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 - 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 V N HỌC VIỆ N KH OA HỌC VÀ CÔN G NGH Ệ - TỔNG HỢP VÀ THỬ NGHI ỆM 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 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 hồn thành luận án tiến sĩ Tơi xin chân thành cảm ơn đến PGS TS quý Thầy Cô Học viện Khoa học Cơng nghệ, Viện Cơng nghệ Hóa học truyền đạt kiến thức, hướng dẫn tận tình, tạo điều kiện cho suốt thời gian thực đề tài nghiên cứu Tôi xin cảm ơn PGS TS , Ban Giám hiệu quý Thầy Cô Trường Đại học Trà Vinh hỗ trợ 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 động viên tinh thần chia sẻ công việc để tơi tập trung học tập hồn thành luận án tiến sĩ Xin chân thành cảm ơn! Thành phố Hồ Chí Minh, năm 2022 LỜI CAM ĐOAN Luận án Tiến sĩ Hóa học: “Tổng hợp thử nghiệm hoạt tính sinh học số dẫn xuất sulfonamide sulfonylurea” th ực hi ệ n, số liệ u, kế t qu ả đề u trung th ực Thành phố Hồ Chí Minh, năm 2022 Nghiên cứu sinh 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 Sơ lược sulfonamide…………………………………………………… Sơ lược sulfonylurea…………………………………………………… Sơ lược chalcone pyrazole……………………………………………8 Sơ lược chalcone Sơ lược pyrazole Ứng dụng vi sóng tổng hợp hữu cơ………………………………… Nguyên tắc lị vi sóng Ứng dụng vi sóng tổng hợp hữu 11 Tình hình nghiên cứu ngồi nước 11 Tổng hợp dẫn xuất sulfonamide sulfonylurea 11 Tổng hợp dẫn xuất sulfonamide sulfonylurea vi sóng 20 CHƯƠNG 2: THỰC NGHIỆM 24 Hóa chất thiết bị 24 2 Nội dung nghiên cứu 25 Phương pháp nghiên cứu 27 Phương pháp tổng hợp xác định cấu trúc sản phẩm 27 Phương pháp thử nghiệm hoạt tính sinh học 29 Thực nghiệm 29 Tổng hợp 4-hydrazinylbenzenesulfonamide (D1) 29 Tổng hợp dẫn xuất chalcone (D1a-D35a) 30 Tổng hợp dẫn xuất sulfonamide khung pyrazole (D1b-D35b) 30 4 Tổng hợp dẫn xuất phenylhydrazone (D1c–D5c) 30 Tổng hợp dẫn xuất sulfonamide khung thiazolidine-4-one (D1d-D5d) 31 Tổng hợp dẫn xuất sulfonylurea (D3e, D10e, D21e, D24e, D26e)31 ii Phương pháp thử nghiệm hoạt tính sinh học 31 Phương pháp thử nghiệm hoạt tính kháng vi sinh vật 31 Phương pháp thử nghiệm hoạt tính gây độc tế bào 33 Phương pháp thử nghiệm hoạt tính kháng viêm 34 CHƯƠNG 3: KẾT QUẢ VÀ THẢO LUẬN 37 Tổng hợp 4-hydrazinylbenzenesulfonamide (D1) 37 Tổng hợp dẫn xuất chalcone (D1a-D35a) 39 3 Tổng hợp dẫn xuất sulfonamide khung pyrazole (D1b-D35b) 64 3 Khảo sát hiệu suất phản ứng tổng hợp dẫn xuất sulfonamide khung pyrazole sử dụng phương pháp hồi lưu thông thường 65 3 Khảo sát hiệu suất phản ứng tổng hợp dẫn xuất sulfonamide khung pyrazole sử dụng phương pháp vi sóng Tổng hợp dẫn xuất phenylhydrazone (D1c-D5c) 66 106 Tổng hợp dẫn xuất sulfonamide khung thiazolidine-4-one (D1d-D5d) 111 Tổng hợp dẫn xuất sulfonylurea (D3e, D10e, D21e, D24e, D26e) 120 Kết thử nghiệm hoạt tính sinh học 136 Kết thử nghiệm hoạt tính kháng vi sinh vật 136 Kết thử nghiệm hoạt tính gây độc tế bào 140 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 CƠNG 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 Thuốc kháng viêm không steroid Quang phổ hồng ngoại biến đổi Fourier Cộng hưởng từ hạt nhân H-NMR Proton Nuclear Magnetic Resonance C-NMR Carbon Nuclear Magnetic Resonance proton Cộng hưởng từ hạt nhân DEPT-NMR HR-ESI-MS HSQC HMBC Distortionless Enhancement 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 Đái tháo đường ĐTĐ 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 ‘ t Triplet Mũi ba ‘ d Doublet Mũi đôi ‘ dd doublet of doublet Mũi đơi đơi MW Microwave Vi sóng TLC Thin layer chromatography Sắc ký lớp ‘ nm Nanometer ‘ h Hour Giờ ‘ δ Chemical shift Độ dịch chuyển hóa học µ Micro v DANH MỤC CÁC BẢNG Bảng 1 Các cấu trúc hệ sulfonylurea Bảng Hóa chất sử dụng 24 Bảng 2 Dụng cụ thiết bị 25 Bảng Bảng Bảng 3 Bảng Bảng Bảng Bảng Dữ liệu phổ H-NMR cấu trúc hydrazinylbenzenesulfonamide (D1) 4– 38 Hiệu suất tổng hợp dẫn xuất chalcone phụ thuộc vào vị trí loại 41 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) 41 45 52 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 69 70 C-NMR HMBC 4-(5-(3- hydroxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzene 71 sulfonamide (D4b) Bảng Bảng 10 Bảng 11 Bảng 12 Hiệu suất tổng hợp dẫn xuất 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xuất sulfonamide sulfonylurea có hoạt tính sinh học cao ứng dụng y học, góp phần... thử nghiệm hoạt tính sinh học dẫn xuất tổng hợp Nội dung luận án - Tổng hợp dẫn xuất sulfonamide chứa khung pyrazole từ 4- hydrazinylbenzenesulfonamide dẫn xuất chalcone - Tổng hợp dẫn xuất sulfonamide. ..BỘ GIÁO DỤC VÀ ĐÀO TẠO VIỆN HÀN LÂM KHOA HỌC V N HỌC VIỆ N KH OA HỌC VÀ CÔN G NGH Ệ - TỔNG HỢP VÀ THỬ NGHI ỆM HOẠT TÍNH SINH HỌC MỘT SỐ DẪN XUẤT MỚI CỦA SULFONAMIDE VÀ SULFONYLUREA Chuyên