Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

[Image: see text] With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes

Foreign capital inflow and economic growth in LDCs

The implications of foreign capital inflow are re-examined in a neoclassical model of economic growth (a la Chow-Zeng, Applied Economics Letters, 8, pp. 613–15, 2001). By following the definition of the steady state stock of aggregate capital, it is shown that under normal depreciation of foreign capital and the natural rate of growth of labour force, an inflow of foreign capital may or may not increase the per capita domestic capital and consumption of the host nation.