Basic Informations

C.V

amira Kamal Mahmoud Ahmed Name: Beni-Suef Place of birth: 21-8-1990 Date of birth: Egyptian Nationality : Arabic-English Language : Pharmaceutical Science General specialization: Pharmaceutical Organic Chemistry Accurate specialization: mrmr_890@yahoo.com E-mail:? ____________ Personal account:

Master Title

Synthesis of Novel PyrazoloPyrimidine Derivatives of Expected Biological Activity

Master Abstract

This thesis comprises four chapters. The first one is an introduction that consists of a brief survey of the different methods to synthesize pyrazolo[3,4-d]pyrimidine derivatives and their anti-inflammatory activity. This chapter also includes biological view of inflammation and anti-inflammatory drugs. The second chapter deals with the aim of the work and schemes that have been carried out to get the target new pyrazolo[3,4-d]pyrimidine derivatives. The third chapter illustrates the theoretical discussion of the experimental work for the preparation of the precursor 5-amino-pyrazole-4-carbonitrile IIa&b through the reaction of ketene dithioacetal I with either phenylhydrazine or p-methylsulphonyl derivative, respectively. Cyclization of pyrazole to Pyrazolo[3,4-d]pyrimidine occurred through two different pathways. Fusion of IIa&b with either formic acid to yield Pyrazolo[3,4-d]pyrimidin-4-one IIIa&b or excess formamide to yield IVa&b. Chlorination of IIIa&b with phosphorus oxychloride yielded the chloro derivative Va&b. The ester derivatives VIa&b were accomplished either from chloro compounds Va&b and glycine ethyl ester hydrochloride or from the reaction of the amino compounds IVa&b and ethyl chloroacetate. Hydrazinolysis of the ester moiety in compounds VIa&b using hydrazine hydrate yielded the acetohydrazide VIIa&b. (Scheme1). Four pyrazolopyrimidine series were prepared with a substitution at position 4 from reaction of the acetohydrazide intermediates VIIa&b with a series of various aldehydes to yield hydrazones VIIIa-f. Condensation of VIIa&b with ethyl isothiocyanate or 4-substituted phenyl isothiocyanate derivatives furnished triazole-3-thiol derivatives IXa&b and Xa-f, respectively. Cyclization of the acid hydrazide VIIa&b with ethyl acetoacetate afforded the ethoxy pyrazole derivatives XIa&b. Heating of the acid hydrazide VIIa&b with an equivalent amount of CS2 and KOH gave XIIa&b bearing oxadiazole scaffold. (Scheme 2) Another new pyrazolopyrimidine series with a substitution at position 5 were prepared from the precursor IIb through direct cyclization with ethyl isothiocyanate or 4-substituted phenyl isothiocyanate derivatives gave XIIIa-d derivatives. Condensation of compound IIb with triethlorthoformate or triethylorthoacetate furnished XVa&b intermediates that further cyclized with hydroxyl amine hydrochloride, hydrazine hydrate or 4-substituted phenyl hydrazine hydrochloride derivatives to obtain XVIa&b, XVIIa&b, XVIIIa&b and XIX, sequentially. (Scheme 3) New tricyclic pyrazolopyrimidine derivatives were prepared starting by 4-imino-5-aminopyrazolopyrimidine derivative XVIIa. Triazepine derivatives XXa-d were obtained from reaction of XVIIa with ethoxyethylene derivatives. Reaction of XVIIa with various aldehydes yielded Schiff's base compounds XXIa-c. Thiourea derivative XXII was prepared by reaction of XVIIa with ethyl isothiocyanate. Triazolopyrazolopyrimidine derivative XXIII was obtained either from reaction of XVIIa with CS2 or 4-substituted phenylisothiocyanate derivatives. The structure elucidation of the new compounds was supported by elemental analysis, IR, 1H NMR, 13C NMR, mass spectral data in addition to 2D NMR [NOESY]. Also, a brief account of the docking study was explained through the binding conformations. Additionally, a theoretical discussion of biological anti-inflammatory activity in vitro and in vivo beside histopathological study for ulcerogenic liability and determination safety margin of the most active compounds was given. The fourth chapter consists of the experimental part of this work which contains the detailed procedures used for the synthesis of the new stating materials IIb, IIIb, IVb, Vb, VIa&b, VIIa&b and XVa&b and the target pyrazolopyrimidine compounds VIIIa-f, IXa&b, Xa-f, XIa&b, XIIa&b, XIIIa-d, XIV, XVIa&b, XVIIa&b, XVIIIa&b, XIX, XXa-d, XXIa-c, XXII and XXIII. In addition to the data obtained from the elemental and spectral analyses as well as their physical properties are given in this chapter. It also compromises docking procedure followed to know the proposed binding mode inside COX-2 active site, results obtained from carrageenan induced rat paw edema method for evaluation of anti-inflammatory activity. In addition to enzyme immunoassay (EIA) kit that utilized for evaluation of COX-2 inhibitory activity of the tested compounds compared with celecoxib, indomethacin and diclofenac sodium as standard drugs. Histopathological results, scoring of different pathological lesions caused by the tested compounds and compared with standard drugs was given in this chapter. Compound VIIIc showed the highest anti-inflammatory activity 96% compared to celecoxib 89% and (S.I. = 94.45) with similar gastro protective profile of celecoxib.

PHD Title

PHD Abstract