Nghiên cứu tổng hợp cấu trúc và hoạt tính sinh học của một số dị vòng ngưng tụ chứa o s n

MỞ ĐẦU Các hợp chất 1,2,4-triazole dẫn xuất chúng chất thường có hoạt tính sinh học cao, đa dạng có nhiều ứng dụng quan trọng y học nhà khoa học nước quan tâm nghiên cứu Chẳng hạn, nhiều cơng trình cơng bố dẫn xuất 1,2,4-triazole có khả kháng khuẩn –khỏng nấm, kháng virut, chống viêm, an thần, chống trầm cảm, chống ung thư, kháng virut HIV, diệt cỏ, trừ sâu, chất bơi trơn hóa chất phân tích [82, 85, 87, 131,171] nhiều hợp chất có chứa vịng 1,2,4-triazole có hoạt tính cao sử dụng điều trị bệnh fluconazole, itraconazole, voriconazole [77,165], triazolam [21], alprazolam [43], etizolam [154] furacrilin [138] Bờn cạnh đó, nhiều hợp chất chứa vịng 1,2,4-triazole kết hợp với vòng 1,3,4-thiađiazole 1,3,4-thiađiazine biểu hoạt tính kháng khuẩn [132], chống viêm [23, 62, 122, 166] có nhiều ứng dụng y học [62,68,82,83,88,115,167,183] Như dẫn xuất triazolothiađiazole vị trí trờn vũng cú chứa nhóm ankyl, aryl dị vịng khác thể hoạt tính kháng khuẩn [163], chống viêm [169], diệt cỏ [133] kháng virut HIV [99] Các thiađiazepine khơng biết đến hoạt tính kháng khuẩn mạnh [74, 110] mà nú cũn sử dụng điều trị virut HIV [80] Sở dĩ dẫn xuất thiađiazole, thiađiazine hay thiađiazepine thể hoạt tính sinh học cao đa dạng phân tử có diện nhóm =N-C-S- [87] Ngồi ra, số dẫn xuất 1,2,4-triazole có khả tạo phức với kim loại chuyển tiếp sử dụng phân tích kim loại như: B, Re, W, Co, Rh, Pt, …[ 7] Các dẫn xuất cumarin có vai trị lớn hóa học hợp chất tự nhiên tổng hợp hữu cơ, nhiều hợp chất chứa vòng cumarin thể nhiều hoạt tính quý trừ sâu [21], trừ giun sán, miên [123], chống đụng mỏu, phát quang [116], Tương tự, dẫn xuất chứa vòng quinolin xuất nhiều phát minh sáng chế liên quan đến hóa trị liệu nhiều hoạt tính sinh học tìm thấy hợp chất chứa vịng quinolin kháng viêm, chống dị ứng [93], chống sốt rét [100], kháng khuẩn [124], [45,51,163], chống ký sinh trùng [163], … ức chế phát triển tế bào ung thư Nhằm góp phần vào nghiên cứu hợp chất triazole, luận án này, tiến hành nghiên cứu tổng hợp số hợp chất dị vòng ngưng tụ chứa O, N, S 1,2,4-triazolo[3,4-b]-1,3,4-thiađiazole, 1,2,4-triazolo[3,4-b]-1,3,4thiađiazine, 1,2,4-triazolo[3,4-b]-1,3,4-thiađiazepine số dãy chất có chứa hợp phần cumarin quinolin với hi vọng việc gắn kết hai hợp phần tạo hợp chất với nhiều ứng dụng Để thực mục đích luận án, chúng tơi thực số nhiệm vụ sau:  Tổng hợp dẫn xuất 1,2,4-triazolo[3,4-b]-1,3,4-thiađiazepine, 7H-1,2,4triazolo[3,4-b]-1,3,4-thiađiazine, b]-1,3,4-thiađiazole, 6-(2-R-quinolin-4-yl)-1,2,4-triazolo-[3,4- 6-(6-X-cumarin-3-yl)-1,2,4-triazolo-[3,4-b]-1,3,4- thiađiazine 5H-quinolino[3,2-f]-1,2,4-triazolo[3,4-b]-1,3,4-thiađiazepine từ 4-amino-3-mercapto-1,2,4-triazole  Nghiên cứu cấu trúc sản phẩm tổng hợp phương pháp phổ hồng ngoại, phổ cộng hưởng từ hạt nhân (1H-NMR, 13C-NMR, cựng cỏc kỹ thuật phổ hai chiều HSQC, HMBC) phổ khối (LC-MS, EI-MS)  Tiến hành thăm dị hoạt tính kháng khuẩn - kháng nấm số hợp chất tổng hợp với số vi khuẩn nấm men, nhằm tìm kiếm chất có hoạt tính sinh học cao CHƯƠNG TỔNG QUAN 1.1 Giới thiệu 4-amino-3-mercapto-1,2,4-triazole Các hợp chất 4-amino-3-mercapto-1,2,4-triazole Hoggarth[81] tổng hợp lần vào năm 1952 tồn hai dạng hỗ biến sau [71]: Dạng “thiol” Dạng “thion” Các dạng tautome tác giả [78] phát chứng minh tồn chúng phương pháp phổ IR, NMR Cụ thể: phổ hồng ngoại xuất pic hấp thụ đặc trưng cho dao động hóa trị liên kết N – H (ở vùng 3350-3450cm-1) C=S (ở 1290 -1180 cm-1) Đồng thời, phổ 1H-NMR xuất tín hiệu rộng proton nhóm SH 10,9-11,1 ppm, điều chứng tỏ tồn đồng thời hai dạng hỗ biến Trong đó, số dẫn xuất khác lại tồn hai dạng cấu trúc “ thiol” “thion” Chẳng hạn, nghiên cứu cấu trúc số azometin chứa dị vòng 1,2,4-triazol từ thimol tác giả [8] thấy rằng: Với dẫn xuất cú nhúm Y 3-CH3O 4-Cl tồn cấu trúc “thion” khảo sát phổ HMBC hợp chất thấy có pic giao tín hiệu H-13a C-12 điều chứng tỏ H-13a C-12 hợp chất phải cách không liên kết tồn hợp chất cấu trúc “thion” hợp lí, cịn với dẫn xuất cú nhúm Y 4-(CH3)2N 4-NO2 tồn cấu trúc “thiol” vỡ trờn phổ HMBC khơng thấy có pic giao tín hiệu H-13a C-12 Bằng phương pháp nhiễu xạ tia X tinh thể, tác giả [185] thấy độ dài liên kết C-S (1,684Å) 4-amino-3-mercapto-1,2,4-triazole ngắn so với liên kết đơn C-S (1,801-1,825Å) đithiaxycloankan dài liên kết đôi C=S (1,646Å) đôi chút, điều lần khẳng định tồn đồng thời dạng tautome Trong phân tử 4-amino-3-mercapto-1,2,4-triazole cú nhóm amino thioxo trung tâm có tính nucleophin cao nên dễ tham gia phản ứng tổng hợp hợp chất dị vòng chứa nitơ, lưu huỳnh triazolothiađiazole, triazolothiađiazine triazolothiađiazepine Ngồi ra, dẫn xuất 4-amino-3mercapto-1,2,4-triazole cịn thu hút ý nhà khoa học đặc tính sinh học phong phú đa đạng chúng kháng khuẩn, kháng nấm, trừ sâu, sát trùng diệt cỏ [50,67,86] Yếu tố quan trọng để tạo nên hoạt tính sinh học dẫn xuất aminotriazolothion đú chớnh nhóm thioxo [58, 59] 1.2 Các phương pháp tổng hợp 4-amino-3-mercapto-1,2,4-triazole 1.2.1 Tổng hợp từ thiocacbohyđrazit Theo tài liệu [27,33,49,63,64,70,72,92,128,137,170,180], số dẫn xuất 4-amino-3-mercapto-1,2,4-triazole (2) tổng hợp cách đun nóng chảy axit cacboxylic với thiocacbohiđrazit (1) Sơ đồ phản ứng sau: S RCOOH + H2N N H N N H NH2 R N N SH NH2 (1) (2) R = H, CH3, CH3CH2CH2, CH3(CH2)2CH2, CF3, C6H5 Bằng cách trên, 1-(6-metoxy-2-naphtyl)-1-(5’-amino-s-triazole-3-yl)etan-4’thion (4) tổng hợp từ axit 2-(6-metoxy-2-naphtyl)-propanoic (3) [83] phản ứng axit cacboxylic (5) với (1) thu 3-[(5,6,7,8-tetrahiđro-naphtalen-2-yl)oximetyl]-4-amino-1,2,4-triazole-5-thion (6) [120,167] Thực phản ứng 1,4-lacton (7-9) với (1) piriđin khan thu 4-amino-3-(D-gluco- (10) D-galacto (11) pentitol-1-yl)-1,2,4-triazole-5thion (D-glyxero-D-gulo-hexitol-1-yl)-1,2,4-triazole-5-thion (12) [25] 5-Ankyl-4-amino-2-(4-amino-4H-3-oxo-1,2,4-triazole-3-yl)-2,4-đihiđro-3H1,2,4-triazole-5-thion (14) tổng hợp cách đun nóng chảy (1) với (3ankyl-4-amino-5-oxo-4,5-đihiđro-1H-1,2,4-triazole-1-yl)axetat (13) [48] tác giả [170] tổng hợp thành công aminotriazolothion (16) với hiệu suất đạt 40% phản ứng (15) (1) có mặt natri metoxit làm xúc tác Theo tài liệu [83], phản ứng axit đicacboxylic với đương lượng thiocacbohiđrazit (1) thu dãy bis(4-amino-5-thioxo-1,2,4-triazole-3yl)ankan (18) với hiệu suất cao: 1.2.2 Tổng hợp từ hiđrazit axit cacboxylic Bên cạnh phản ứng axit cacboxylic este với thiocacbohiđrazit, người ta tổng hợp dẫn xuất 4-amino-3-mercapto-1,2,4-triazole (21) từ hiđrazit axit cacboxylic phương pháp tổng hợp Hoggarth [81] sau: cho hiđrazit axit cacboxylic (18) tác dụng với CS2 EtOH/KOH để chuyển thành muối kali 3-aroylđithiocacbazat (19), sau metyl hóa CH3I tạo metyl 3-aroylđithiocacbazat (20) thực phản ứng vũng với hiđrazin hiđrat Hoặc từ muối kali 3-aroylđithiocacbazat cho phản ứng trực tiếp hiđrazin hiđrat theo phương pháp Reid Heindel thu (21) [18, 32, 64,74,81,101,107, 126,137, 146,150,155,164] Đõy phương pháp hay sử dụng tổng hợp triazole tính đơn giản việc tỡm cỏc chất đầu hiệu suất cao Tương tự, tác giả [112] thực phản ứng adamantan-1-cacbohiđrazit (22) với CS2 etanol/KOH tạo kali axylhiđrazinđithioformat (23), sau vòng với hiđrazin hiđrat (dư) tạo sản phẩm 4-amino-3-(D-glucopentitol-1-yl)-1,2,4triazole-5-thion (24) Đặc biệt, đun hồi lưu kali đithiocacbazat (25) với hiđrazin dung mơi ethanol thu hỗn hợp sản phẩm gồm 4-amino-1,2,4-triazole-5-thion (26) 1,3,4-oxađiazolin-5-thion (27) [41,149] Ngoài ra, từ bishiđrazit axit terephtalic tác giả [127] thu sản phẩm 1,4-bis-(4-amino-5-thioxo-s-triazole-3-yl)benzen (28) theo phương pháp Reid Heindel [146] Trong đó, Udupi cộng [168] sử dụng tác nhân hiđrazit axit isonicotinic thay cho hiđrazin hiđrat phản ứng với kali đithiocacbazat (29) nhận sản phẩm 4-(N-piriđylcacboxamido)-3-aryl-1,2,4-triazole-5-thion (30) Cũng theo phương pháp tổng hợp Reid Heindel, tác giả [17, 32, 42,52,56,58,61,94-96,118,145,148,162,172,177-179] tổng hợp thành công dẫn xuất 4-amino-3-mercapto-1,2,4-triazole (31-42) sau: 1.2.3 Tổng hợp từ 1,3,4-oxađiazol-5-thion Một phương pháp khác để tổng hợp dẫn xuất 4-amino-3-mercapto-1,2,4triazole nhiều tác giả thực chuyển hóa dẫn xuất 1,3,4-oxađiazol thành aminotriazolothion phản ứng trực tiếp với hiđrazin hiđrat Reid Heindel [146] tổng hợp thành công aminotriazolothion (44) phản ứng 5-aryl-1,3,4-oxađiazole-3-thion (43) với hiđrazin hiđrat Bằng cách tương tự, tác giả [22,48,60,65,97,121,152,157,170 ] tổng hợp hợp chất (45-53) từ oxađiazol tương ứng, phản ứng thực dung môi khác như: etanol, nước đioxan Bên cạnh phương pháp đun hồi lưu, tác giả [102a,159a] tổng hợp số 4-amino-3-mercapto-1,2,4-triazole từ muối kali đithiocacbazat 1,3,4- oxađiazol-5-thion phản ứng với hiđrazin hiđrat lò vi sóng Ưu điểm phương pháp thời gian phản ứng ngắn hiệu suất cao 1.3 Các phản ứng chuyển hoá 4-amino-3-mercapto-1,2,4-triazole Các hợp chất 4-amino-3-mercapto-1,2,4-triazole nhiều nhà khoa học nghiên cứu chuyển hóa, hướng chuyển hóa chủ yếu tập trung vào nhóm SH (hoặc nhóm NH), nhóm NH2 vũng với tham gia hai nhóm NH SH Dưới số chuyển hóa nhà khoa học thực năm qua: 1.3.1 Phản ứng nguyên tử H nhóm SH (hoặc NH) Căp electron nguyên tử lưu huỳnh tham gia vào hệ liên hợp với vòng triazole, nguyên tử H nhóm SH (dạng thiol) dễ tham gia phản ứng với tác nhân metyl iodua [92], cloroaxetonitril [63,64], axit monocloaxetic [128] dẫn xuất 2’-bromoaxetophenon [54,128,170] Tác giả [33,118,114] thực phản ứng ankyl húa cỏc dẫn xuất 4-amino-3-mercapto-1,2,4triazole với ankyl halogen KOH/etanol K 2CO3/DMF thu sản phẩm (53-55) sau: Phản ứng 4-amino-3-mercapto-5-phenyl-1,2,4-triazole với 2’-aryl-2oxoetanhiđrazonoyl (54) etanol có mặt C 2H5ONa thu thiohiđrazonat este (55) [156] Các dẫn xuất triazole (56-59) tác giả [44,151] tổng hợp đun hồi lưu aminomercaptotriazole với halonitril, acrylonitril clorotetrazol etanol có mặt trietyl amin K2CO3 10 57 58 59 60 61 62 63 64 65 El-Din N S., El-Fatatry H M., and El-Hamamsy M (1998), “Synthesis of some heterocyclic azomethine derivatives of antimicrobial interest”, Alexandria J Pharm Sci., Vol 12(1), pp 15-20; CAN 129: 67740 El-Khawass S M and Habib N S (1989), “Synthesis of 1,2,4-triazole, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole and 1,2,4-triazolo[3,4-b][1,3,4] thiadiazine derivatives of benzotriazole”, J Heterocycl Chem., Vol 26, pp 177-181 El-Khawass S M., Hazzaa A A B.,El-Din S A S (1979), Sci Pharm., 47, 314 El-Masry A H., Fahmy H H., and Abdelwahed S H A (2000), “Synthesis and antimicrobial activity of some new benzimidazole derivatives”, Molecules, Vol 5, pp 1429-1438 Ergenc N., Ulusoy N., Apan G C, Sanıs G., and Kiraz M (1996), “Synthesis and antimicrobial properties of new 4-(alkylidene/arylidene)-amino5-(2-furanyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones and 6-Aryl-3-(2-furanyl)7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines”, Arch Pharm Pharm Med Chem., Vol 329, pp 427-430 Erhan Palaska, Gỹlay Şahin, Pelin Kelicen, N.Tuğba Durlu, Gỹlỗin Altinok (2002), “Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones”, II Farmaco, Vol.57(2), pp 101-107 Eweiss N F and Bahajaj A A (1973), “Synthesis of heterocycles Part VII Synthesis and antimicrobial activity of some 7H-s-triazolo[3,4-b][1,3,4] thiadiazine and s-triazolo[3,4-b][1,3,4]thiadiazole derivatives”, J Heterocycl Chem., Vol 24, pp 1173 Eweiss N F., Bahajaj A A., and Elsherbini E A (1986), “Synthesis of heterocycles Part VI Synthesis and antimicrobial activity of some 4-amino5-aryl-1,2,4-triazole-3-thiones and their derivatives”, J Heterocycl Chem., Vol 23, pp 1451-1458 Farghaly A A H (2004), ‘Synthesis, reactions and antimicrobial activity of some new indolyl-1,3,4-oxadiazole, triazole and pyrazole derivatives”, J Chin Chem Soc., Vol 51, pp 147-156 126 66 67 68 69 70 71 72 73 74 75 76 Farghaly A R., De Clercq E., El-Kashef H (2006), “Synthesis and antiviral activity of novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles, [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazin and [1,2,4]triazolo[3,4-b][1,3,4] thiadiazepines”, Arkivoc (x), pp 137151 Findeisen K., Kuhnt D., Muller K H., et al (1992), EP 513,621; C.A., 118, 101956d Foroumadi A, Mirzaei M, Shafiee A., (2001), “Antituberculosis agents, I: Synthesis and antituberculosis activity of 2-aryl-1,3,4-thiadiazole derivatives”, Pharmazie, Vol 56, pp 610-612 Gakhar H K., Jain A., and Gupta S B (1982), “Triazolo[3,4-b] [1,3,4]thiadiazloes”, J Indian Chem Soc., Vol 59(7), pp 900-901 Gakhar H K and Gill J K (1985), “Pyrimido[4,5-e](1,2,4)triazolo[3,4-b](1,3,4)-thiadiazine-7,9(6H,8H)-dione”, Monatsh Chem., Vol.116, pp 633-637 Garrett P J., Katritzky A R., Rees C W., and Scriven E F V., Eds., Pergamon(1996), Comprehensive Heterocyclic Chemistry II, Oxford, vol 4, pp.127 George T., Mehta D V., Tahilramani R., David J., Talwalker P K (1971), “Synthesis of some s-triazoles with potential analgesic and antiinflammatory activities”, J Med Chem., Vol.14(4), pp 335-338 Golgolab H., Lalezari I., and Hosseini G L (1973), “1,3,4-Thiadiazolo[2,3c]-as-triazines and s-triazolo[3,4-b]-1,3,4-thiadiazoles”, J Heterocycl Chem., Vol 10, pp 387-390 Goswami B N., Kataky J C S., and Baruah J N (1984), “Synthesis and antibacterial activity of 1-(2,4-dichlorobenzoyl)-4-substituted thiosemicarbazides, 1,2,4-triazoles and their methyl derivatives”, J Heterocycl Chem., Vol 21, pp.1225-1229 Gupta R., Paul S., Gupta A K., and Kachroo P L (1994), “Improved syntheses of some substituted 5,6-dihydro-s-triazolo(3,4-b) ( 1,3,4)-thiadiazoles in a microwave oven”, Indian J Chem., Vol 33B, pp 888 Gupta R., Sudan S., and Kachroo P L (1996), “Rection of 3-substituted-4amino-5-mercapto-1,2,4-triazoles with substituted cinnamic acids”, Indian J Chem., Vol 35B, pp 718 127 77 Haber, J (2001), “Present status and perspectives on antimycotis with syntermatic effects”, Cas Lek Cesk, Vol.140 (19), pp.596-604 78 Himatkumar V Patel, P S Fernandes and Kavita A Vyas (1990), “A novel synthesis of a few substituted s-triazolo[3,4-b][1,3,4]thiadiazoles and evaluation of their antibacterial activity”, Indian Journal of Chemistry, vol 29B, pp.135-141 79 Heravi M M., Rahimizadeh M., Seyf M., Davoodnia A., and Ghassemzadeh M (2000), “Bicyclic compound derived from 4-amino-3-mercapto-1,2,4triazoles: facile routes to 1,2,4-triazolo[3,4-b][1,3,4]thiadiadiazoles and 1,2,4triazolo [3,4-b]1,3,4]thiadiazines”, Phosphorus, Sulfur Silicon, Relat Elem., Vol 167, pp 211 80 Hodge C N., Fernadez C H., Jadhav P K., Lam P., PCT Int Appl WO 1994, 94, 22840 Chem Abstr 1995, 123, 33104 81 Hoggarth E (1952), “2-Benzoyldithiocarbazinic acid and related compounds”, J Chem Soc., pp 4811-4817 82 Holla B S., Akberali P M., Shivananda M K (2001), “Studies on nitrophenylfuran derivatives: Part XII Synthesis, characterization, antibacterial and antiviral activities of some nitrophenylfurfurylidene-1,2,4-triazolo[3,4-b]1,3,4-thiadiazines”, Il Farmaco, Vol.56, pp 919-927 Holla B S., Gonsalves R., Shenoy S (1998), “Studies on some N-bridged heterocycles derived from bis-[4-amino-5-mercapto-1,2,4-triazol-3-yl]alkanes”, Il Farmaco, Vol 53, pp 574 – 578 Holla B S., Kalluraya B., and Sridhar K R (1988), “Studies on nitrofuran heterocycles Part I: synthesis and antibacterial activity of 7H 6-(5-nitro-2furyl)-s-triazolo[3,4-b]-1,3,4-thiadiazines”, Rev Roum Chim., Vol 33(3), pp 277-282 Holla B S., Kalluraya B., Sridhar K R., Drake E., Thomas L M , Bhandary K K., Levine M J (1994), “Synthesis, structural characterization, crystallographic analysis and antibacterial properties of some nitrofuryl triazolo[3,4-b]-1,3,4-thiadiazines”, European journal of medicinal Chemistry, Vol.29, pp.301-308 Holla B S., Poojary K N., Kalluraya B (1996), “Synthesis, characterization and antifungal activity of some N-bridged heterocycles derived from 3-(3- 83 84 85 86 128 87 88 89 90 91 92 93 94 bromo-4-methoxyphenyl)-4-amino-5-mercapto-1,2,4-triazole”, Il Farmaco, Vol 51, pp 793-799 Holla B S., Poojary K N., Rao B S., Shivananda M K (2002), “New bisaminomercaptotriazoles and bis-triazolothiadiazoles as possible anticancer agents”, European journal of medicinal Chemistry, Vol.37, pp.511-517 Holla B S., Sarojini B K., Rao B S., Akberali P M., Kumari N S., Shetty V (2001), “Synthesis of some halogen-containing 1,2,4-triazolo-1,3,4thiadiazines and their antibacterial and anticancer screening studies - Part I”, Il Farmaco, Vol 56, pp 565 – 570 Holla B S., Shivananda M K., Shenoy M S., and Antony G (1998), “Studies on arylfuran derivatives: Part VII Synthesis and characterization of some Mannich bases carrying halophenylfuryl moieties as promising antibacterial agents”, Il Farmaco, Vol 53, pp 531-535 Holla B S., Shridhara K., and Kalluraya B (1991), “Reaction of 3substituted-4-amino-5-mercapto-1,2,4-triazoles with chalcone dibromides and αbromochlcones”, Indian J Chem., Vol 30B(7), pp.672-675 Holla B S., Veerendra B., Shivananda M K., Boja Poojary (2003), “Synthesis characterization and anticancer activity studies on some Mannich bases derived from 1,2,4-triazoles”, European Journal of Medicinal Chemistry, Vol 38, pp 759 Hosur M C., Tahwar M B., Laddi U V., Bennur R S., and Bennur S C (1995), “Synthesis and antimicrobial activity of bridgehead nitrogen heterocycles: Reactions of 3-N-methyl/ethyl (or-methyl) morpholino/piperidino4-amino-5-mercapto-4(H)-1,2,4-triazoles”, Indian J Chem., Vol 34B, pp.707-712 Hugh Cairns, David Cox, Ken J Gould, Anthony H Ingall, John L Suschitzky (1985), “New antiallergic pyrano[3,2-g]quinoline-2,8-dicarboxylic acids with potential for the topical treatment of asthma”, Journal of Medicinal Chemistry, Vol 28(12), pp 1832-1842 Hui X P., Dong H S., Xu P F., Zhang Z Y., Wang Q., and Gong Y N (2000), “Heterocyclic systems containing bridged nitrogen atom: synthesis and antibacterial activity of 3-(2-phenylquinolin-4-yl)/3-(1-p-chlorophenyl-5methyl-1,2,3-triazol-4-yl)-s-triazolo[3,4-b]-1,3,4-thiadiazine derivatives”, J Chin Chem Soc., Vol 47, pp.1115-1119 129 95 Hui X P., Xu P F., Wang Q., Zhang Q., and Zhang Z Y (2001), “Synthesis and antibacterial activity of 3-(5-methylisoxazol-3-yl)−1,2,4-triazolo [3,4-b]-1,3,4-thiadiazine derivatives”, Chin J Chem., Vol.19, pp 991-995 96 Hui X P., Zhang L M., Zhang Z Y., Wang Q., and Wang F (1999), “Study on condensed heterocyclic compounds: Part XVIII-Synthesis of 6-(1-aryl-5-methyl-1,2,3-triazol-4-yl)-3-(4-pyridyl)-s-triazolo[3,4-b]1,3,4-thiadiazoles”, Indian J Chem., Vol 38B, pp 380-383 97 Husain M I and Kumar V (1992), “Synthesis and studies of 3-((2benzothiazolyl/benzimidazolyl/benzoxazolylthio)methyl) -1,2,4-triazolo(3,4-b) (1,3,4)thiadiazol-6-yl substituted phenyl as possible anthelmintics”, Indian J Chem., Vol 31B, pp 673-676 98 Ibrahim Y A., Elwaly A H M., and Fiky A E M (1994), “Stereospecific synthesis of 6,7-dihydro-5H-1,2,4-triazolo[3,4-b] [1,3,4]thiadiazines”, Heteroat Chem., Vol 5, pp 321-325 99 Invidiata F P., Simoni D., Scintu F., Pinna N (1996), “3,6-Disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles: synthesis, antimicrobial and antiviral activity, Il Farmaco, Vol 51(10), pp 659-664 100 Jain R., Jain S., Gupta R C., Anand N., Dutta G P., Puri S K (1994), “Synthesis of amino acid derivaties of 8-(4-amino-1-metylbutylamino)-6methoxy-4-substituted/4,5-disubstituted quinolines as potential tissueschizontocidal anti-malarial agents”, Indian J Chem., Vol 33B, pp 251-254 101 Jia G and Li Z (1996), “Synthesis of some new 4-amino-5-(N-methylarylsulfonamido)methyl-1,2,4-triazole-3-thiones and their derivatives”, Heteroat Chem., Vol.7, pp 263-267 102 Jin J Y., Zhang L X., Zhang A J., Lei X X., and Zhu J H (2007), “Synthesis and biological evaluation of some novel derivaties of 4-amino-3-(Dgalactopentitol-1-yl)-5-mercapto-1,2,4-triazole”, Molecules, Vol 12(8), pp.5961605 102a Joshi S., S., and Karnik A V (2006), “Rapid and efficient microware-assisted synthesis of 4-amino-3-mercapto-5-substituted-1,2,4-triazoles”, Indian Journal of Chemistry, Vol 45B, pp 1057-1059 103 Kalluraya B and Chimbalkar R (1995), “Synthesis and biological activity of some 3-substituted 7H-6-(6-bromo-3-coumarinyl)-s-triazolo[3,4-b][1,3,4]thiadiazines”, Oriental J Chem., 11(3), 242-245; Ref: C.A 125:167924 130 104 105 106 107 108 109 110 111 112 Kalluraya B., D’Souza A., and Holla B S (1994), “Reaction of 3substituted-4-amino-5-mercapto-1,2,4-triazoles with acetylenic ketones and αbromochlcones”, Indian J Chem., Vol 33B(11), pp 1017-1022 Kalluraya B., D’souza A., and Holla B S (1995), “Synthesis and structural characterization of some nitrothienyltriazolo[3,4-b]-1,3,4-thiadiazines”, Indian J Chem., Vol 34B (11), pp 939-943 Karegoudar P., Prasad D J., Ashok M., Mahalinga M., Poojary B., Holla B S (2008), “Synthesis, antimicrobial and anti-inflammatory activities of some 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles and 1,2,4-triazolo [3,4-b] [1,3,4]thiadiazines bearing trichlorophenyl moiety”, European Journal of Medicinal Chemistry, vol 43, pp.808 – 815 Katica C R., Vesna D., Vlado K., and Dora G M (2001), “Synthesis, antibacterial and antifungal activity of 4-substituted-5-aryl-1,2,4-triazoles”, Molecules, Vol 6(10), pp 815-824 Karegoudar P., Prasad D J., Ashok M., Mahalinga M., Poojary B., Holla B S (2008), “Synthesis, antimicrobial and anti-inflammatory activities of some 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles and 1,2,4-triazolo [3,4-b] [1,3,4]thiadiazines bearing trichlorophenyl moiety”, European Journal of Medicinal Chemistry, Vol 43, pp 808-815 Karthikeyan M S., Holla B S., Kumari N S (2007), “Synthesis and antimicrobial studies of novel dichlorofluorophenyl containing aminotriazolothiadiazines”, European Journal of Medicinal Chemistry, Vol 43(2), pp 309-314 Khalil M A., El-Sayed O A., El-Shamy H A (1993), “Synthesis and antimicrobial evaluation of novel oxa(thia)diazolylquinolines and oxa(thia)diazepino[7,6-b] quinolines”, Arch Pharm., Vol.326(8), pp 489-492 Chem Abstr 1994, 120, 270336w Kidwai K., Sapra P., Misra P., Saxena R K., and Singh M (2001), “Microwave assisted solid support synthesis of novel 1,2,4-triazolo[3,4-b]-1,3,4thiadiazepines as potent antimicrobial agents”, Biorg Med Chem., Vol (2), pp 217 Kritsanida M., Mouroutsou A., Marakos P., Pouli N., Garoufalias S P., Pannecouque C., Witvrouw M., and De Clercq E (2002), “Synthesis 131 113 114 115 116 117 118 119 120 121 122 and antiviral activity evaluation of some new 6-substituted 3-(1-adamantyl)1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles”, Il Farmaco, Vol 57, pp.253-257 Kukaniev M A and Shukurov S S (1994), “Reaction of cyanoacetic ester with 4-amino-3-mercapto-5-substituted-1, 2,4-triazoles”, Khim Geterotsikl Soedin., Vol 1, pp 137; C.A.,121, 157585 Labanauskas L., Bucinskaite V., Bucyte D., and Brukstus A (2004), “Synthesis of a novel heterocyclic system: 7-methyl-3-methylthio-7,8dihydro[1,2,4]triazolo[3,4-f][1,2,4]triazine”, Chem Heterocycl Compd., Vol 40, pp 125-126 Labanauskas L., Kalcas V., Udrenaite E., Gaidelis P., Brukstus A., Dauksas, V (2001), “Synthesis of 3-(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-5-thiol and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole derivatives exhibiting antiinflammatory activity”, Pharmazie, Vol 56, pp 617-619 Lawrence A Singer, Noland P Kong (1966), “Vinyl Radicals Stereoselectivity in Hydrogen Atom Transfer to Equilibrated Isomeric Vinyl Radicals”, J Am Chem Soc., Vol.88 (22), pp 5213-5219 Li M., Wen L R., Cao W., and Li G Q (2001), “Synthesis of 3-(alkyl or 3’chloro-phenyl)-6-pipemidic-s-triazolo[3,4-b]-1,3,4-thiadiazioles”, Qingdao, Huagong Xueyuan Xuebao 22(3), 215-217 Ref: C.A., 136, 401672 Liu X Y., Xu W F., and Hou N (2001), Acta Academica Med Shandong, Vol 39, pp 112-115 Martha De La Rosa cộng (2006), “Tri-substituted triazoles as potent non-nucleoside inhibitors of the HIV-1 reverse transcriptase”, Bioorganic & Medicinal Chemistry Letters, Vol 16, pp 4444–4449 Masso K and Hiroshi T (1986), Japan Patent, 21, 420 (1986); C.A., 64, 2097 Mekuskiene G., Gaidelis P., and Vainilavicius P (1998), “Synthesis and properties of 5-(4,6-diphenyl-2-pyrimidin-2-yl)-1,2,4-triazolin-3-thione and its derivatives”, Pharmazie, Vol 53, pp 94-96 Michael D Mullican, Michael W Wilson, David T Conner, Catherine R Kostlan, Denis J Schrier, Richard D Dyer (1993), “Design of 5-(3,5-di-tertbutyl-4-hydroxyphenyl)-1,3,4-thiadiazoles, -1,3,4-oxadiazoles, and -1,2,4triazoles as orally active, nonulcerogenic antiinflammatory agents”, Journal of Medicinal Chemistry, Vol 36(8), pp 1090-1099 132 123 124 125 126 127 128 129 130 131 Mitra, A.K.; Misra, S.K.; Patra, A (1980), “New synthesis of 3-alkyl coumarins”, Synth Commun., Vol.10, pp.915-919 Mohammed A., Abdel-Hamid N., Maher F., Farghaly A (1992), “Synthesis and antibacterial activity of certain quinoline derivatives”, Czech Chem Commun., Vol.57(7), pp.1547-1552 Mohamed A Al-Omar (2010), “Synthesis and antimicrobial activity of new 5-(2-thienyl)-1,2,4-triazoles and 5-(2-thienyl)-1,3,4-oxadiazoles and related derivatives”, Molecules, Vol 15, pp 502-514 Mohan J., Anjaneyulu G., and Kiran (1988), “Heterocyclic systems containing bridgehead nitrogen atom: synthesis of s-triazolo[3,4-b] [1,3,4]thiadiazole-6(5H)-thiones, s-triazolo[3,4-b][1,3,4]thiadiazin and related heterocycles”, Indian J Chem., Vol 27B, pp.128-131 Mohan J., Anjaneyulu G S R., Sudhir S., and Arora D R (1989), “Heterocyclic systems containing bridgehead nitrogen atom Reaction of p-bis(5-mercapto-4-amino-s-triazol-3-yl)-phenylene”, J Indian, Chem Soc., Vol 66, pp 330-301 Mohan J and Kumar V (1998), “Bridgehead nitrogen heterocyclic systems: synthesis and antimicrobial activity of s-triazolo[3,4-b] [1,3,4]thiadiazoles, s-triazolo[3,4-b][1,3,4]thiadiazines and striazolo[3′,4′:2,3]thiadiazino[5,6-b]quinoxaline”, Indian J Chem., Vol 37B, pp 183 Molina P., Kajarin M A., and De La Vega M J (1987), “Synthesis of 6,7-dihydro-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines by a C–C ring cyclization under mild conditions”, J Chem Soc Perkin Trans 1, pp 1853-1860 Naik A D., Annigeri S M., Gangadharmath U B., Revankar V K., Mahale, V B and Reddy V K (2002), “Anchoring mercapto-triazoles on dicarbonyl backbone to assemble novel binucleating, acyclic SNONS compartmental ligand”, Indian J Chem., Vol 41B, pp 2046-2053 Ned D Heindel, Jack R Reid (1980), “4-Amino-3-mercapto-4H-1,2,4triazoles and propargyl aldehydes: A new route to 3-R-8-Aryl-1,2,4-triazolo[3,4b]-1,3,4-thiadiazepines”, Journal of Heterocyclic Chemistry, Vol 17, pp 10871088 133 132 Neslihan Demirbas, Sengỹl Alpay Karaoglu, Ahmet Demirbas, Elif ầelik (2005), “Synthesis and antimicrobial activities of some new [1,2,4]triazolo[3,4b][1,3,4]thiadiazoles and [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazines”, Arkivoc 2005(i), pp.75-91 133 Nizamuddin; Gupta, M.; Khan, M H.; Srivastava, M K (1999), J Sci Ind Res., Vol 58, pp 538 134 Noriko Yamauchi, Hiroyuki Fujii, Akikazu Kakehi, Motoo Shiro, Masaki Kurosawa, Takeo Konakahara, Noritaka Abe (2008), “Facile synthesis of (2benzimidazolyl)-1-azaazulenes, (2-benzothiazolyl)-1-azaazulenes, and related compounds and evaluation of their anticancer in vitro activity”, Heterocycles, Vol 76, pp 617-634 135 Patil S A., Badiger B M., Kudari S M., and Kulkarni V H (1984), “Syntesis of 5-mercapto-4-amino-3-substituted 1,2,4-triazoles and their monoand bisulfide derivatives”, J Indian Chem Soc., Vol 61(8), pp.713-714 136 Pinna G A., Loriga G., Murineddu G., Grella G., Mura M., Vargiu L., Murgioni C., and Colla P.(2001), “Synthesis and anti-HIV-1 activity of new delavirdine analogues carrying arylpyrrole moieties”, Chem Pharm Bull, Vol 49, Issue 11, pp 1406-1411 137 Potts K T and Huseby R M (1966), “1,2,4-Triazoles XVI Derivatives of the s-triazolo[3,4-b][1,3,4]thiadiazole ring system”, J Org Chem., Vol 31, pp 3528-3531 138 Povelitsa, F D., Gural, A G (1973), “Antibacterial effect of furacriline on Brucella”, Antibiotiki Moscow, Vol 18(1), 71-74 Chem Abstr., 78, 93044 139 Prabhuswamy B and Ambekar Y S (1999), “Synthesis of linearly fused tetracyclic heterocycles through a novel base catalyzed intramolecular rearrangement involving scission of N-N bond”, Synth Commun., 29(20), 3487 140 Qiao R Z., Hui X P., Xu P F., Zhang Z Y., and Cheng D L (2001), “Microwave induced synthesis of 3-aryl-6-(6-/8-substituted 4-chloroquinoline-3yl) - s -triazolo [3,4-b] −1,3,4-thiadiazoles”, Chin J Chem., Vol 19, p.800-806 140a Raafat M Shaker, Ashraf A Aly (2006), “Recent trends in the chemistry of 4Amino-1,2,4-triazole-3-thione”, Phosphorus, Sulfur, and Sillicon, Vol.181, pp 2577-2613 134 141 142 143 144 145 146 147 148 149 150 151 Rajeswar R V., Rao M S., and Padmanabha R T V (1986), “A novel synthesis of thiazolyl, imidazothiadiazolyl, and thiadiazinyl-2H-1-benzopyran-2ones”, Collect Czech Chem Commun., Vol 51, pp 2214 -2221 Rani B R., Rahman M F., and Bhalerao U T (1991), “A facile one pot synthesis of 3-substituted 1,2,4-triazolo[4,3-b][4,1,2]benzothiadiazine-8-ones”, Org Prep Proceed Int., Vol 23, pp 157-162 Rao M S., Rao V R., and Rao T V P (1985), Sulfur Letters, Vol 4, pp 19 Rao M S., Rajeswar R V., and Padmanabha R T V (1986), Org Prep Proceed Int., Vol 18, pp 104 Raslan M A and Khalil M A (2003), “Heterocyclic synthesis containing bridgehead nitrogen atom: Synthesis of 3-[(2H)-2-oxobenzo[b]pyran3-yl]-s-triazolo[3,4-b]-1,3,4-thiadiazine and thiazole derivatives”, Heteroat Chem., Vol 14, pp 114-120 Reid J R., Heindel N D (1976), “Improved syntheses of 5-substituted-4amino-3-mercapto-(4H)-1,2,4-triazoles”, J Heterocycl Chem., Vol.13, pp.925-926 Ricardo Pộrez-Tomỏs, Beatriz Montaner, Esther Llagostera, Vanessa SotoCerrato (2003), “The prodigiosins, proapoptotic drugs with anticancer properties”, Biochemical Pharmacology, Vol 66, pp 1447–1452 Robba M and Lancelot J C (1984), “Etude des conditions d'acces au tetrazolo-1,2,3,4-[5',1':6,1]triazino-1,2,4-[4,5-b]indazole et au thioxo-3 triazolo1,2,4-[2',1':6,1]triazino-1,2,4-[4,5-b]indazole”, J Heterocycl Chem., Vol 21, pp 91-95 Sandstrom J and Wennerbeck I (1996), “Tautomeric cyclic thiones Part II Tautomerism, acidity and electronic spectra of thioamides of the oxadiazole, thiadiazole and thiazole groups”, Acta Chem Scand., Vol.20, pp 57-71 Sarva M C., Romeo G., Guerrera F., Siracusa M., Salerno L., Russo F., Cagnotto A., Goegan M., and Mennini T (2002), “[1,2,4]Triazole derivatives as 5-HT1A serotonin receptor ligands”, Biorg Med Chem., Vol.10(2), pp.313-323 Sauleau A and Sauleau J (2000), “Selective alkylation of aminomercapto-1,2,4-triazoles: Synthesis of aminonitriles and mercaptonitriles”, Phosphorus, Sulfur, Silicon, Relat Elem., Vol 167, pp 219-237 135 152 Shafiee A., Naimi E., Mansobi P., Foroumadi A., and Shekari M (1995), “Syntheses of substituted-oxazolo-1,3,4-thiadiazoles, 1,3,4-oxadiazoles, and 1,2,4-ttriazoles”, J Heterocycl Chem., Vol 32, pp 1235-1239 153 Shawali A S., Abdallah M A., Mosselhi M A N., and Mohamed Y F (2002), “Synthesis and tautomeric structure of 1,2-bis-(7-arylhydrazono-7H[1,2,4 ]triazolo [3,4-b ][1,3,4 ]thiadiazin-3-yl)ethanes”, Z Naturforsch B, Vol 57, pp 552- 556 154 Shiroki, M., Tahara, T., Araki, K (1975), Japan Patent, 75100096 Chem Abstr., 84, 59588k 155 Sengupta S K., Sahni S K., and Kapoor R N (1981), J Indian Chem., Vol 20A, pp 692 156 Shawali A S., Zeid I F., Abdelkader H., Elsherbini A A., and Altalbawy F M A (2001), “Synthesis, acidity constants and tautomeric structure of 7-arylhydrazono[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines in ground and excited states”, J Chin Chem Soc., Vol 48, pp 65-72 157 Shiba S A., El-Kamary A A., Shaban M E., and Atia K S (1997), “Reaction of bis-2,2-(3,1-benzoxazin-4-one)phenylene (m-) with some nitrogen nucleophiles: synthesis of new oxadiazole, triazole, pyrazole, pyrazolone and quinazolone derivatives”, Indian J Chem., Vol 36B, pp.361-365 158 Shukurov S S., Kukaniev M A., Bobgaribov B M., and Sabirov S S., Izv Akad Nauk SSSR, Ser Khim., 10, 2035 (1995); C.A., 124, 289363 159 Singh S P., Naithani R., Aggarwal R., and Prakash O (1998), “A facile [hydroxy(tosyloxy)iodo]benzene mediated synthesis of symmetrical triazolo[3,4-b]-1,3,4-thiadiazines”, Synth Commun., Vol 28, pp 3133-3141 159a Spalinska K., Foks H., Kedzia A., Wierzbowska M., Kwapisz E., Gebska A., Zilkolwska-Klinkozs M (2006), “Synthesis and antibacterial activity of substituted thiosemicarbazides and of 1,3,4-thiadiazole or 1,2,4-triazole dervaties”, Phosphorus, Sulfur and Silicon and the Related Elements, Vol 181(3), pp 609-625 160 Sridhara A M, Venugopala Reddy K R, Keshavayyac J., Chidananda B., Yaragola Prasad, Satish Kumar G., Vadiraja S.G., Prosenjit Bosea, Gouda S K., Peethambard S K (2010), “Synthesis and antimicrobial activity of phthalazine 136 161 162 163 164 165 166 167 168 169 170 substituted 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles and 7H-[1,2,4]triazolo[3,4b][1,3,4]thiadiazines”, Der Pharma Chemica, Vol (5), pp 201-211 Sun X W., Chu C H., Zhang Z Y., Wang Q., and Wang S F (1999), “Studies on condensed heterocyclic compounds XX Synthesis and antibacterial activity of novel 6-aryl-3-(1-p-chlorophenyl-5-methyl-1,2,3-triazol-4-yl)-striazolo[3,4-b]-1,3,4- thiadiazoles”, Pol J Chem., Vol 73, 1203-1208 C.A., 131, 199655 Sun X W., Zhang Y., and Zhang Z Y (1998), “Studies on condensed heterocyclic compounds XVII Synthesis of 6-(1-aryl-5-methyl-1, 2, 3-triazol-4yl)-3-phenyl-s-triazolo [3, 4-b]-1, 3, 4-thiadiazoles”, J Chin Chem Soc., Vol 45, pp 535 -538 Sun, Xiao-Wen; Zhang, Yan; Zhang, Zi-Yi; Wang Qin; Wang, Shu-Fang (1999), “Studies on condensed heterocyclic compounds Part 18 Synthesis of 6(1-aryl-5-methyl-1,2,3-triazol-4-yl)-3-(4-pyridyl)-s-triazolo[3,4-b]-1,3,4thiadiazoles”, Indian Journal of Chemistry, Vol 38B(3), pp 380-385 Sung K and Lee A R (1992), “Synthesis of [(4,5-disubstituted-4H1,2,4-triazol-3-yl)thio]alkanoic acids and their analogues as possible antiinflammatory agents”, J Heterocycl Chem., Vol.29, pp.1101-1109 The Merck Index (1996), 12th Edition, Merck Co Inc Whitehouse Station Tozkoparan B., Gửkhan N., Aktay G., Yeşilada E., Ertan M (2000), “6Benzylidenethiazolo [3,2-b]-1,2,4-Triazole-5-(6H)-ones Substituted with Ibuprofen: Synthesis, Characterization and Evaluation of Antiinflammatory Activity”, European journal of medicinal Chemistry, Vol.35, pp.743-750 Turan-Zitouni G., Kaplancikli Z A., Erol K., Kiliỗ F S (1999), “Synthesis and analgesic activity of some triazoles and triazolothiadiazines”, Il Farmaco, Vol.54, pp 218-223 Udupi R H., Kushnoor A and Bhat A R (1999), “Synthesis and antimicrobial, antitubercular activity of some substituted 1,2,4triazoles”, J Indian Chem Soc.,Vol 76, pp 461–468 Udupi R.H., Suresh G.V., Setty S.R and Bhat A.R (2000), “Synthesis and biological evaluation of 3-substituted 1-[2'(4”isobutylphenyl) propiononamido] 1,2,4-triazoles and their derivatives”, J Indian Chem Soc., Vol.77, pp.302-304 Vainilavicins P., Smicius R., Jakubkiene V., and Tunkevicius S (2001), “Synthesis of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3- 137 171 172 173 174 175 176 177 178 pyrimidinyl)-methyl-4-amino-1,2,4-triazole-3-thione and its reactions with polyfunctional electrophiles”, Monatsh Chem., Vol.132, pp 825831 Wu J., Liu X., Cheng X., Cao Y., Wang D., Li Z., Xu W., Pannecouque C., Witvrouw M., De Clercq E (2007), “Synthesis of novel derivatives of 4-amino3-(2-furyl)-5-mercapto-1,2,4-triazole as potential HIV-1 NNRTIs”, Molecules, Vol 12(8), pp.2003-2016 Xu P F., Zhang Z H., Hui X P., Zhang Z Y., and Zheng R L (2004), “Synthesis of triazoles, oxadiazoles and condensed heterocyclic compounds containing cinchopheny and studies on biological activity of representative compounds”, J Chin Chem Soc., Vol 51, pp 315-320 Yadawe M S., and Patil S A (1992), Indian J Heterocycl Chem., Vol 2, p.41 d[106] Yanchenko V A., Demchenko A M., and Lozinskii M O (2004), “6-Arylamino-3-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines: Novel Narylamidine structures”, Chem Heterocycl Compd., Vol 40, pp 516; C.A., 141, 379901 Ye X X., Chen Z F., Zhang A J., and Zhang L X (2007), “Synthesis and biological evaluation of some novel Shiff’s base from 1,2,4-triazole”, Molecules, Vol 12(6), pp 1202-1209 Yu J X., Liu F M., Lu W J., Li Y P., Tian L L., Liu Y T., Liu C., Cai M S., (1999), Gaodeng Xuexiao Huaxue Xuebao, 20(8), 1233; C.A., 131, 322875 Zhang L X., Zhang A J., Chen X X., Lei X X., Nan X Y., Chen D Y., and Zhang Z Y (2002), “Synthesis and biological activity of 3-(2furanyl)-6-aryl-1,2,4-triazolo[3,4-b]-1,3,4 –thiadiazoles”, Molecules, Vol 7, pp 681-689 Zhang Y., Sun X W., Hui X P., Zhang Z Y., Wang Q., and Zhang Q (2002), “Synthesis and antibacterial activities of 4-amino-3-(1-aryl-5methyl-1,2,3-triazol-4-yl) -5-mercapto-1, 2,4-triazoles/2- amino-5-(1-aryl-5methyl-1,2,3-triazol-4-yl)-1,3,4-thiadiazoles and their derivatives”, Chin J Chem., Vol 20, pp 168 -173 138 179 Zhang Z., Li M., Zhao L., Li Z., and Liao R (1993), “Synthesis of 3alkyl/aryl-6-(3’-pyridyl)-s-triazolo[3,4-b]-1,3,4-thiadiazoles”, Youji Huaxue, 13(4), 397-402 Ref: C.A 119, 271088 180 Zhang Z Y and Sun X W (1998), “s-Triazolo[3,4- b]-1,3,4-thiadiazole derivatives”, Heterocycles, Vol 48, pp 561-584 181 Zhang Z Y., Sun X W., Chu C H., and Zhao L (1997), “Studies on condensed heterocyclic compounds XVI Synthesis of 3-alkyl-6-(2,4dichlorophenoxymethyl)-s-triazolo [3,4-b] -1,3,4-thiadiazoles and 6,6-bis(3aryl-s-triazolo [ 3,4- b ] -1,3,4-thiadiazoles)”, J Chin Chem Soc., 44, 535-538 182 Zhang Z., Zhao L., Li M., Li Z., and Liao R (1994), Youji Huaxue, 14(1), 74; C.A., 121, 9267 183 Zhiwei Wang, Baogen Wu, Kelli L Kuhen, Badry Bursulaya, Truc N Nguyen, Deborah G Nguyen and Yun He (2006), “Synthesis and biological evaluations of sulfanyltriazoles as novel HIV-1 non-nucleoside reverse transcriptase inhibitors”, Bioorganic & Medicinal Chemistry Letters, Vol 16, pp 4174–4177 184 Zhongyi Wang, Haoxin Shi, Haijian Shi (2001), “Synthesis of chiral fused heterocyclic compounds containing 1,2,4-triazole ring”, Journal of Heterocyclic Chemistry, Vol 38, pp 355-357 185 Zou K H., Zhang, L X., Zhou S N., Zhang A J., Jin J Y., Yin P., (2006), “Synthesis and crystal structurea of 4-amino-3-(3-hydroxypropyl)-1H-1,2,4triazole-5(4H)-thione and 6-(4-biphenyl)-3-(3-hidroxypropyl)-7H-1,2,4triazolo[3,4-b][1,3,4]-thiadiazine”, Chinese J Struct Chem., Vol.25 (12), pp 1517-1523 Tiếng Đức 186 Nguyen Dinh Trieu und siegfried Hauptmann, (1973), “Zur Kondensation von β-chlovinylcarbonyl verbin dungen mit α-Mercaptocarbonsauren”, Zeitschrift fiir chemie, Vol 13(2), pp 57 187 Z Arnold und J Zemlicka, (1959), “Synthetis reaktionen von dimethylformamid III darstellung von β-chlorvinylaldehyden”, Collection Czechoslov Chem Commun, Vol 24, p 2378 – 2384 139 PHỤ LỤC 140 ... n? ?m g? ?n có hoạt tính sinh học phong phú nhiều ứng dụng y học Chính chúng tơi ch? ?n đề tài: ? ?Nghi? ?n cứu tổng hợp, cấu trúc hoạt tính sinh học s? ?? dị vòng ngưng tụ chứa O, S, N? ?? 25 CHƯƠNG THỰC NGHIỆM...Nhằm góp ph? ?n v? ?o nghi? ?n cứu hợp chất triazole, lu? ?n ? ?n này, ti? ?n hành nghi? ?n cứu tổng hợp s? ?? hợp chất dị vòng ngưng tụ chứa O, N, S 1,2,4-triazolo[3,4-b]-1,3,4-thiađiazole, 1,2,4-triazolo[3,4-b]-1,3,4thiađiazine,... 1,2-bis-(7-arylhiđrazono-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiađiazine-3-yl)etan (118) B? ?n cạnh đó, hợp chất (119) tổng hợp từ ph? ?n ứng (4) với bromomalononitril [24], ph? ?n ứng vũng (2) với 2-bromoxyclopentanon 2- bromoxyclohexanon α-haloxeton 2,4-đinitroclorobenzen pbenzoquinon