الفهرس 
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Abstract
The presented study is concerning with the design, synthesis and mechanistic study of new derivatives of benzimidazole bearing hydrazone, 1,2,4-triazole and 1,3,4-oxadiazole scaffolds IVa-t, Xa-j, VIa-d, XIIa-c, VII and XIII, respectively. The synthesized compounds were identified by different spectroscopic techniques and evaluated for different biological activities such as antibacterial, antifungal, and anticancer activities. Furthermore, molecular docking study was performed for the active benzimidazole derivatives as antifungal agents.
The thesis consists of the following parts:
1. Introduction
This section displayed certain synthetic routes for benzimidazole derivatives, biological activities of benzimidazole derivatives such as anticancer and the mechanism of action of these derivatives as anticancer agent, antimicrobial activity including antibacterial and antifungal activities, anti-inflammatory, antiprotozoal, antimalarial, antitubercular and antiviral activities. Moreover, the mechanism of action of different antifungal agents was also involved.
2. Aim of the work
It incorporated the research goals and the major purposes that directed the theoretical and practical work including; synthesis of novel benzimidazole derivatives by gathering the benzimidazole moiety in one compact structure with different aldehydes through Schiff base formation, with 1,2,4-triazole moiety and with 1,3,5-oxadiazole moiety aiming at synergistic activities. The synthesized compounds were evaluated for their antimicrobial activity, the molecular mechanism of antimicrobial and antifungal activities for final compounds was also involved. Moreover, molecular modeling and computational analysis of the most active final compounds were also included.
3- Results and Discussion
Chemistry part
In this part, various experimental methods and conditions of reactions adopted for the target compounds and the intermediates were discussed. Mechanism of formation of these final and intermediate compounds was also involved, Moreover, structural elucidations of the newly synthesized compounds were identified using infrared, 1H NMR, 13C NMR and elemental analyses techniques.
Biological study
This part illustrated the results obtained from the biological screening of synthesized compounds against various biological activities including:
1- Antimicrobial activity
Compounds IVa-t, Xa-j, VIa-d, XIIa-c, VII and XIII were evaluated for their antibacterial and antifungal activity against five bacterial strains: S. aureus (MRSA), K. pneumoniae, E. coli, P. aeruginosa and A. baumannii. Furthermore, the antifungal activity was screened against C. neoformans and C. albicans.
2- Cytotoxicity against human embryonic kidney cell line and hemolysis of human red
blood cells effects
Compounds IIIa, b, IVa, IVc, IVi, IVk, IVm, IVo, IVp, IVt and Xf were evaluated for their cytotoxicity against a human embryonic kidney cell line and hemolysis of human red blood cells. Most of tested compounds were non-toxic and safe.
3- Mechanism of action of compounds act as antifungals
3.1. Sorbitol Assay (Inhibition of fungal cell wall synthesis)
The MIC of IVa, IVi and IVk in the presence and absence of 0.8 M sorbitol was studied.
3.2. Ergosterol binding assay
This part is to investigate the ability of compounds IVa, IVi and IVk to form complex with ergosterol in the fungal cell membrane.
3.3. The Sterol Quantitation Method (SQM) by spectrophotometric assay
This part exhibited the effect of the tested compounds IVa, IVi and IVk on ergosterol biosynthetic enzymes including: (squalene epoxidase and lanosterol 14α-demethylase) resulting in reduction of ergosterol content.
3.4. Lanosterol 14α-demethylase (CYP51) inhibition activity
This part discussed the inhibitory activity of most active compounds IIIa, IVa, IVi and IVk on lanosterol 14α-demethylase (CYP51).
4- Anticancer activity
It included the screening results of final target compounds against NCI 60 cell line panels (six cell lines of CNS cancer, seven cell lines of colon cancer, six cell lines of leukemia, nine cell lines of lung cancer, six cell lines of ovarian cancer, eight cell lines of melanoma, eight cell lines of renal cancer, eight cell lines of breast cancer and two cell lines of prostate cancer) representing on full nine human systems as; melanoma, leukemia and cancers of colon, lung, breast, brain, ovary, prostate and kidney, according to their applied protocol. Compounds IVf, IVj and IVn selected for advanced five dose testing and showed potent antiproliferative activity.
Molecular Modeling
The molecular modeling study involved the essential binding features of the target compounds to lanosterol 14α-demethylase (CYP51) to realize the nature of the interaction with amino acid of CYP51 active site, a molecular modeling study was performed using crystal structure data for CYP51 (PDB: ID 5FSA) which is obtained from protein data bank and compared to the docking results of the parent co-crystallized ligand posaconazole.
In silico study analysis
Prediction of physicochemical properties, pharmacokinetic: ADME (absorption, distribution, metabolism, and excretion) and drug likeness score for the most active compounds were also performed and evaluated.
1.References:
This part included 164 references covering the period 1995-2020.