Nghiên cứu tổng hợp cấu trúc và hoạt tính sinh học của các hợp chất tương tự flavon có chứa nhân dị vòng

DAI HOC o u c (;f A HA NAI BAO CAO KfiT QUA THUC HI$N Dfi TAI DAc BlfiT CA'P DHQG: 2001 - 200.1 Tôn dt Ml ã "NGHIEN CtJtJ T N G HOP, CAU TRUC VA HOAT TfNH SINH HOC COA CAC HOP CHAT TlTONG TV FLA VON, C6 CHtTA NHAN DI VONG" M&s6 : Chu i.hi«m d^ m: QG.01-02 GS TSKH Nguyin Minh Thdo Hh n6l- 2003 PHAN MO DAU MUC LUC Trang PHAN Md DAU ' Danh sdch nhChig ngUiVi tham gia dC tai Danh muc cac bang s6 li6u ^ Danh miic c^c hinh ^ TOM TAT NHUNG KET QUA CHINH ^ L Ke't qua v6 mat khoa hoc K6t qua phuc vu thuc te K6x qua dao tao K6'l qua niing cao tiOm luc khoa hoc Tmh hinh su dung kinh phi ABSTRACT PHAN N O I DUNG CHINH I DillvAiid^ II Tdng quan cac vA'n de nghien cuu 2.1 Ve pli.ln inij.' (.huven vj I rii*s 2.2 Ve cac xeton a (3-khong no 10 2.3 Vrti net v6 riavon va flavonoit 11 IIL Phuang phap nghien cuu va Ihuc nghiem 12 3.1 Pliuotig phap xac djnh cau tao tinh khiet yh hoat tfnh sinh hgc ciia cac hgp cliiit tdng hop dugc 12 3.2 Tdng hgp cac este ciia phenol va thuc hien phan ung chuyen vi Fries cua chiing 12 '5-3 HiU(/ng phap chung tdng hgp cac xeton a, \\- khAng no: 14 3.4 Pliuang phap chung tdng hgp cac hgp chat tuong tu ^.5 Hurtrng phap chung (dng hgp cac pira/olin thua nhan di vong: flavon 19 21 24 4.1 Axetyl hoa c^c phenol vh chuyen vj Fries cua chiing 24 4.2 Tdng hgp cdc xclon a \\- khOng no 25 4.3 Tdng hgp cac hgp chAt tuctng tir flavon co dura nhAn di vong 25 4.4 Tdng hgp cdc hgp chflft kieu pira/olin chi'fa nhrui

rmalit)ns Tlicn, the Fries rearrangement producls have been condensed in the conditions of ClaisenSchmidt reaction with indole- 3- andehydes or furfuraldehydes to give a, P- unsaturated ketones containing heterocyclic nucleus ( about 50 new compounds) The a, p- unsaturated ketones were cyclo-aditionaly transformed by Sulfur as an oxidizing reagent, forming about 40 new flavone analogs containing heterocyclic nucleus The a Punsaturated ketones also easily reacted with phenylhydrazine to form about 50 new derivatives of pirazoline ring The constitutions of the producls have been determined by using IR-, UV-, MS- and 'HNMR- spectroscopies, and the their antibiotic abilities have also been tested Some of them have shown good results and wc have been proposed to enlarge the research in order to dclerminc and developc the resulls Besides synthetic reactions Chemical Softwares, such as HypcrCiicm 7.0 have also been used lo help determining charge density, binding length, and binding energy of molecularly optimal confonnations and studying mechanisms of the reactions The anli-bacleria and anli-ycarst abilities of Ihc (X, \\~ unsaturated ketones and pyrazolines were tested Tlicse synthetic products have showed the biological activities m different levels Some considerable ones need more deeply studying >an phim thu dugc bang cdc phuong phap hien dai : hdng ngoai, tir ngoai, cong hudng tir proton va khdi lugng cung nhu sir dung cac phuong phap tinh hoa lugng tir gdn dung de xdc dinh mdi d(nniii.niii Ind Tndolyh.'^ o.ao/ : • ••> m ;UOmalie l l \ ' d l o ; ' ( n i I n m s m l o c l h y m n no X :h ' p i n h ' i i ;ii n W i l l i *> ' ' l ' ; d > I c : ' 11 NMK i A ,n! )|'-A,,; >i i d spetlm I l,.V»/»/v// 11 h o i i d n m A / ^ |/|[) ')K/ (k -n) The re.sidls ao- ui^-en ni i;d>le n The pirii/.olin p/indnch; c h r o m a lop',i a))li y r ' n l n i p m ! h.nl ^ \^ w n,niiiiip pn.mh, ,nid e l h \ n n h u n i h h n i d o rn K, \ m-, 1} d i l l on thm hi\ci n m 11 n m d m i f |5- un.salUliiled ki h nma T h e ab.SC'ntm n l p e a k - , , e h i i i ,n !ei m! h n i < n i i j i i ' a i h d ( ,11 h n n VI p j n t i p , vn-nthe e x i s l a n c e n n l k u l o n e ( in i i o n \ d p t n n p - AWII o h ' - e o ' d , hill p h n n * die h \ ' d i o \ N ' p n i | a \ | i|| , i p p c ; i r c d Oil t l i e I R s p e i l i i n | d u n e p i n i / t i i m ; W h i l e lln.: M A i i i I ul N I hom \ n n I | a o b o u d i / l i j ; l o ( " ;il "> > m i d ' ( d r ; l 12.5//:) -Speclrim (indole) nC j ) i i a / i d n i imp -, ' iipponnd aksn c x h i h i l e i l l m s p i i n n k d k^ I2.l('*ppilh an] ;; ^4 i.i \', ,i-, n n i ]>,, \ r t t mi id i h llm Ml lli NMR aimcdrimi NW nl n T !f Ip ' : i i , ! I* ) pmlmm n n , i l ' nl p n )h m hi n u h n ' nl ,• r d U - :i >* n( Ik .1 c /kn' pi n h n m al i > d ' , | I, Ik-odes, the I r/'ppm I I N i Ima nkihi 'a.cic c o i n p a l l M c \\ i l h i b o s c w i i l l e n i n " h o m c p-1 T h e m o l e c u k n i n n p e a k o ( ,X, nw o n - a , a pet 11 i i i i ! w ;m n h s ' \ c t i m , Consi.SlCJiee \ \ i l h i l s c v p e t i c d n n d \e.\e.i Applyinj; A M I ! •- " o \ h m h wiw in weiphl e a k i d ; i l i ( u i r | ina i p a l t n e e d i h e i h e d i a i i l i M i I i o n nk d i e i l o n i i e d c i m i l y okcharjii::; (lip,, li [(.9 Mn /' ;,, A : lins I , (M ( leid l-l e m ' I v I I IndoKh.^ )0 M e i l n hiukiiv I 2d':mm,lnid i N " I ; A\\ r; I k m / y l n i ' d n h d 2> N nm.ihvhndol '• I I'lmiiykiA m ken/\!iiid anldsK Icna piraxolin.s \\'-\n S-cpn: ahiciil i imd ' i 2\: : u ; ; r d : I o_'r.2 I i:::2 !:•;•.' ; ( i p / " dim: n \ / I' \eml.'.": At 7(i '^O 'I e\ \ I , pi ;|K2 90 j •r'2 •27 ! 2rh : f;.rh r9 i 17 d P2 liA- o \\- niahim- oniiein \ ,d j.io.k e-'^r- -m j ! I I ! I r:i I d'l I 'IIS i 0.7 I 2r| •n.Avco ,'n ml I nnh im'.eoinled inc.n v c n al knione' .md I h , c l ^ ' i i,i m l i \ i i i m hiin' -v n i l , niulnhi ( i o n ! - - ••! i VlMc d / o n / ' ; / !-a< minmm.NniO •.e,ii:l iind Comp mi inUA n • ' / / / / • o / ' ' ;.:;^a!m n d \ I X 2.N 20 ro/v, N ' M Ili\l \ '•• ,c,a \ b y d l vn,\ {i am ' ina ivai I nipn I kepnn V r' Ill he, o i ;^ n^ \\ i i I < '^ i o i : mi.'-,} \:\W 1, i m Tlu" • nan h n o • \ ir ; 20 • v IID h C'A 1!^ nhi ' h ', d l o 1 1 I1 '"• 2.i) I'd ; 19 Id 1( Id Id ; 20 20 s ; o i lin • ; ,i ! M ni i d :,., A O, ;: •!; i m ll •dc n.n I r k n - l i o n n o i n ,d,d^l • i2d.l' ,d, n, [,A w a(n;.nina ihinr c m d k !'in a I Ml h> M! I ^ j n ' ' I n a ' h l l e ,md de n I n 1;: o n : i h n '\A\^\ n 11m \\ !i-n',.ilm;iln,| 1, , | i ; n.a I i.>ii h ' I • , n h i m :, M n , - mid ;h i i A C h d c i C ! n i l A o ; ' /n i n i c h i \ h, ( C n i n n n i niln 20 • ih' iOt Itmini; j 20 •4.\\cn tl '• A.:.: \ nn.l h o ( l l l i h in I: r 11 20 17 IS '0 i Id 19 l i e n - h i u k ' h , ! ,- 2l1iOi;,l-\ , ! S him,2 i \ k ihvlnid-;., I ^ I ! \A i \ i e l i i v l n i d ' J ^ 20 !.''"• 20 hukdvr; ' ' \\ 20 •" ( I ' h e n s I N n ; rh_\ i n u k \ ! ,niJnhi ' •• l-l :o 2.2)0 ( i;< 2! (k.2(} eii\ ' a " t m u d i m i m d n l \ i-.^ \U\\ i'hnies nno !c> nm h hakdyh > - l \ ' i e l h ) I I I K U I I V I i \] ! !•' i t d m a ( d a n : n h n i.i n m I i i m i \ ' c i i al X, X; X, lied •'.a\ • n i ; , | lia\e ' ' 2;:i-''A2 ,.nin,'.na' p.-afol ' ami\i 24\ V, ] M v l c l h y l dA-h, ii/vinid(d' I with 1, M e i l p v l m k a ' v I - ! I'lKOyl y.A /,, ^ 2,kn I ) m m t | i \ tind(d\ ^) ! nin: r ' n l l ^ It' h O ' d i i ^ ' h I ! V I A 'Iiavcip N.Ya Rodbahi/nm TTWl p" r lerenccs A.Vk Vil^i^n^ , A V M;m:i-v C d - n n o i i , Y '/henp,, h i , c (n, ,„|^ ip,,\ .Shm/ncp-, K M M m / , C o m p C l i c m - , V o l 15, pp MdO d o |0 ( j 9 d ) N g u y e n M i n h T h a o N p n o n \ m N,mh I'lmm \ ,m i'lnnip C l m i i i Xdd dO N" ?>, pp.d.V-d6 (200?.) (U^ \ i hmiiu- a ) X.V d Mikeini;ni, V.M kJhh nicidNn^ A k laiy.n, \ A ! it\ i n d i i n 'd\hiin H c r e r o e y e k S o e d i n " , N"2 •: dn;: ^kd ! 9f2)) f ir,' R'ns'.iim) V k l i d n v e i i k o , I v d ' ()p mli' o ,!h k'.!' / \ ' d m a ! , ) i , \ ' k / , i k l m i i ) \ a ' d d i i m r ' a r m / I h " ' k 10, N'2 I I, ' r' " ' d ! / r ) ( i ; - d o i , M ! I ) ;• S Y N - i J i K S E S A N I > d t r \ N S i - m U N i , V M ( ) N Ok-S< :.•;:•: (^,(^ l:NSA'M!iiA'l'E':i>k!7r\j:SkR< [ I * C O i I R M A K l N !)!• p i \ A T I \ \ M > SNKOLS-: - A^ L n k : i ; Y i ) K s Ni:nye,, Minh ihao, i'hain Van ilm/iy, Hanoi S^k\i 7"/n' rcnclum n/ j)(d\pln'\plnnu pradih neid I wns mined ihc hues u-hieh ic.mlnni llm/: Ihe lun'c inyii im en\( sliu.lme /,,/- ,/ •.ene^ nilihn easily * indolvlp oi m mnnpnundsj ci ,dme\ hy ic': i cn< Hon .rul milivi\n\l ihiic', \ lA epidci mnl\{ I ,2 ili have h en d.-leiniiiicd hy Hy \IS and II NMR in'Siifpies / \ s AC knn\v , nnnr,' e n m p n n n d w i l h n u h \ I ; n n o p ll have :ik.n h n o i I [1011 '.ill ! p ' ,i( i, ,1 h,,e [nmm' dmi lb'/ o h m mm ( m u m n i i n i i m " 11 m m n ' nli llnn nm , • ' n ' ni (,'.,|l-nn.':alniide.l kelnnea n-.pcc i.ilh, I be i im'.a ip 10 hv i n n i o \ n I p m n \ ' a n , i m A n 'nil' ;.:,'icc' m d n i e d m n i c a o n l ) l i ( l i I C i e s ( h l O i h l i \ ' e 1, OA' pl n d i r ! 'w sonic A nimiivln irv /,, n, ,• / nmllivh pn>dn.- !:> i;,m, n cf un-cmie inc in e\, ! - >',/,/( :\ iula'im / m n , / / / , /', I'.scml •nnnnt\ \pei 'Inae.o, Univcrnly Xnan \IAl»\' \-vl / / , / r e l>,-cn lennA.^micA plnnivlhydrti rilCKC ynvc m,l inl.> A o el-l rrairanycinen: eaa.lcnsalnm wiih r. n n//n/ Ni^iiyrn , ,1 iimi,; m al 1 d n m i l l ' Anon.innip hnih ;; nv d c i tdc 111.1, d •- Willi \\)c niiplil pi\c •,\'nlllCM a , id I h i m d n i i i m l i n i l n l irmrniaiiiK.' n,I indole linps and d e l e p i n i i i e d d i e i i sliuAnr :; m i d h i n n e i i \ ' n m a X iita-tsd '/ l u d m w ihe In i c rormed o a d o , l e n o i a i I I I , d m ' h n l m p , • i d v i i n e, ^^';t^ n b h i i i i c d 'Cin I ,tii'.n'iiiv-in n l d i o a > i.n \)\ AO.-inot.nknra.iin o V l d A a v h ,: • ' In Il na \ , • av-inn! b\ I n m l Im '•) nn n n n m w h n h wam \ l i b Ci!i;o :.o'lnnccl;i!e m lln; r o i l o V ' ' i o A a, O A A I C ( n, I 11 ( >ll m ho n n M '.' 11 a n( I jl I )i >i -'• O •" *- 1;, I Mv I, I j Oh The prodnal h.td r c l b i e i i e e l l |, d i m dm a:mf i.n-hnm , ni.l ' i I k i f d : • p o n n o n,)ii' pCilka nim;.-f n i n i p , l^n A', j C , J , 7271 ( ' l k ( ; J i i n d I 1-9 r ; ni.l (Kl M I k ' •; , d m >A i In IR jo(.liiiin d.h;i o b s e m m l n an' • M d i h ) ( ) ' - l n,, n ^^• 175 ^js_,p m m rO)., !k, li.^' iTW mik n l ' : i^i dm h M ' - ( ) ) ( d l h i a p a h m i c - d n l n l e d o : 2.rA ,( d R C O ) ' 2! ,, , M - n i 'd l o i h d m n m ' [ ( Inaipe in ( I l - C r f,2>2 Ml ), • •pm l A i l l i ^ p n i c m i h n n n l i h m m i n p o i m d iP, ,., , • dcn.siM' m v i , I i c n V 1, ,• i n • • • - - • • •• : d i r i i ' ,.) i M ' < nhn M l ' nm [aok ! 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