Synthesis and biological activity of conformationally restricted indole-based inhibitors of neurotropic alphavirus replication: Generation of a three-dimensional pharmacophore.

ABSTRACT: We have previously reported the development of indole-based CNS-active antivirals for the treatment of neurotropic alphavirus infection, but further optimization is impeded by a lack of knowledge of the molecular target and binding site. Herein we describe the design, synthesis and evaluation of a series of conformationally restricted analogues with the dual objectives of improving potency/selectivity and identifying the most bioactive conformation. Although this campaign was only modestly successful at improving potency, the sharply defined SAR of the rigid analogs enabled the definition of a three-dimensional pharmacophore, which we believe will be of value in further analog design and virtual screening for alternative antiviral leads.

SUBMITTER: Barraza SJ 

PROVIDER: S-EPMC8272561 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature