Investigating the scope of the pentafluorosulfanyl group in medicinal chemistry

Jose, Arathy (2021) Investigating the scope of the pentafluorosulfanyl group in medicinal chemistry. Doctoral thesis (PhD), University of Sussex.

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Abstract

This thesis focuses on developing SF5-substituted biologically active compounds or building blocks, often using microwave synthesis. SF5 is a fluorine containing functional group that has only recently been explored in medicinal chemistry due to lack of commercially available building blocks. Exploring its biological activities as well as expanding the repertoire of SF5 chemistry appeared necessary.
Chapter 2 explores the scope of SF5 in medicinal chemistry by incorporating it into known drugs, teriflunomide and leflunomide, HDHODH inhibitors. Affinity of the SF5 analogues towards HDHODH will be discussed and compared with the parent drugs’ affinity. In addition their potential as SARS-CoV-2 antivirals will be presented.
Chapter 3 contains a brief description of the development of a small library consisting of 3 and 4- SF5-substituted phenyl rings that are bonded to heterocycles including morpholine, piperidine, piperazine, and pyridine via an amide bond. Small libraries of novel compounds consisting of SF5, which is a bioisostere of the familiar trifluoromethyl group (CF3) and halogens, have been developed to improve commercial availability of SF5-containing building blocks. SF5 is often compared to the trifluoromethyl group and even dubbed as a ‘super trifluoromethyl group’ due to its superior lipophilicity, bulkiness, electronegativity, electron withdrawing properties, etc. A few compounds from this library have been contributed to the COVID Moonshot program, which is an initiative to accelerate the development of a COVID antiviral.
Chapter 4 describes the synthesis of a series of SF5 substituted oxindoles. Included in the series are two SF5 cognates of Semaxanib. Using molecular modelling and a radioactive kinase assay we compared activities of Semaxanib and its SF5 counterparts in the VEGFR2 binding site.
Chapter 5 explores SF5 as a bioisostere in 1,4 diazepines. We synthesised and compared bioisoteres of SF5- and the known Cl-analogues of diazepam and nordiazepam.
Chapter 6 concludes the thesis and describes future directions.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Chemistry
Subjects: R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine > RA0643 Communicable diseases and public health > RA0644 Individual diseases or groups of diseases, A-Z > RA0644.C67 COVID-19. Coronavirus disease 2019
R Medicine > RS Pharmacy and materia medica > RS0153 Materia medica > RS0400 Pharmaceutical chemistry
Depositing User: Library Cataloguing
Date Deposited: 14 Sep 2021 14:03
Last Modified: 14 Sep 2021 14:03
URI: http://sro.sussex.ac.uk/id/eprint/101694

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