Studies On The Synthesis Of 2-propen-1-ones, 2-propenamides And Arylacyl Hydrazides And Their Antiparasitic Activities

Parasitic diseases remain serious endemic diseases in the world. Chemotherapeutical agents are still widely used therapeutically and prophylactically in the diseases. Antiparasitic drugs work in clinic through inhibiting different steps of the life cycle of parasites and drug resistance problem occurs frequently. In this thesis, we tried to do basic research on developing new antiparasitic drugs to inhibit the new drug targets of cysteine proteins falcipain and cruzain. Three kinds of compounds (E)- 1, 3 -diaryl-2-propen- 1-ones, (E)-N-a.ryl-3 -aryl-2-propenamides and arylacyl hydrazides were designed and synthesized by combining molecular modeling with chemical modification. All compounds were identified by 1H-NMR and MS. Their antimalarial and anticruzi activities were respectively tested by an assay of parasitemia of red blood cell quantitated through a fluorescence-activized cell sorter analysis and a high throughput screening system of the cysteine protease cruzain. A useful lead compound, N2, N2?bis(2-hydroxy-1-naphthyl- methylene)oxalyl hydrazide was found by Dr. Christing S. Ring in 1993 through a DOCK program search using a homology model as a template for falcipain. Then the derivatives of (E)- 1, 3 -diaryl-2-propen- 1-ones and arylacylhydrazides were preliminarily identified to have antiparasitic activities by lead optimization. Compound zl was the best active candidate in former research. Based on a known X-ray structure of cruzain, we studied the putative binding orientation of compound zl to the active sites of cruzain by DOCK program to achieve the further modification of hydrazides. 7 target hydrazides (zZ梲8) were designed and synthesized. Compound z7, N?(2, 3-dihydroxy ?-dimethylamino- 1 -naphthylmethylene)-3 -hydroxy-2-naphthoichydrazide, was obtained from a start material 2, 3-dihydroxynaphthalene through a seven-step reaction sequence including O-methylation, nitration, reduction, N-dimethylation, formylation, deprotection and condensation. Compound z7 gave better inhibition against cruzain with an IC50 value of 0.20 ~.tmol/L arid became one of the best active V 憕1 compounds in this project. Its anticruzain activity increased 2 times more than that of compound zl. The DOCK program was further proven to be a powerful tool not only in lead identification against a target enzyme, but also in lead optimization through chemical modification for the development of more potent inhibitors of the target enzyme. In an attempt to improve the synthesis of (E)-1, 3-diaryl-2-propen-l-ones, Claisen-Schmidt condensation was carried out by using an organic base 1, 8-diazobicyclo [5.4.0]undec-7-ene (DBU) as catalyst instead of sodium hydroxide. 12 compounds (cl挆c12) were prepared by the developed method with the yield range of 30~90%. In order to introduce combinatorial chemistry into the project of new drug research, a procedure of solid-phase synthesis for hydroxyl substituted (E)- 1, 3-diaryl-2-propen條-ones has been developed. 20 analogues (gk-g20) were given by the parallel synthetic method with reasonable yields. Most of them were less active against malaria. Compound (E)-1-(2, 4, 5-trifluorophenyl)-3-(2-chloro-quinolin-3-yl) -2-propen- 1-one (c3) had definite activity against cruzain with an IC50 value of 1 ~.tmo1/L. (E)-N-aryl-3-aryl-2-propenamides was the third group of inhibitors to b...