Structure–Activity Relationship Studies of Antimalarial Plasmodium Proteasome Inhibitors─Part II

Abstract

With increasing reports of resistance to artemisinins and artemisinin-combination therapies, targeting the Plasmodium proteasome is a promising strategy for antimalarial development.We recently reported a highly selective Plasmodium falciparum proteasome inhibitor with anti-malarial activity in the humanized mouse model. To balance the permeability of the series of macrocycles with other drug-like properties, we conducted further structure−activity relationship studies on a biphenyl ether-tethered macrocyclic scaffold. Extensive SAR studies around the P1, P3, and P5 groups and peptide backbone identified compound TDI-8414. TDI-8414 showed nanomolar antiparasitic activity, no toxicity to HepG2 cells, high selectivity against the Plasmodium proteasome over the human constitutive proteasome and immunoproteasome, improved solubility and PAMPA permeability, and enhanced metabolic stability in microsomes and plasma of both humans and mice.

Aza‐Heterocyclic Building Blocks with In‐Ring CF2‐Fragment

“…[216] Aside from Pd-assisted reduction benzyl protecting group can be removed with 2-chloroethoxycarbonyl chloride, though in lower yields of 644, as it was communicated in a patent disclosing derivatives to treat mycobacterial infections, [217] Mimura's work on (piperidinomethylene)bis(phosphonic acid) derivatives as antiosteoporosis agents [218] and the project for Plasmodium falciparum proteasome inhibitors. [219] N-Boc protection was also used in a couple of patents affording comparable yields for compound 644. [220,221] An approach to enantiopure (R)-3-Me-4,4-di-F piperidine (R-650) in 100 + g scale was reported in the patent on immune modulators (Scheme 111).…”