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Novel N-, O- and S-substituted pyridyl-benzamides, -benzylamines and -sulfonamides were prepared by means of palladium-catalysed cross-coupling reactions. The synthetic approach, using Pd2(dba)3 as palladium source and rac-BINAP as supporting ligand, proved to be successful for C N, C O and C S cross-coupling reactions. One of the substrates underwent an unexpected nucleophilic aromatic substitution of fluorine, rather than the expected C N cross-coupling reaction.

The wastewater treatment process, besides discharging pharmaceuticals into the environment, has been found to result in the formation of a variety of undescribed compounds. Here we investigate the laboratory scale chlorination of the commonly used anti-HIV drug Nevirapine, characterise its disinfection transformation products (DTPs), and using liquid chromatography with high resolution mass spectrometry, screen environmental surface water for these DTPs. Chlorination of Nevirapine was scaled up, fractioned by preparative chromatography and the fractions were tested in vitro for toxicity and anti-HIV activity. Nevirapine was found to be resistant to degradation at relevant chlorination levels, which may partially explain its ubiquitous presence in South African surface water. During simulated chlorination, a variety of DTPs with varying properties were formed, some of which were detected in the environment, close to wastewater treatment plants. Interestingly, some of these compounds, although not as toxic as Nevirapine, retained antiviral activity. Further purification and synthesis is required to fully characterise these novel molecules.

The human immunodeficiency virus (HIV) pandemic remains a significant problem, especially in developing nations where the social and economic impacts are severe. Until a cure or vaccine for the disease is found, a constant supply of new compounds to fill the drug development pipeline is a requirement, given the tendency for the virus to rapidly develop resistance to current therapies. Here we disclose our efforts to improve upon the efficacy of cyclopropyl-indole derivatives developed as NNRTIs in our laboratories. To this end, modifications to the functionality occupying the small Val179 pocket have resulted in nearly two orders of magnitude increase in potency.