200 - - - - 200 - 200 200 150 - 150 - 200 - - 200 200 - - - - - - - - Test results have shown that: - Samples 4B5, 5A, 5B, 8B1, 9B1, 9A2, 10A1, 11A3, 11A11, 11A12, 11A14 did not exhibit any antimicrobial activity against tested bacterial and fungal strains - The remaining samples exhibited tested antimicrobial activity against at least bacterial strain or fungal strain with MIC values between 150-200 g/mL 3.9.2 Antioxidant activity 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 Table 3.62 Test results of antioxidant activity of some substances Sample symbol No 10 Prototype (+) / [acid ascorbic] Prototype (-) / [DPPH/EtOH+DMSO] 4A 4B 15B1 16B1 5A 5B 18B2 4A1 4A2 4A6 Free radical neutralization capacity (SC, %)* 87.53±0.3 0±0 83.92±0.7 88.52±0.2 69.49±0.5 80.69±0.6 36.38±0.8 36.85±1.4 45.77±0.8 80.78 0.91 78.87 1.02 82.21 0.77 SC50 (µg/ml) 11.5 12.23 22.96 24.01 14.81 ≥50 ≥50 47.26 116.85 209.87 104.32 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 20 - 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 No Sample symbol 8B1 (La) 9A2 (L1b) 9B1 (Lb) 9B2 (L2b) Ellipticine (ĐC) IC50 value, µg/mL >128 13.12 71.86 80.69 0.45 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 No Sample symbol 5A 5B 9B2 Paclitaxel (ĐC) A549 >100 >100 3.23 49.13 Cell line (IC50 value, µg/mL) HepG2 MCF7 >100 18.18 25.82 24.81 15.09 5.51 42.01 37.91 HGC-27 >100 30.65 99.04 61.23 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 HGC27 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 21 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 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 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 b Plant growth stimulant activities of 9A2 and 9B2 on some rice varieties 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 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%) 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 10 M), especially at concentration 10-3M, starting from day onwards, the plants gradually withered and died after 10 days of testing 22 CONCLUSION 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-2yl)-6-methoxyphenol (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 13 C 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, 11A111A16; 11B1-11B8 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 IC 50 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 23 (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 µg/mL iv 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 24 LIST OF PUBLISHED RESEARCH WORKS 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