Drug discovery for Human Immunodeficiency Virus has resulted in life-saving therapies. However, retroviral resistance to antiretroviral therapy is an inevitable challenge; therefore, the continuous advancement of novel therapeutics is vital. The use of current combination therapy drugs has many complications such as poor bioavailability, toxicity, and undesired drug interactions and side effects. This study focuses on the dual-mode inhibition (competitive and associative) of retroviral HIV-1 protease by novel boronates. Recent studies have shown boron-modified inhibitors have a higher inhibitory affinity for HIV-1 protease than the corresponding non-boron analogs. The proposed cyclic 1,3-azaborine structures resemble scissile bond residues of the viral Gag-Pol polyproteins hydrolyzed by the protease. This work highlights the en-route synthesis of cyclic 1,3-azaborines via three distinct approaches. The target boronates have the potential for greater affinity towards the protease enzyme, increased bioavailability, and fewer adverse side effects. Furthermore, the proposed boronates will serve to expand molecular diversity, as well as organoboron chemistry in general.

Towards the synthesis of novel cyclic 1,3-azaborines, potential inhibitors of HIV-1 protease

ACS Spring 2022

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