New methods were developed to produce thiolated analogues of Mycobacteria
components. Thiolated tuberculostearic acid, (S)-18-mercapto-10-methyloctadecanoic acid, was firstly produced in seven steps in an overall yield of 7.6 %. This was followed by the first synthesis of a thiolated simple mycolic acid, the disulfide, ((2R,2' R,3R,3 'R)-2,2'-(disulfanediylbis(tetradecane-14,1-diyl))bis(3-hydroxyhenicosanoic acid, in 11 steps in an overall yield of 2.6 %. The first synthesis of a thiolated a-methyl-trans-cyclopropane methoxy mycolic acid was also achieved using the newly developed methods with the thiol
introduced at two different positions within the molecule. (S,S,S,R,S,R,2R,2R')-26-26' -Disulfanediylbis(2-( (R)-1-hydroxy-19-( (1S,2R)-2-( (2S, l 9S,20S)-19-methoxy-20- methyloctatriacontan-2yl)cyclopropyl)nonadecyl)hexacosanoic acid, which includes the thiolated disulfide at the end of the α-alkyl chain, was synthesised in 18 steps from
synthetically prepared starting materials in an overall yield of 2.6 %. (S)-2-((S)-1-Hydroxy-19-((1R,2S)-2-((2R, 19R,20R)-19-methoxy-20-methyloctatriacontan-2-yl)cyclopropyl)nonadecyl)-N-(2-((2-((R)-2-((R)-1-hydroxy-19-((1S,2R)-2-((2S, 19S,20S)-19-methoxy-20-methyloctatria-contan-2-yl)cyclopropyl)nonadecyl)hexacosanamido)ethyl)disulfanyl)ethyl)hexacosan-amide, which contains a thiolated linker on the carboxylic acid, was synthesised in two steps from the free synthetic mycolic acid in an overall yield of 8.7 %. The different methods attempted for the formation of the thiolated analogues are discussed.
To attempt to maximise the inhibitory effect of sterculic acid against Plasmodium falciparum Δ⁹ desaturase, which is essential for parasite growth, analogues of sterculic acid were designed and synthesised. 7-(2-Octyl-cycloprop-1-enyl)-heptanoic acid methyl ester and 9-(2-octyl-cycloprop-1-enyl)-nonanoic acid methyl ester which contain one more and one less carbon atoms than sterculic acid in their chain lengths respectively were both
synthesised in five steps in overall yields of 8 % and 4.6 % respectively. (±)-8-Methoxy-8-(2-octyl-cycloprop-1-enyl)-octanoic acid methyl ester was subsequently synthesised in three steps in an overall yield of 36 % whilst (±)-8-hydroxy-8-(2-octyl-cycloprop-1-enyl)octanoic acid methyl ester was also synthesised in three steps in an overall yield of 25 %. In four steps both (± )-8-(tert-butyldimethylsilyloxy)-8-(2-octyl-cycloprop-l-enyl)-octanoic acid methyl ester and (±)-8-acetoxy-8-(2-octyl-cycloprop-1-enyl)-octanoic acid methyl
ester were synthesised in an overall yield of 22.7 % and 34.9 % respectively. The
inhibitory effects of these analogues were investigated.