Development of new drug leads against dynamin and for the treatment of infectious diseases

<p dir="ltr">Single target drug discovery has long been the main objective of pharmaceutical research. This approach has been successful in finding many single target drugs while avoiding adverse effects due to off-target interactions. However, this stance has been challenged in recent years. Many diseases, such as neurodegenerative and psychiatric disorders, metabolic/cardiovascular diseases, and cancer, have a multifactorial nature and treatment of these diseases requires modulation of multiple targets to restore the physiological balance and generate sufficient therapeutic efficacy. Polypharmacology is commonly referred to as the ability of small molecules to bind to more than one target and is a key element in drug discovery and development. Multi-targeting drugs offer an advantage compared to single-targeting molecules and are much more efficacious due to its cumulative efficacy at all of its individual targets making it much more effective towards treating these complex diseases. The polypharmacology paradigm has numerous applications, such as in drug repurposing where an already established drug is redeveloped for a new indication.</p><p dir="ltr">This thesis reports on the development of an extensive structure–activity relationship (SAR) analysis of the lead compound, Ceritinib (coded as DC– 01), through the systematic modification of three distinct regions of the compound – the sulfone moiety, the pyrimidine linker, and the terminal aromatic ring (Chapter 3). DC–01 is a compound currently in clinical use for the treatment of non-small cell lung cancer (NSCLC) as an anaplastic lymphoma kinase (ALK) inhibitor and have been identified to inhibit both dynamin I and endocytosis with remarkably promising potency. Modelling guided library development led to the synthesis of 66 DC–01 analogues. None of the analogues exhibited improved activity when compared to the lead compound. However, biological evaluation suggested the preference of bulky and hydrophobic groups attached in the sulfone moiety, as in 4–piperidinylsulfonyl 119 which has the highest exhibited dynamin inhibitory activity (IC50 = 90.4 μM).</p><p dir="ltr">The extensive literature and high potential of targets built around the pyrimidine moiety led to the expansion of new and possible medicinal applications and finding of new biological targets for the DC–01 analogues. This thesis also reports on the discovery of new leads towards the development of novel antigiardial agents (Chapter 5), potential antiparasitic candidates (Chapter 6), and new antimalarial drugs (Chapter 7). Preliminary screening of the initial DC–01 compound library identified three lead candidates – compounds 73, 82, and 99 – that enabled further derivatisation and SAR exploration through the systematic modification of three distinct regions of the compound – the sulfone moiety, the pyrimidine linker, and the terminal aromatic ring.</p><p dir="ltr">The SAR exploration of lead compound 82 (IC50 = 1.1–1.2 μM) for its anti-Giardia duodenalis activity elucidated the tolerance for substituents in the terminal aromatic ring and the substitution of the methyl to a chloro or nitro group in the pyrimidine linker. This led to the discovery of ten analogues that were active against Giardia duodenalis. Two analogues – 4–methoxyphenyl chloropyrimidine 176 and nitropyrimidine 180 – were highly potent with IC50 values of 0.1–0.2 μM, which is a 6–fold improvement from lead 82.</p><p dir="ltr">Investigations of lead compound 73 (IC50 = 0.19 μM) found the introduction of methyl and alkoxy groups in the terminal aromatic ring were favourable towards their anti–Toxoplasma gondii (T. gondii) activity. 21 analogues exhibited >50% percent growth inhibition against T. gondii proliferation, with nine analogues displaying potent anti–T. gondii IC50 values of <1.0 μM. The most potent analogue 4–methoxyphenyl 230 exhibited the highest inhibitory activity (IC50 = 0.12 μM) and is 1.6–fold more potent than lead 73.</p><p dir="ltr">The SAR development of two lead compounds, 73 (71% growth inhibition) and 99 (IC50 = 13.45 μM) for its antimalarial activity led to further identification of six analogues with increased potency compared to leads 73 and 99. The introduction of methoxy or thiomethyl group in the terminal aromatic ring and the replacement of chloro with methyl in the pyrimidine linker identified three analogues – 3–methoxyphenyl 299 (87% growth inhibition), 3–methylthiophenyl 301 (93% growth inhibition), and 3–methoxyphenyl methylpyrimidine 307 (78% growth inhibition) – with a 1.1– to 1.3–fold potency enhancement relative to lead 73. The introduction of bulkier substituents in the sulfone moiety gave three analogues – 4–piperidinylsulfonyl 322 (IC50 = 6.36 μM), 4–piperidinylsulfonyl 3–methylthiophenyl 325 (IC50 = 6.28 μM), and 4–azepanylsulfonyl 343 (IC50 = 10.03 μM) – exhibiting 1.3– to 2.1–fold improvement in potency compared to lead 99.</p><p dir="ltr">The work embodied in this thesis suggests there is a wide scope of structural derivatisation tolerated in DC-01 analogues as exhibited from their promising biological activity across different targets and is a viable starting point for the design and development of multi-targeting drugs.</p>