الفهرس 
Natural Product isatin and Drug DiscoveryOnly 14 pages are availabe for public view
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Abstract
Bacterial infections are account for the majority of hospital- and communityacquired infections. The rapid emergence of resistant bacteria to antibiotic has
further worsened the situation. In recent years, natural products considered to be
a great source of drug leads and provide great diversity of extracted compounds
with remarkable biological activity. Most compounds were isolated from natural
sources where isatin I and quinoline II (Figure 1) extracted from Couroupita
guianensis and Rutaceae displayed wide pharmaceutical applications. Many
literatures illustrate and investigate the biological importance of isatin and
quinoline derivatives by screening for their antibacterial activities, and some of
them demonstrated promising in vitro and in vivo potency. from this point, this
thesis presented synthesis of novel conjugates bearing isatin and quinoline
scaffolds and investigated their in vitro antibacterial activity in details.
The first chapter of the thesis presented an overview on the chemistry and
biological applications of isatin I, and quinoline II scaffolds.
The second chapter illustrated the synthetic pathways for the starting materials
and their target conjugates 10 and 11 (Figure 2) including the mechanism of their
formation as well as their characterization using different spectroscopic tools
such Fourier transform infrared (FT-IR), nuclear magnetic radiation (NMR) and
mass spectrophotometry (MS) where the data are in consistence with the expected
structures. Furthermore, in vitro antibacterial screening were evaluated against
Gram positive and Gram negative clinical isolates bacteria. Moreover, time kill
assay and anti-biofilm activity for synthesized conjugates were also assessed. In
addition, the mode of action for synthesized conjugates were reported using
transmission electron microscopy (TEM). Furthermore, structure activity
relationships (SARs) were discussed.
The third chapter illustrated the synthetic routes for the preparation of the starting
materials and the target conjugates as well as analytical data of the synthesized
intermediates and the targets. In addition, the operated methodology for the in
vitro antibacterial screening, time kill assay and antibiofilm assessment were
presented.
The following are the summary of the overall results Chemistry
Synthesis of N-bromobutyl isatin derivatives (3)
The starting N-bromobutyl isatin derivatives 3 was accomplished by the reaction
of isatin derivatives 1 with 1,4-dibromobutane 2 in presence of potassium
carbonate anhydrous as a base in DMF with stirring at room temperature to afford
3a, b with good yields as depicted 1.1. Synthesis of 4-bisamino quinoline derivatives 6 and 9
The preparation of 6a-c were obtained by the reaction of 4,7-dichloroquinoline 4
with excess aliphatic diamines or hydrazine 5a-c in DMF under reflux. In
addition, the product 8a-c was prepared in good yields by the reaction of 6a-c
with chloroacetyl chloride 7 in presence of potassium carbonate anhydrous in
DMF. Further reaction of 8a-c with excess hydrazine yielded 9a-c in good yields
as illustrated in Scheme 2. Synthesis of isatin –quinoline conjugates of 10 and 11
The afforded conjugates 10a-f and 11a-f bearing isatin and quinoline scaffolds
was achieved by the reaction of 3a,b with 6a-c or 9a-c in equimolar ratio (1:1) in
presence of triethyl amine in DMF under reflux condition to obtain the target
products 10a-f and 11a-f with good yields as depicted in Scheme 3.Structure elucidation of the synthesized conjugates 10 and 11
The establishment of the synthesized conjugates was affirmed using the different
spectroscopic methods as FT-IR, NMR and mass spectrophotometry (MS).
Table 1 illustrated in brief the spectral data for the appearance of characteristic
groups presented in synthesized conjugates.n vitro antibacterial activity
All tested conjugates against Gram-positive (MRSA and Streptococcus mutans)
and Gram-negative (Klebsiella pneumonia and Serratia marcescens) clinical
isolates. They showed significant biocidal activity with lower MIC than the
reference antibiotics. Conjugates 10a, 10b and 10f displayed the most potent
activity against all clinical isolates. The antibiofilm activity for all conjugates
were screened against the reference drug vancomycin using MRSA stain revealed
that all compounds have an inhibitory activity against the biofilm formation
where conjugate 11a showed 83.60% inhibition at 10 mg/mL. Moreover, TEM
studies were used to prove the mechanism of antibacterial action of conjugates
10a and 11a against the ultrastructure of (MRSA). The results confirmed that the
title conjugates caused the bacterial cell organelles to shrink by acting on the surface of the bacterial cell wall. Therefore, the designed conjugates can be used
as potential lead for further optimization to develop new antibacterial agent.
Conclusion
Isatin - quinoline conjugates 10 a-f and 11a-f were assembled by the reaction of
N-bromobutyl isatin derivatives 3 with bis aminoquinolines 6a-c and 9a-c in good
yields. The structures of the resulting conjugates have been established by
spectroscopic tools and the data are in agreement with the proposed structures. In
vitro antibacterial activity against Gram-positive (MRSA and Streptococcus
mutans) and Gram-negative (Klebsiella pneumonia and Serratia marcescens)
clinical isolates. All tested conjugates showed significant biocidal activity with
lower MIC than the reference antibiotics. Conjugates 10a, 10b and 10f displayed
the most potent activity against all clinical isolates. The antibiofilm activity for
all conjugates were screened against the reference drug vancomycin using MRSA
stain revealed that all conjugates have an inhibitory activity against the biofilm
formation where conjugate 11a showed 83.60% inhibition at 10 mg/mL.
Moreover, TEM studies were used to prove the mechanism of antibacterial action
of conjugates 10a and 11a against the ultrastructure of (MRSA). The results
confirmed that the title compounds caused the disruption of bacterial cell
membranes. Therefore, the designed conjugates can be used as potential lead for
further optimization to develop new antibacterial agents.