Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.731237
Title: Spirooxindoles derivatives as novel inhibitors of the respiratory syncytial virus
Author: Paradowski, Michael
ISNI:       0000 0004 6495 1171
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2017
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Abstract:
Respiratory Syncytial Virus (RSV) is an important pathogen that affects the lower respiratory track resulting in hospitalisation in infants and young children and is a significant cause of morbidity and mortality in the elderly and immunocompromised patients. The RSV F protein plays a crucial role in the life cycle of the virus and its entry into the host cells. Once the fusion has been initiated, it causes a series of conformational changes facilitating the fusion of the virus with the host's cellular membranes which eventually leads to releasing viral RNA strands into the host cells. Disruption of the viral envelop and in particular of the RSV F protein by small molecules has been shown to be efficacious in the treatment of RSV infection in rodent models. Small molecule inhibitors of the RSV fusion protein have been reported over the last 15 years and several compounds have progressed into early clinical development but none have reached the market. RV-39 had previously been reported as a RSV fusion inhibitor, exhibiting excellent in vitro antiviral activity in both the fusion and plaque reduction assays. Although RV-39 showed good stability in rat liver microsomes, the compound showed high clearance in human liver microsomes. Furthermore, RV-39 showed high plasma clearance and low bioavailability when progressed to a rat pharmacokinetic study. In this work, a series of novel 3,3'-spirocyclic oxindoles and aza-oxindoles were designed and synthesised as potential RSV fusion inhibitors, aiming to improve on human liver microsomes and on the pharmacokinetic profile of RV-39 in rat. Novel chemistry was established to synthesise the spirocyclic oxindoles and aza-oxindoles via a palladium catalysed -arylation of 2-bromo anilides as the key synthetic step. The scope of the reaction was explored, demonstrating that access to spirocyclic oxindoles could be obtained in good to excellent yield from readily available carboxylic acids and 2-bromo anilines. Conditions for the removal of the para-methoxybenzyl protecting group were optimised to enable the preparation of a series of analogues with potent antiviral activity against the RSV virus The novel compounds prepared demonstrated excellent antiviral potency in both the fusion and the plaque reduction cellular assays and also showed improved metabolic stability in human liver microsomes compared to RV-39. A selection of compounds was further profiled in in vivo rat pharmacokinetic studies and the preliminary results suggested that whilst the plasma clearance remained high, good half-life and significant improvement in bioavailability compared to RV-39 could be achieved across this novel series of compounds
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.731237  DOI: Not available
Keywords: QD Chemistry
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