Synthesis and antiproliferative evaluation of n alkylated (2 (4 methoxyphenyl) 1hbenzodimidazol 5(6) yl)(phenyl)methanone derivatives

VIETNAM GENERAL CONFEDERATION OF LABOUR TON DUC THANG UNIVERSITY FACULTY OF APPLIED SCIENCE LE QUOC TUAN SYNTHESIS AND ANTIPROLIFERATIVE EVALUATION OF N- ALKYLATED (2-(4METHOXYPHENYL)-1HBENZO[D]IMIDAZOL-5(6)YL)(PHENYL)METHANONE DERIVATIVES UNDERGRADUATE THESIS OF CHEMICAL ENGINEERING ORGANIC SYNTHESIS HO CHI MINH CITY, YEAR 2023 VIETNAM GENERAL CONFEDERATION OF LABOUR TON DUC THANG UNIVERSITY FACULTY OF APPLIED SCIENCE LE QUOC TUAN- 61602260 SYNTHESIS AND ANTIPROLIFERATIVE EVALUATION OF N- ALKYLATED (2-(4METHOXYPHENYL)-1HBENZO[D]IMIDAZOL-5(6)YL)(PHENYL)METHANONE DERIVATIVES UNDERGRADUATE THESIS OF CHEMICAL ENGINEERING ORGANIC SYNTHESIS Advised by Assoc Prof., Dr Hoang Thi Kim Dung M.Eng., Phan Ngoc Kim Ngan HO CHI MINH CITY, YEAR 2023 ACKNOWLEDGMENT I sincerely thank all Faculty of Applied Sciences lecturers who provided me with valuable information in their respective fields Headforemost, I want to express my thankful gratitude to Assoc Prof., Dr Hoang Thi Kim Dung, for all of her guidance and support throughout the writing of my thesis and her kindness, patience, and knowledge In addition to writing and conducting academic research in organic chemistry, I have received many helpful and constructive recommendations about my field Additionally, I would like to thank Ms Phan Ngoc Kim Ngan, who has supported and managed my project and has been encouraging and instructive throughout the research Her extensive knowledge and academic guidance were crucial in assisting me in completing my thesis Besides, I'd like to thank everyone in the Organic Chemistry and Polymer department for their continued friendliness and assistance during the period with report documents and presentations Finally, I sincerely thank my family, especially my parents Through every accomplishment in my life, they have always been there for me with their unconditional love and wholehearted support Ho Chi Minh City, day … month … 2023 Author This thesis was carried out at Ton Duc Thang University Advisor: Assoc Prof., Dr Hoang Thi Kim Dung M.Eng., Phan Ngoc Kim Ngan This thesis is defended at the Undergraduate Thesis Examination Committee was hold at Ton Duc Thang University on… Confirmation of the Chairman of the Undergraduate Thesis Examination Committee and the Dean of the faculty after receiving the modified thesis (if any) CHAIRMAN DEAN OF FACULTY DECLARATION OF AUTHORSHIP I hereby declare that this thesis was carried out by myself under the guidance and supervision of Assoc Prof Dr Hoang Thi Kim Dung, and that the work and the results contained in it are original and have not been submitted anywhere for any previous purposes The data and figures presented in this thesis are for analysis, comments, and evaluations from various resources by my own work and have been duly acknowledged in the reference part In addition, other comments, reviews, and data used by other authors and organizations have been acknowledged, and explicitly cited I will take full responsibility for any fraud detected in my thesis Ton Duc Thang University is unrelated to any copyright infringement caused on my work (if any) Ho Chi Minh City, day month year Author i ABSTRACT In this thesis, ten (2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5(6)- yl)(phenyl)methanone derivative was successfully synthesis via condensation of the o-phenylenediamine derivative with aromatic aldehyde derivative in the presence of Na2S2O5 using the mixed solvent of EtOH: H2O (9:1, v/v) Subsequently, ten derivatives of N-alkylated benzimidazole were designed and synthesized by alkylation reactions in the presence of K2CO3 using dimethyl sulfoxide as a solvent All synthesized compounds were characterized by HPLC, UV-Vis, FT-IR, 1D and 2D-NMR, and HRMS The antiproliferative test determined activity against a human breast cancer cell line (MDA-MB-231) by the SRB method The results revealed that compounds 3, 6b, and 6d displayed antiproliferative activities against tested cancer cell line with IC50 values ranging from 48,58- 70,93 M TÓM TẮT Trong luận văn này, 10 dẫn xuất (2-(4-methoxyphenyl)-1Hbenzo[d]imidazol-5(6)-yl)(phenyl)methanone tổng hợp thành công phản ứng ngưng tụ dẫn xuất o-phenylenediamine dẫn xuất aldehyde thơm có sử dụng xúc tác Na2S2O5 hỗn hợp dung mơi EtOH: H2O (9:1, v/v) Sau đó, mười dẫn xuất alkyl hóa vị trí N-1 benzimidazole tổng hợp phản ứng alkyl hóa với xúc tác K2CO3 dung môi DMSO Các hợp chất tổng hợp xác định tính chất HPLC, UV- Vis, FT- IR, 1D 2D- NMR, HRMS Khả ức chế tăng sinh tế bào thử nghiệm dòng tế bào ung thư vú MDAMB-231 phương pháp SRB Kết thử nghiệm cho thấy hợp chất 3, 6b 6d thể hoạt tính ức chế phát triển dòng tế bào ung thư nghiên cứu với giá trị IC50 từ 48.58– 70.93 µM ii CONTENTS ABSTRACT i TÓM TẮT i LIST OF FIGURES v LIST OF SCHEMES vi LIST OF TABLES vii LIST OF ABBREVIATIONS viii INTRODUCTION .1 CHAPTER LITERATURE REVIEW 1.1 Benzimidazoles 1.1.1 Introduction .3 1.1.2 Physicochemical properties .3 1.1.3 Application 1.2 Overview to 2,5(6)-disubstituted benzimidazole derivatives 1.2.1 Synthetic method .6 1.2.2 Biological activities 1.3 Overview to N- alkylated benzimidazole derivatives .11 1.3.1 Synthesis of N- alkylated 11 1.3.2 Antiproliferative activities 12 CHAPTER EXPERIMENTAL 15 2.1 Materials and instrumentations .15 2.1.1 Materials 15 2.1.2 Instrumentations 16 iii 2.2 Procedure for synthesis of (2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5(6)yl)(phenyl)methanone (3) 16 2.3 General procedure for the synthesis of N- alkylated (2-(4-methoxyphenyl)1H-benzo[d]imidazol-5(6)-yl)(phenyl)methanone derivatives .17 2.4 Isolation method and structure determination .18 2.4.1 Isolation method 18 2.4.2 Structure determination 19 2.5 Antiproliferative test .21 CHAPTER 3: RESULT AND DISCUSSION .22 3.1 Chemistry .22 3.1.1 (2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5(6)-yl)(phenyl)methanone 26 3.1.2 N- alkylated (2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5yl)(phenyl)methanone derivatives .27 3.2 Structure determination 36 3.2.1 Compound (2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5yl)(phenyl)methanone (Compound 3) .36 3.2.2 Compound (2-(4-methoxyphenyl)-1-propyl-1H-benzo[d]imidazol-5yl)(phenyl)methanone (Compound 5a) .37 3.2.3 Compound (2-(4-methoxyphenyl)-1-propyl-1H-benzo[d]imidazol-6yl)(phenyl)methanone (Compound 6a) .38 3.2.4 Compound (1-butyl-2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5yl)(phenyl)methanone (Compound 5b) 39 3.2.5 Compound (1-butyl-2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6yl)(phenyl)methanone (Compound 6b) 40 3.2.6 Compound (2-(4-methoxyphenyl)-1-pentyl-1H-benzo[d]imidazol-5yl)(phenyl)methanone (Compound 5c) .41 iv 3.2.7 Compound (2-(4-methoxyphenyl)-1-pentyl-1H-benzo[d]imidazol-6yl)(phenyl)methanone (Compound 6c) .42 3.2.8 Compound (1-hexyl-2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5yl)(phenyl)methanone (compound 5d) .43 3.2.9 Compound (1-hexyl-2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6yl)(phenyl)methanone (compound 6d) .44 3.2.10 Compound (1-heptyl-2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5yl)(phenyl)methanone (compound 5e) 45 3.2.11 Compound (1-heptyl-2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6yl)(phenyl)methanone (compound 6e) 46 3.3 Discussion 46 3.3 Antiproliferative result 53 CHAPTER CONCLUSION .56 4.1 Concluding remark .56 4.2 Suggestion on future work 56 REFERENCES 57 v LIST OF FIGURES Figure 2.1 Illustration of procedure for synthesizing compound 16 Figure 2.2 Illustration of procedure for synthesizing 5a-e and 6a-e 17 Figure 3.1 Sample and TLC of 26 Figure 3.2 Sample and TLC of 5a 27 Figure 3.3 Sample and TLC of 5b 28 Figure 3.4 Sample and TLC of 6b 29 Figure 3.5 Sample and TLC of 5c 30 Figure 3.8 Sample and TLC of 6c 31 Figure 3.7 Sample and TLC of 5d 32 Figure 3.8 Sample and TLC of 6d 33 Figure 3.9 Sample and TLC of 5e 34 Figure 3.10 Sample and TLC of 6e 35 Figure 3.11 UV-Vis absorption spectra of compounds 3, 5a−e, 6a−e 46 Figure 3.12 1H-NMR spectra of compound 6b (A) and compound 5b (B) Figure 3.13 2D-NMR spectra of 6b a) NOESY spectrum, correlations between H-7 and H-1” are circled in red color b) HMBC spectrum, correlations between H-1” and C-2 and C-8 are circled in blue color Figure 3.14 2D-NMR spectra of 5b a) NOESY spectrum, correlations between H-7 and H-1” are circled in red color b) HMBC spectrum, correlations between H-1” and C-2 and C-8 are circled in blue color D.28 Figure AD.49 1H-NMR spectra of compound 5e D.29 Figure AD.50 13C-NMR spectra of compound 5e Figure AD.51 HSQC spectra of compound 5e D.30 Figure AD.52 HMBC spectra of compound 5e D.31 Figure AD.53 NOESY spectra of compound 5e Figure AD.54 1H-NMR spectra of compound 6e D.32 Figure AD.55 13C-NMR spectra of compound 6e D.33 Figure AD.56 HSQC spectra of compound 6e Figure AD.57 HMBC spectra of compound 6e D.34 Figure AD.58 NOSEY spectra of compound 6e E.1 APPENDIX E HRMS SPECTRUM OF COMPOUNDS Figure AE.1 HRMS spectra of compound Figure AE.2 HRMS spectra of compound 6a Figure AE.3 HRMS spectra of compound 5a E.2 Figure AE.4 HRMS spectra of compound 6b Figure AE.5 HRMS spectra of compound 5b Figure AE.6 HRMS spectra of compound 6c E.3 Figure AE.7 HRMS spectra of compound 5c Figure AE.8 HRMS spectra of compound 6d Figure AE.9 HRMS spectra of compound 5d E.4 Figure AE.10 HRMS spectra of compound 6e Figure AE.11 HRMS spectra of compound 5e F.1 APPENDIX F RESULT OF ANTIPROLIFERATIVE ACTIVITIES TEST F.2 F.3 F.4