In view of this Gilbert IH [60] reported the screening of 62000 compound libraries against T. brucei. High through put screening (HTS) which resulted into identification of two novel compound series active against the enzyme trypanothione reductase. Series 1 was based on the quinoline scaffold (Figure 18a ) in which compound 2 (Figure 19a) with methylfuran group at R 3 position, Br at 6 th position of quinoline ring and N-methylethanamine group at R 1 position was the most potent and significant TR inhibitor with TR inhibitory activity of 1.1 µM. According to SAR study the replacement of methylfuran with other groups like furan, phenyl, pyridinyl, thiophene led to decrease in activity. Also the replacement of Br with H or F reduced the activity while Cl group retained the activity. At 4 th position the NH and NMe groups were equally active. The alkylamines at R 1 were active whereas the simple alkyl or aryl groups led to inactive compounds. The second series was based on the pyrimidopyridazine scaffold (Figure 18b) , in which the compound 49 ( Figure 19b ) showed promising inhibitory activity of 2.6 µM. In case of series 2 replacement of methyl group at R 1 position by H led to the decrease in activity. At R 2 position methyl and ethyl group showed activity while the H and chain extensions to propyl, butyl and cyclopentane led to decrease in activity. Substituted phenyl and alkenylphenyl group at R 3 position gave the most active compound of the series. Thus these quinoline compounds with promising activity could serve as lead compounds for further development of targeted drugs against African trypanosomiasis. In addition to this synthetic optimization study based on the lead anti-trypanosomal compound 1,2-dihydro-2,2,4-trimethylquinolin-6-yl 3,5-dimethoxybenzoate ( Figure 20 ) was undertaken by Werbovetz KA et al [61] in an attempt to discover new trypanocides with potent in vivo activity targeting TR enzyme. In course of this a total of 53 compounds were evaluated in vitro for their anti-trypanosomal activity and cytotoxicity. The compounds with oxygen atom at 6 th position were the most active compounds in the series, for example compound 9 ( Figure 21 ) showed better anti-trypanosomal activity (0.007 µM) and low cytotoxicity (6.8 µM) than melarsoprol (IC 50 = 0.008µM and cytotoxicity = 7.9µM). Whereas compounds lacking the 6-oxygen atom or bearing an oxygen atom at the 7-position rather than the 6-position were far less potent than those containing an alcohol or acyloxy group at the 6-position. Compounds carrying aliphatic or a 2-phenylacetyl ester side chains were as potent and selective as their benzoylated or acetylated counterparts. However compound 9a was unstable due to auto-oxidation, so the unstable alcohols were esterified to generate prodrug 10a ( Figure 21 ) having promising activity of 0.014µM against these parasites and a selectivity index of 1700. The in vivo evaluation of compound 10a in a murine model of African trypanosomiasis showed good results as the prodrug extended the lifespan of mice infected with T. b. brucei.