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Inhibitors of the ‘point of no return’ in human immunodeficiency virus infectivity – discovery of novel antihuman immunodeficiency virus integrase compounds with dual mechanism of action
Although the global therapeutic response to human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has seen tangible progress, this viral pandemic continues to ravage many worldwide communities nevertheless. At least 34 million people in the world are infected with HIV and a few million additional HIV infections occur each year. Moreover, co-infection of HIV and tuberculosis (TB), and particularly multidrug-resistant (MDR)-TB, has taken the pandemic to a substantially elevated level of seriousness with significant increases in mortality. Although progress has been made in the field of anti-HIV active integrase inhibitors and their use in combination therapeutics against HIV/AIDS, some very significant challenges still remain to be surmounted with next-generation integrase inhibitors for HIV/AIDS. These include appropriate profiles with respect to phase I and II metabolism, minimizing adverse drug–drug interactions, cross-resistance issues and, very importantly, HIV co-infections involving drug-resistant infections. In our laboratory we have discovered a novel class of HIV integrase inhibitors, exemplified by 4-[5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1-yl)but-3-enamide (compound 2), which exhibits potent anti-HIV activity against a large and diverse set of HIV isolates. This drug displays low cytotoxicity and its resistance and related drug susceptibility data are also positive. Its profile with respect to phase I and II metabolic isozymes/isoforms of cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferase are very favourable, which is of significant advantage in drug–drug interaction issues. Preclinical studies in animals revealed a positive pharmacokinetic profile and no adverse treatment-related findings. The ability to synthesize pure compounds of this family in very high yields, and therefore the potential for worldwide availability, is another positive aspect of this drug discovery. Finally, the most significant part of this drug discovery is the remarkable dual mechanism of action of these conceptually new small molecules against both HIV and MDR-TB.