Part A: Synthesis of N-heterocycles with dual pharmacology for the treatment of asthma The most common and effective anti-inflammatory asthma treatment is carried out through use of steroids but these can have significant side effects. An alternative non-steroidal oral treatment is montelukast which targets the leukotriene inflammatory pathway, but is less effective at controlling asthma symptoms. The asthma inflammation pathway is complex involving many inflammatory mediators, and it was anticipated that a compound with dual pharmacology which impacted both leukotriene and prostaglandin pathways simultaneously would yield compounds with an enhanced ability to treat asthma. An attractive novel dual target strategy was the inhibition of the 5-lipoxygenase activating protein (FLAP) and antagonism of the prostaglandin D2 receptor CRTh2. A combination of GlaxoSmithKline and literature SAR studies were elaborated in the design of the target compounds, incorporating known pharmacophores for FLAP inhibitors and CRTh2 antagonists. Synthetic routes towards the target compounds were developed and their biological activity against the intended targets determined. Part B: Synthesis of tetrahydroisoquinolines, tetrahydrobenzazepines and profens and their antimycobacterial properties Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis pathogen. The increasing prevalence of drug resistant strains of M. tuberculosis means there is an urgent need to develop new anti-TB drugs with novel modes of action. Aporphine alkaloid natural products and synthetic tetrahydroisoquinolines have demonstrated a specific antimycobacterial effect, as well as M. tuberculosis MurE inhibitory activity. The tetrahydroisoquinoline skeleton therefore provides a unique template for the development of new anti-TB drugs. Recently we developed biomimetic reaction conditions for the Pictet-Spengler condensation of aldehydes and amines into tetrahydroisoquinolines. The reaction is mediated by phosphate and proceeds under mild reaction conditions. The scope of the phosphate mediated Pictet-Spengler reaction was investigated in order to access novel alkaloid structures and identify new leads for mycobacterial growth inhibitors. Studies into asymmetric versions of the reaction using chiral phosphates and extending the reaction for the construction of larger ring sizes were explored. Another interesting class of compounds recently identified as active against mycobacterial growth were non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Analogues of profen compounds were synthesised for evaluation as mycobacterial growth inhibitors
