Design, Synthesis and Molecular Modeling Studies of Some Novel Trisubstituted Pyrazole Derivatives as Anticancer Agents

Abstract

In this thesis a new series of tri-substituted pyrazole derivatives was designed as anti-cancer agents and synthesized, starting by the formylation of semicarbazone via Vilsmeier-Haack reaction to give 3-(4-Bromophenyl)-1H-pyrazole-4-carbaldehyde 36 which was the precursor of compounds I-XIX. All the structures were confirmed by analytical and spectral measurements in addition to a single crystal X-ray study performed on compound VII confirming our proposed molecular structure. The new chemical entities were screened for their anti-cancer activity on various human cancer cell lines namely: hepatocellular carcinoma HepG2, breast cancer MCF7, lung carcinoma A549, prostatic cancer PC3 and colon carcinoma HCT116 at the National Research Centre (NRC, Egypt). Most of the synthesized compounds showed remarkable activity on the tested cell lines, especially compounds VId, VII and IX. The molecular modeling study was used to explain the synthesized compounds’ mechanism of action as potential B-Raf kinase inhibitors. The presented thesis comprises the following chapters: 1- Introduction:

It contains a survey covering the definition of cancer, its risk factors and etiology. This section also explains cancer therapeutic strategies, with a focus on protein kinases and a review on the B-Raf kinase inhibitory activity of pyrazole derivatives.

2- Rationale and design:

In this section a series of novel tri-substituted pyrazole derivatives was designed as potential B-Raf kinase inhibitors. Our design was based on the bioisosteric modifications of the reference compound after exploring the key interactions with the binding site. The different routes adopted for the preparation of the target compounds are outlined in schemes (1-3). 3- Results and Discussion:

This part contains the results and their theoretical discussions.

3.1. Chemistry:

Different methods of preparation used in the synthesis of the intermediate and final compounds were explained, in addition to their physical and spectroscopic elucidation.