Basic Informations

C.V

Name: Shaimaa Gamal Ahmed
Nationality: Egyptian.
Telephone: 01092177812
E-mail: shaimaa_gamal146@yahoo.com
Current Mailing Address: Medicinal Chemistry Department, Faculty of Pharmacy Beni-Suef University.
Current Appointment: Demonstrator of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, present.

Master Title

Design and Synthesis of New Pyrazole Derivatives of Potential Anti-inflammatory Activity

Master Abstract

ABSTRACT Everyday scientific researches reveal the increasing significance of discovering newly anti-inflammatory agents with elevated safety margins to control cellular inflammatory response. The present work shows design and synthesis of several trisubstituted pyrazole derivatives VIIa-h, VIIIa-f, XIIa,b, XIIIa,b and XIVa-d. 4-Methanesulfonylphenylhydrazine hydrochloride III reacted with the appropriate acetophenone IVa,b to produce phenylhydrazine derivatives Va,b. Then, the formed compounds Va,b underwent Vilsmeier-Haack reaction to form carbaldehyde derivatives VIa,b which were considered as key intermediates for the preparation of compounds VIIa-h and VIIIa-f via reaction with the appropriate amine or ketone, respectively. Furthermore, oxidation of the carbaldehydes VIa,b afforded the corresponding carboxylic acids IXa,b which upon esterification followed by reaction with hydrazine hydrate produced compounds Xa,b and XIa,b, respectively. 4-Carbohydrazide derivatives XIa,b were used as second key intermediates for the synthesis of compounds XIIa,b, XIIIa,b and XIVa-d through reactions with CS2/KOH, ethyl acetoacetate or the appropriate aldehyde, respectively. Chemical structures of the newly synthesized compounds were characterized using spectral and elemental analyses. The prepared compounds were evaluated for their in vitro (SI range = 20.67 – 348.71) and in vivo (% edema inhibition range after 3 hours = 29.77 – 85.21) activities compared to the reference standard, celecoxib (SI = 308.163 and % edema inhibition after 3 hours = 74.02) with calculation of ED50 values. Also, ulcerogenic liability of the most active compounds VIId,f, VIIIb,e,f, XIIb, XIIIb and XIVb,d was evaluated. Finally, docking studies were performed for the most active compounds to determine their binding mode in the active site of the enzyme. This thesis consists of the following parts: 1- Introduction: This section presents a literature review about inflammation, anti-inflammatory targets, various biological activities of pyrazole nucleus and certain synthetic approaches for pyrazole derivatives. 2- Aim of the work: It includs the research objectives and the major aims that directs the theoretical and practical work. 3- Discussion: This part discusses several experimental methods and conditions of reactions adopted for the preparation of the designed compounds. Also, it deals with the confirmation of the newly synthesized compounds by different methods including microanalytical data, infrared, mass, 1H NMR and 13C NMR spectra. 4- Expermintal: This section shows the practical procedures used for the synthesis of the reported and newly synthesized intermediates as well as the new final compounds. In addition, it includes their spectral and microanalytical data. Synthesis of the following compounds was found to be essential for our study. Reported intermediates: (3 compounds) 1. 1-(1-(4-methoxyphenyl)ethylidene)-2-(4-(methylsulfonyl)phenyl)hydrazine (Va). 2. 1-(1-(4-bromophenyl)ethylidene)-2-(4-(methylsulfonyl)phenyl)hydrazine (Vb). 3. 3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carbaldehyde (VIb). Newly synthesized intermediates: (7 compounds) 1. 3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carbaldehyde (VIa). 2. 3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carboxylic acid (IXa). 3. 3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carboxylic acid (IXb). 4. Methyl 3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carboxylate (Xa). 5. Methyl 3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carboxylate (Xb). 6. 3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carbohydrazide (XIa). 7. 3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carbohydrazide (XIb). Newly synthesized final compounds: (22 compounds) 1. The first series included: 1. N-((3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)methylene)aniline (VIIa). 2. 4-chloro-N-((3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)methylene)aniline (VIIb). 3. 4-(((3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)phenol (VIIc). 4. 4-methoxy-N-((3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)methylene)aniline (VIId). 5. N-((3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)methylene)aniline (VIIe). 6. N-((3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)methylene)-4-chloroaniline (VIIf). 7. 4-(((3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)phenol (VIIg). 8. N-((3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)methylene)-4-methoxyaniline (VIIh). 2. The second series included: 1. 3-(3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-one (VIIIa). 2. 1-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)prop-2-en-1-one (VIIIb). 3. 1-(4-methoxyphenyl)-3-(3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)prop-2-en-1-one (VIIIc). 4. 3-(3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-one (VIIId). 5. 3-(3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-1-(4-chlorophenyl)prop-2-en-1-one (VIIIe). 6. 3-(3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (VIIIf). 3. The third series included: 1. 5-(3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-1,3,4-oxadiazole-2(3H)-thione (XIIa). 2. 5-(3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-1,3,4-oxadiazole-2(3H)-thione (XIIb). 4. The fourth series included: 1. 1-(3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carbonyl)-3-methyl-1H-pyrazol-5(4H)-one (XIIIa). 2. 1-(3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carbonyl)-3-methyl-1H-pyrazol-5(4H)-one (XIIIb). 5. The fifth series included: 1. N-benzylidene-3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carbohydrazide (XIVa). 2. N-benzylidene-3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carbohydrazide (XIVb). 3. N-(furan-2-ylmethylene)-3-(4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carbohydrazide (XIVc). 4. N-(furan-2-ylmethylene)-3-(4-bromophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-4-carbohydrazide (XIVd). 5- Biological screening: It involves the techniques used for in vitro and in vivo pharmacological evaluation of the finally synthesized compounds. In addition, all results of biological evaluation of finally synthesized compounds were listed in tables and illustrated with charts in comparison to standard reference, celecoxib. • In vitro screening: The ability of the newly synthesized compounds to inhibit both COX-1 and COX-2 activities was determined using COX colorimetric inhibitor screening kit. The finally synthesized compounds were evaluated for their COX inhibitory activity where they showed better selectivity towards COX-2 than COX-1. • In vivo screening: 1. Anti-inflammatory screening: The anti-inflammatory activity of the finally synthesized compounds was evaluated using "rat paw carrageenan edema" method. The compounds showed moderate to high anti-inflammatory activity compared to the standard celecoxib. Also, ED50 value was evaluated for the most active compounds relative to celecoxib. 2. Ulcerogenic liability: Ulcer index was calculated for the most active compounds compared to celecoxib and indomethacin. All compounds were less ulcerogenic than indomethacin and compounds VIIIb,e,f, XIIIb and XIVb were less ulcerogenic than celecoxib. The results proved the safety gastric profile of the newly synthesized compounds. 5- Molecular Docking 6- References: This part included 156 references covering the period 1901-2018. 7- Arabic summary

PHD Title

newer and safer agents to control cellular inflammatory response

PHD Abstract

In the present work, design and synthesis of several substituted diazepinoindolizines Xa-c and XIIa-c, diazepinopyrrolizines XIa-c, pyrrolizines XIIIa-c and XVa-c, indolizines XIVa-c and XVIa-c, pyrimidopyrrolizines XVIIa-c and pyrimidoindolizine XVIII were discussed. Reaction of the starting materials Va-c and VIa-c with chloroacetyl chloride, afforded the 2-chloroacetamido derivatives VIIa-c and VIIIa-c, which undergo intramolecular cyclization into diazepino [5,6-b]pyrrolizines IXa-c and diazepino[5,6-b]indolizines Xa-c which were alkylated with ethyl chloroacetate to give ethyl acetate derivatives XIa-c and XIIa-c. Reaction of 2-chloroacetamido derivatives VIIa-c and VIIIa-c with piperidine gave the 2-(piperidin-1-yl)acetamido derivatives XIIIa-c and XIVa-c. The target compounds XVa-c, XVIa-c, XVIIa-c and XVIII were obtained from the reaction of compounds Va-c and VIa-c with 4-nitrobenzaldehyde and triethyl orthoacetate. The rational for these compounds was discussed. Characterization of the chemical structure of the new compounds was done using spectral and elemental analyses.