Investigation of Molecular Properties of Antiretroviral Agents to Enhance CNS Penetration Abilities for the Treatment of Cognitive Impairment in HIV-Associated Neurocognitive Disorder.

HIV-associated neurocognitive disorder (HAND) can be represented by neurological and neuropathological abnormalities with a consequence of motor and cognitive loss. It has become a critical unmet medical need for infected people, and the number continues to rise every year. Pathological investigations have revealed its occurrence due to the release of free radicals from the HIV infected microglia and macrophages. So far, no effective clinical trials have been conducted for its treatment other than the use of some antiretroviral therapies which have failed to show good results due to poor CNS penetration and hence low CNS distribution. This collective information from the updated literature reports motivated us to share the idea of conjugated products of antiretroviral agents and antioxidants leading to better brain penetration abilities due to higher log p values, higher molecular weight and possibly low toxicity and better neuroprotective action. In this Viewpoint, we have attempted to analyze the chemical and pharmacological classes of antiretroviral agents (ARAs) and their clinical failures for the treatment of cognitive dysfunction due to HIV infection. As the causes of clinical insufficiency of antiretroviral agents and neuropathological mechanisms of HAND have been well established, it would be a good opportunity for medicinal chemists to develop new potential antiretroviral agents or to improve their molecular properties for better therapeutic implications. Furthermore, in silico based molecular properties have been investigated correlating them to the brain penetration abilities.