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Identification of Leads against Chronic Obstructive Pulmonary Disease from natural and synthetic sources

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Field Value
 
Title Identification of Leads against Chronic
Obstructive Pulmonary Disease from
natural and synthetic sources
 
Creator Sengupta, Sayantan
 
Subject Cell Biology & Physiology
 
Description Asthma and chronic obstructive pulmonary disease (COPD) are significant and growing
global health issues. About 80–90% of all COPD cases worldwide are caused by
smoking. Emphysema is predominantly brought on by neutrophil elastase in COPD,
which results in the loss of lung tissue and the closure of tiny airways. When it comes to
the advancement of the disease in COPD patients, neutrophil elastase has become a
crucial target for therapeutic development. The Indian Sundarban regions are home to a
variety of mangrove plants, including Sonneratia apetala Buch.-Ham. Fruit and leaf
extracts have been demonstrated to alleviate the symptoms of cough and asthma, despite
the fact that the plant's fruits also include antibacterial, antifungal, antioxidant, and
astringent properties. This study aims to determine if fruit extracts of Sonneretia apetala
inhibit neutrophil elastase and so stop the advancement of lung emphysema caused by
neutrophil elastase. The IC50 of the hydroalcoholic extract of the fresh fruits of Sonneratia
apetala Buch.-Ham. (SAM) was calculated using the neutrophil elastase enzyme kinetic
test. The extract was standardised using gallic acid and ellagic acid as standards using the
new HPLC technique. The extract underwent additional LC-MS2 profiling to determine
the main phytochemicals and ten such compounds were identified. According to the
HPLC calibration, Sonneretia apetala crude extract (SAM) contains 53 g/mg of gallic
acid and 95 g/mg of ellagic acid. Human epithelial cells' in vitro morphological change
caused by elastase was likewise reversed by SAM, and the vitality was determined by an
MTT experiment which showed no toxicity of the herbal extracts. Furthermore, in the
mice model, neutrophil elastase-induced alveolar collapse was lessened by 10mg/kg
SAM. Thus, we discovered for the first time in this work that Sonneretia apetala fruit
extract (SAM) has the ability to both in vitro and in vivo block human neutrophil elastase. In a quest for novel synthetic neutrophil elastase inhibitors, we synthesised and
tested seven brand-new benzoxazinone derivatives. By using an enzyme substrate kinetic
assay and discovered that they were inhibitors of human neutrophil elastase. One of these
substances, PD05, became the most effective inhibitor with a lower IC50 compared to the
sivelestat control substance. ONO 6818 and AZD9668 are two well-known elastase
inhibitors. However, PD05 demonstrated a high binding affinity for human neutrophil
elastase (Kd=1.63nM) and a faster association and dissociation rate, and its interaction
with human neutrophil elastase was totally reversible. In vitro preclinical
pharmacokinetic investigations revealed a protein binding efficiency of 72%, a rapid
recovery rate, an aqueous solubility of 194.7μM, a low permeability, and a favourable
hERG. The chemical successfully inhibited elastase-induced rounding and retracted cell
morphology and cell cytotoxicity, per the experiments with human lung epithelial cell
lines. In a mouse model, neutrophil elastase-induced alveolar collapse can be decreased
by PD05. In conclusion, we show that the newly synthesised benzoxazinone derivative
PD05 has anti-elastase capability in situ, in vitro, and in vivo, making it a suitable option
for additional research as a COPD treatment.
 
Date 2022
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2865/1/Thesis_Sayantan_Sengupta_ID_No_8354%2D_Dr_Arun_Bandyopadhyay.pdf
Sengupta, Sayantan (2022) Identification of Leads against Chronic Obstructive Pulmonary Disease from natural and synthetic sources. PhD thesis, JADAVPUR UNIVERSITY.
 
Relation http://www.eprints.iicb.res.in/2865/