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Title: Polypharmacology approaches for treatment of idiopathic pulmonary fibrosis
Author: Maduli, Elvis
ISNI:       0000 0004 5993 2013
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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Idiopathic pulmonary fibrosis (IPF) is a severe lung disease with a poor survival rate and it currently has no known cure. In this thesis, the signs and symptoms, diagnosis and epidemiology of IPF are discussed. Existing therapies for IPF are highlighted herein as well as new small molecule targets such as acylidene oxindoles, isatins and natural products such as febrifugine. These novel compounds can potentially be used for polypharmacology approaches for IPF treatment. The preparation of isatin analogues has been explored with the motivation to screen them as potential treatments for IPF. Several types of biological and pharmacological activities are also associated with isatin derivatives which highlight their potential as novel drugs for the treatment of a number of diseases. Various methods for the synthesis of isatin have been reported which include early protocols involving aniline derivatives, the oxidation of indole, as well as more modern procedures employing transition metal catalysis. Previously reported strategies suffer from many disadvantages such as low yielding multi-step approaches and use of harsh conditions and toxic reagents which warrants a novel and much improved strategy. In this research, a palladium-catalyzed cyclization of o-alkynylnitrobenzenes has been employed for the synthesis of different isatin analogues. An alternative strategy was developed in which a copper-catalyzed cycloisomerization of oalkynylnitrobenzenes afforded 2-iodoisatogens in good yields. The corresponding isatins were then obtained via the reduction of the novel 2-iodoisatogens in a very efficient manner. In addition, alternative nitrogen-containing heterocycles have been prepared from 2-iodoisatogens to demonstrate the versatility of these substrates. Finally, the preparation of febrifugine analogues has been explored with the incentive to identify polypharmacological mixtures of molecules which could potentially be combined into a single molecule. Using the reported model for the binding of febrifugine with its target receptor site, different analogues were designed to interrogate binding and potentially improve biological activity.
Supervisor: Harrity, Joseph Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available