Starting from methyl-1,4-Dioxo-3-phenyl-3,4-dihydro-1H-phthalazin-2-yl-acetate (2) eighteen newly Phthalazine dione derivatives were synthesized. The starting material 2 was prepared by N-alkylation of 2-phenyl-2,3-dihydrophthalazine-1,4-dione (1) with ethyl chloro acetate under reflux over night. 2-(1,4-dioxo-3-phenyl-3,4dihydrophthalazin-2(1H)-yl)acetohydrazide (3) was prepared by hydrazinolysis of ester 2 with hydrazine hydrate under reflux. Monopeptide methyl-3-[2-(1,4-dioxo-3phenyl-3,4-dihydro-1H-phthalazin-2-yl)-acetylamino]-alkanoate 4a-c were prepared via azide coupling method by coupling of hydrazide 3 with different methyl ester of glycine, β-alanine and L-leucine respectively. The hydrazides 2-(1,4-Dioxo-3-phenyl-3,4-dihydro-1H-phthalazin-2-yl)-N-(2-hydrazinocarbonyl-ethyl)-amides 5a-c were prepared by hydrazinolysis of esters 4a-c with hydrazine hydrate respectively. Similarly; dipeptides methyl-3-[2-(1,4-Dioxo-3-phenyl-3,4-dihydro-1H-phthalazin-2yl)-acetylamino]-propionylamino-alkanoates 6a-i were prepared form coupling of methyl esters of glycine, β-alanine and L-leucine with hydrazides 5a-c via azide coupling method. Schiff's base hydrazones N-[2-(Arylidene-hydrazinocarbonyl)ethyl]-2-(1,4-dioxo-3-phenyl-3,4-dihydro-1H-phthalazin-2-yl)-amides 7a-i were prepared by condensation of hydrazides 5a-c with different aldehydes such as 4chlorobenzaldehyde, 4-methoxybenzaldehyde and 4-nitrobenzaldehyde.The anti-bacterial activities of the synthesized compound were screened in vitro against E.coli, Salmonella and Staphylococcus aureus with comparison to 2-phenyl-2,3-dihydrophthalazine-1,4-dione (1). The results showed that most compounds have activities against E.coli and a little compounds were sensitive to Salmonella but there 2 no significance response to Staphylococcus aureus. Also the anti-cancer activities were assayed and some synthesized phthalazinedione has high activity in inhibition of HEPG2 and MCF-7 cancer cell lines.
Nucleophilic Reactions of 9-Isopropyl-2,4-dimethoxy-7,12-dimethyl-3-(phenylsulfonyl)benzo[a]heptalene with Lithium Dialkylamides. -Treatment of the title compound (I) with lithium piperidide (II) leads to substitution of the two methoxy groups by piperidino substituents, whereas lithium diisopropylamide induces the formation of heptaleno-annulated dibenzothiophenes (V) and (VI). The mechanism of the latter reaction is discussed. -(EL RAYES, S.; LINDEN, A.; ABOU-HADEED, K.; HANSEN*, H.-J.; Heterocycles 82 (2011) 2, 1195-1202, http://dx.doi.org/10.3987/com-10-s(e)30 ; Org.-Chem. Inst., Univ. Zuerich, CH-8057 Zuerich, Switz.; Eng.) -R. Langenstrassen 28-102
A series of 25 compounds were synthesized based on structure modification of the model methyl 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoateas potent HDACIs.Saponification and hydrazinolysis of the model ester afforded the corresponding acid and hydrazide, respectively.The model ester was transformed into corresponding trichloroacetimidate or acetate by the reaction with trichloroacetonitrile and acetic anhydride, respectively. N-alkyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanamides and methyl 2-[(3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoyl)amino] alkanoates were obtained by the reaction ofcorresponding acid or hydrazide with amines andamino acid estersviaDCC and azidecoupling methods. Methyl 3-aryl-3-(4chlorophenyl)-2,2-dimethylpropanoates were obtainedin good yields and short reaction timefrom the corresponding trichloroacetimidate or acetate by the reaction with C-active nucleophiles in the presence of TMSOTf(0.1eq %)via C-C bond formation.
Methyl 2-(4-oxobenzotriazin-3(4H)-yl) alkanoates4a-c proved to be important intermediates for the preparation of some biologically interesting compounds containing the benzotriazinone ring system. Esters 4a-c were prepared by direct diazotization of methyl anthranilate followed by addition of amino acid esters hydrochloride in a one-pot strategy. An equivocal synthesis of methyl 2-(4oxobenzotriazin-3(4H)-yl) acetate 4a was achieved by alkylation of benzotriazin-4(3H)one with methyl chloroacetate on the basis of chemoselective reaction of heterocyclic amide with electrophiles. A series of N-alkyl-2-(4-oxobenzotriazin-3(4H)-yl) alkanamides7-8(a-h) and methyl 2-(2-(4oxobenzotriazin-3(4H)-yl)alkanamido)alkanoates (dipeptides) 9-10(a-d) were prepared via azide coupling from 4a-b. Esters 4a-b were converted into the corresponding hydrazides followed by condensation with aldehydes; 4-methoxybenzaldehyde, 4-dimethylamino benzaldehyde and arabinose to afford the corresponding hydrazone derivatives11-13. All the synthesized compounds were subjected to the molecular docking using MOE 2008-10 software as agonist for; E. coli Fab-H receptor and Vitamin D receptor for antibacterial and anticancer evaluation, respectively. The most pronounced strong binding affinity towards the target E. coli Fab-H receptor were compounds 7a, 11a, 11b,10a,10cand 12b. On the other hand, the most pronounced strong binding affinity towards the target Vitamin D receptor were compounds 3, 9c, 11a and 10d. The in vitro antibacterial activity of highest binding affinity docked compounds were tested against E. coli, Staphylococcus aureus and Salmonella spp. All the tested compounds gave effective positive results against E. coli with inhibitory zone of about 1.1 cm, while were inactive against Staphylococcus aureus and Salmonella spp. The in vitro cytotoxic activity of the highest binding affinity docked compounds were tested against human liver carcinoma cell line (HepG2) cancer cell lines. Many compounds showed potent cytotoxic activity with low IC 50 values, especially for 3(6.525µM) and 11a (10.97 µM), while for standard drug doxorubicin (5.8 µM).
Series of new synthesized biologically active phthalazinone derivatives were obtained. Starting from the amino acid methyl esters of 4-benzyl-1(2H)phthalazinone 2a,b which were synthesized from the aceto hydrazide of 4-benzyl-1(2H)-phthalazinone 1 via azide coupling method. The hydrazides 3a,b were prepared from hydrazinolysis of corresponding esters 2a,b. N-substituted-2-(4-Benzyl-1-oxo-1H-phthalazin-2-yl)-methyl-acetamide 4a-f and the dipeptides methyl {2-[2-(4-Benzyl-1-oxo-1H-phthalazin-2-yl)-acetylamino]-acetylamino}alkanoates 6a-c were obtained by the reaction of corresponding hydrazide 3a with amines and amino acid esters respectively via azide coupling method. Similarly; Nsubstituted -3-[2-(4-Benzyl-1-oxo-1H-phthalazin-2-yl)-acetyl amino] propionamide 5a-f and the dipeptides methyl{3-[2-(4-Benzyl-1-oxo-1Hphthalazin-2-yl)-acetylamino]-propionylamino} alkanoates 7a-c were obtained by the reaction of corresponding hydrazide 3b with amines and amino acid esters respectively via azide coupling method
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