Luận án Tiến sĩ Tổng hợp và thử nghiệm hoạt tính sinh học một số dẫn xuất mới của sulfonamide và sulfonylurea

BỘ GIÁO DỤC VÀ ĐÀO TẠO VIỆN HÀN LÂM KHOA HỌC VÀ CÔNG NGHỆ VIỆT NAM HỌC VIỆN KHOA HỌC VÀ CÔNG NGHỆ - THẠCH THỊ DÂN TỔNG HỢP VÀ THỬ NGHIỆM HOẠT TÍNH SINH HỌC MỘT SỐ DẪN XUẤT MỚI CỦA SULFONAMIDE VÀ SULFONYLUREA LUẬN ÁN TIẾN SĨ HĨA HỌC TP HỒ CHÍ MINH – 2022 BỘ GIÁO DỤC VÀ ĐÀO TẠO VIỆN HÀN LÂM KHOA HỌC VÀ CÔNG NGHỆ VIỆT NAM HỌC VIỆN KHOA HỌC VÀ CÔNG NGHỆ - THẠCH THỊ DÂN TỔNG HỢP VÀ THỬ NGHIỆM HOẠT TÍNH SINH HỌC MỘT SỐ DẪN XUẤT MỚI CỦA SULFONAMIDE VÀ SULFONYLUREA Chuyên ngành: Hóa hữu Mã số chuyên ngành: 44 01 14 LUẬN ÁN TIẾN SĨ HÓA HỌC NGƯỜI HƯỚNG DẪN KHOA HỌC PGS.TS ĐẶNG CHÍ HIỀN TS ĐẶNG VĂN SỬ TP HỒ CHÍ MINH – 2022 LỜI CẢM ƠN - -Trước hết, xin cảm ơn Học viện Khoa học Công nghệ, Viện Hàn lâm Khoa học Công nghệ Việt Nam tạo điều kiện thuận lợi để tơi hồn thành luận án tiến sĩ Tôi xin chân thành cảm ơn đến PGS.TS Đặng Chí Hiền, TS Đặng Văn Sử quý Thầy Cô Học viện Khoa học Công nghệ, Viện Cơng nghệ Hóa học truyền đạt kiến thức, hướng dẫn tận tình, tạo điều kiện cho tơi suốt thời gian thực đề tài nghiên cứu Tôi xin cảm ơn PGS.TS Phạm Tiết Khánh, Ban Giám hiệu quý Thầy Cô Trường Đại học Trà Vinh hỗ trợ tơi q trình học tập nghiên cứu Cảm ơn bạn nghiên cứu sinh, bạn học viên cao học bạn sinh viên động viên, chia sẻ q trình tơi thực đề tài nghiên cứu sinh Cảm ơn tất người thân gia đình ln động viên tinh thần chia sẻ công việc để tập trung học tập hoàn thành luận án tiến sĩ Xin chân thành cảm ơn! Thành phố Hồ Chí Minh, năm 2022 THẠCH THỊ DÂN LỜI CAM ĐOAN Luận án Tiến sĩ Hóa học: “Tổng hợp thử nghiệm hoạt tính sinh học số dẫn xuất sulfonamide sulfonylurea” thực hiện, số liệu, kết trung thực Thành phố Hồ Chí Minh, năm 2022 Nghiên cứu sinh THẠCH THỊ DÂN i MỤC LỤC DANH MỤC CÁC KÝ HIỆU, CÁC CHỮ VIẾT TẮT iii DANH MỤC CÁC BẢNG v DANH MỤC CÁC HÌNH vii DANH MỤC CÁC SƠ ĐỒ VÀ ĐỒ THỊ viii MỞ ĐẦU CHƯƠNG 1: TỔNG QUAN 1.1 Sơ lược sulfonamide…………………………………………………… 1.2 Sơ lược sulfonylurea…………………………………………………… 1.3 Sơ lược chalcone pyrazole……………………………………………8 1.3.1 Sơ lược chalcone 1.3.2 Sơ lược pyrazole 1.4 Ứng dụng vi sóng tổng hợp hữu cơ………………………………… 1.4.1 Nguyên tắc lị vi sóng 1.4.2 Ứng dụng vi sóng tổng hợp hữu 11 1.5 Tình hình nghiên cứu ngồi nước 11 1.5.1 Tổng hợp dẫn xuất sulfonamide sulfonylurea 11 1.5.2 Tổng hợp dẫn xuất sulfonamide sulfonylurea vi sóng 20 CHƯƠNG 2: THỰC NGHIỆM 24 2.1 Hóa chất thiết bị 24 2.2 Nội dung nghiên cứu 25 2.3 Phương pháp nghiên cứu 27 2.3.1 Phương pháp tổng hợp xác định cấu trúc sản phẩm 27 2.3.2 Phương pháp thử nghiệm hoạt tính sinh học 29 2.4 Thực nghiệm 29 2.4.1 Tổng hợp 4-hydrazinylbenzenesulfonamide (D1) 29 2.4.2 Tổng hợp dẫn xuất chalcone (D1a-D35a) 30 2.4.3 Tổng hợp dẫn xuất sulfonamide khung pyrazole (D1b-D35b) 30 2.4.4 Tổng hợp dẫn xuất phenylhydrazone (D1c–D5c) 30 2.4.5 Tổng hợp dẫn xuất sulfonamide khung thiazolidine-4-one (D1d-D5d) 31 2.4.6 Tổng hợp dẫn xuất sulfonylurea (D3e, D10e, D21e, D24e, D26e) 31 ii 2.4.7 Phương pháp thử nghiệm hoạt tính sinh học 31 2.4.7.1 Phương pháp thử nghiệm hoạt tính kháng vi sinh vật 31 2.4.7.2 Phương pháp thử nghiệm hoạt tính gây độc tế bào 33 2.4.7.3 Phương pháp thử nghiệm hoạt tính kháng viêm 34 CHƯƠNG 3: KẾT QUẢ VÀ THẢO LUẬN 37 3.1 Tổng hợp 4-hydrazinylbenzenesulfonamide (D1) 37 3.2 Tổng hợp dẫn xuất chalcone (D1a-D35a) 39 3.3 Tổng hợp dẫn xuất sulfonamide khung pyrazole (D1b-D35b) 64 3.3.1 Khảo sát hiệu suất phản ứng tổng hợp dẫn xuất sulfonamide khung pyrazole sử dụng phương pháp hồi lưu thông thường 65 3.3.2 Khảo sát hiệu suất phản ứng tổng hợp dẫn xuất sulfonamide khung pyrazole sử dụng phương pháp vi sóng 66 3.4 Tổng hợp dẫn xuất phenylhydrazone (D1c-D5c) 106 3.5 Tổng hợp dẫn xuất sulfonamide khung thiazolidine-4-one (D1d-D5d) 111 3.6 Tổng hợp dẫn xuất sulfonylurea (D3e, D10e, D21e, D24e, D26e) 120 3.7 Kết thử nghiệm hoạt tính sinh học 136 3.7.1 Kết thử nghiệm hoạt tính kháng vi sinh vật 136 3.7.2 Kết thử nghiệm hoạt tính gây độc tế bào 140 3.7.3 Kết thử nghiệm hoạt tính kháng viêm 142 KẾT LUẬN VÀ KIẾN NGHỊ 146 KẾT LUẬN 146 KIẾN NGHỊ 148 DANH MỤC CÁC CƠNG TRÌNH ĐÃ CÔNG BỐ iii DANH MỤC CÁC KÝ HIỆU, CÁC CHỮ VIẾT TẮT Ký hiệu Tiếng Anh CFU Colony Forming Unit Tiếng Việt CTCT Công thức cấu tạo CTPT Công thức phân tử D Tỷ trọng DMSO Dimethyl sulfoxide COX-1 Cyclooxygenases COX-2 Cyclooxygenases PTSA p-Toluenesulfonide Acid NSAIDs Non-steroidal anti-inflammatory drugs FT-IR Fourier-transform Infrared Spectroscopy Proton Nuclear Magnetic Resonance H-NMR 13 C-NMR DEPT-NMR HR-ESI-MS HSQC HMBC Carbon Nuclear Magnetic Resonance Distortionless Enhancement Thuốc kháng viêm không steroid Quang phổ hồng ngoại biến đổi Fourier Cộng hưởng từ hạt nhân proton Cộng hưởng từ hạt nhân carbon Phổ DEPT of Polarisation Transfer High Resolution Electrospray Ionisation Phổ khối lượng phun mù Mass Spectrometry ion hóa phân giải cao Heteronuclear Single Quantum Phổ tương tác dị nhân qua Coherence nối Heteronuclear Multiple Bond Phổ tương tác dị nhân qua Correlation nhiều nối ĐTĐ Đái tháo đường MIC Minimum Inhibitory Concentration Nồng độ ức chế tối thiểu IC50 Half maximal inhibitory concentration Nồng độ ức chế 50 % MBC Minimum Bactericidal Concentration Nồng độ tối thiểu LB Lysogeny Broth PDA Potato Dextrose Agar iv MTT (3-[4,5-dimethylthiazol-2-yl]-2,5diphenyltetrazol bromide) NCI National Cancer Institute Viện ung thư quốc gia OD Optical Density Mật độ quang học SRB Sulforhodamine B TCA Trichloracetic acid LD50 Lethal Concentration Nồng độ gây chết FACs Flow cytometry Đo dòng chảy tế bào PBS Phosphate buffer saline CA Carbonic anhydrase J Coupling constant Hằng số ghép m Multiplet Mũi đa s Singlet Mũi đơn Triplet Mũi ba Doublet Mũi đôi dd doublet of doublet Mũi đôi đôi MW Microwave Vi sóng TLC Thin layer chromatography Sắc ký lớp ‘ ‘ ‘ t ‘ d ‘ ‘ nm Nanometer h Hour Giờ ‘ δ Chemical shift Độ dịch chuyển hóa học  Micro ‘ v DANH MỤC CÁC BẢNG Bảng 1.1 Các cấu trúc hệ sulfonylurea Bảng 2.1 Hóa chất sử dụng 24 Bảng 2.2 Dụng cụ thiết bị 25 Bảng 3.1 Bảng 3.2 Bảng 3.3 Bảng 3.4 Bảng 3.5 Bảng 3.6 Bảng 3.7 Dữ liệu phổ H-NMR trúc 4– hydrazinylbenzenesulfonamide (D1) Hiệu suất tổng hợp dẫn xuất chalcone phụ thuộc vào vị trí loại nhóm Điểm chảy dẫn xuất chalcone phụ thuộc vào vị trí loại nhóm Dữ liệu MS, HR-MS phổ FT-IR dẫn xuất chalcone (D1a-D35a) Dữ liệu phổ NMR dẫn xuất chalcone (D1a-D35a) Dữ liệu phổ 1H-NMR 4-(5-(3-hydroxyphenyl)-3-phenyl-4,5dihydro-1H-pyrazol-1-yl)benzenesulfonamide (D4b) Dữ liệu phổ 13C-NMR DEPT 4-(5-(3-hydroxyphenyl)-3phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide (D4b) Dữ liệu phổ 1H-NMR, Bảng 3.8 cấu 13 38 41 41 45 52 69 70 C-NMR HMBC 4-(5-(3- hydroxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzene 71 sulfonamide (D4b) Bảng 3.9 Bảng 3.10 Hiệu suất tổng hợp dẫn xuất sulfonamide chứa khung pyrazole phụ thuộc vào vị trí loại nhóm Điểm chảy dẫn xuất sulfonamide chứa khung pyrazole phụ thuộc vào vị trí loại nhóm Bảng 3.11 Bảng 3.12 Dữ liệu HR-MS FT-IR dẫn xuất sulfonamide khung pyrazole (D1b-D35b) Dữ liệu phổ NMR dẫn xuất sulfonamide khung pyrazole (D1b-D35b) 72 72 76 88 Khảo sát hiệu suất phản ứng tổng hợp dẫn xuất Bảng 3.13 phenylhydrazone sử dụng phương pháp hồi lưu thông thường 106 chiếu xạ vi sóng (D1c-D5c) vi Bảng 3.14 Dữ liệu phổ 1H-NMR dẫn xuất phenylhydrazone (D1cD5c) 109 Khảo sát hiệu suất phản ứng tổng hợp sulfonamide khung Bảng 3.15 thiazolidine-4-one sử dụng phương pháp hồi lưu thơng thường chiếu xạ vi sóng Hiệu suất tổng hợp dẫn xuất thiazolidine-4-one 112 Bảng 3.16 phenylhydrazone sử dụng phương pháp hồi lưu thông thường 113 vi sóng Bảng 3.17 Bảng 3.18 Bảng 3.19 Dữ liệu HR-MS phổ FT-IR sulfonamide khung thiazolidine-4-one (D1d-D5d) Dữ liệu phổ NMR sulfonamide khung thiazolidine-4-one (D1d-D5d) Dữ liệu phổ 1H-NMR 4-(3,5-di-p-tolyl-4,5-dihydro-1Hpyrazol-1-yl)-N-(p-tolyl carbamoyl) benzenesulfonamide (D10e) Dữ liệu phổ 13 115 117 122 C-NMR DEPT 4-(3,5-di-p-tolyl-4,5- Bảng 3.20 dihydro-1H-pyrazol-1-yl)-N-(p-tolyl carbamoyl) benzene 123 sulfonamide (D10e) Dữ liệu phổ 1H-NMR, 13C-NMR HMBC 4-(3,5-di-p-tolylBảng 3.21 4,5-dihydro-1H-pyrazol-1-yl)-N-(p-tolylcarbamoyl) benzene 124 sulfonamide (D10e) Dữ liệu phổ 13C-NMR sulfonylurea D3e, D10e, D21e, Bảng 3.22 D24e, D26e 126 Kết thử nghiệm hoạt tính kháng VSV sulfonamide Bảng 3.23 khung pyrazole (D1b-D33b) sulfonamide khung thiazolidine-4-one (D1d-D5d) Hoạt tính chống tăng sinh dẫn xuất sulfonamide khung Bảng 3.24 pyrazole Khả ức chế sản sinh NO triarylpyrazole Bảng 3.25 sulfonamide 137 141 143 148 Kiến nghị Từ số kết thu q trình nghiên cứu, chúng tơi đề nghị hướng phát triển cho đề tài sau: Tiếp tục phát triển nghiên cứu tổng hợp dẫn xuất sulfonamide từ sulfanilamide qua trung gian chalcone, qua trung gian dẫn xuất phenylhydrazone với nhóm đa dạng Tiếp tục phát triển tổng hợp dẫn xuất sulfonylurea dựa dẫn xuất phenylhydrazone, dẫn xuất sulfonamide chứa khung pyrazole khung thiazolidine-4-one tổng hợp Tiếp tục phát triển tổng hợp dẫn xuất sulfonamide dạng oxazolidine-4one từ dẫn xuất phenylhydrazone với 2-hydroxyacetic acid nhằm làm phong phú dẫn xuất sulfonamide Tiếp tục phát triển thử nghiệm hoạt tính kháng vi sinh vật, kháng viêm, gây độc tế bào dẫn xuất sulfonamide sulfonylurea tổng hợp DANH MỤC CÁC CƠNG TRÌNH ĐÃ CƠNG BỐ Trong nước Thạch Thị Dân, Bùi Thị Bích Hạnh, Nguyễn Hữu Thiên An, Nguyễn Thành Danh, Đặng Văn Sử, Đặng Chí Hiền, Tổng hợp số dẫn xuất thiazolidinone qua trung gian phenylhydrazone kỹ thuật vi sóng, Tạp chí hóa học, 2017, 55 (5E34), 274-279 Thạch Thị Dân, 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