Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages—erythrocytic, gametocyte, liver, and gamete activation stages—indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission‐blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time‐dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin‐sensitive and artemisinin‐resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum‐infected mice.

The catalytic asymmetric aza-Morita-Baylis-Hillman reaction using unactivated methyl acrylate is described. A simple Lewis acidic metal catalyst, such as La(OTf)(3), was not suitable for the reaction, but rare earth metal alkoxide/linked-BINOL complexes possessing bifunctional Lewis acid and Brønsted base properties efficiently promoted the reaction in combination with an achiral nucleophilic organocatalyst. The combined use of a La(O-iPr)(3)/(S,S)-TMS-linked-BINOL complex with a catalytic amount of DABCO promoted the aza-Morita-Baylis-Hillman reaction of a broad range of N-diphenylphosphinoyl imines. Products from aryl, heteroaryl, and alkenyl imines were obtained in 67-99% yield and 81-95% ee. It is noteworthy that isomerizable alkyl imines could be employed as well, giving products in 78-89% yield and 94-98% ee. Initial rate kinetic studies as well as kinetic isotope effect experiments using alpha-deuterio-methyl acrylate support the importance of both the nucleophilicity of La-enolate and the Brønsted basicity of a La-catalyst for promoting the reaction.

With over 200 million cases and close to half a million deaths each year, malaria is a threat to global health, particularly in developing countries. Plasmodium falciparum, the parasite that causes the most severe form of the disease, has developed resistance to all antimalarial drugs. Resistance to the first-line antimalarial artemisinin and to artemisinin combination therapies is widespread in Southeast Asia and is emerging in sub-Saharan Africa. The P. falciparum proteasome is an attractive antimalarial target because its inhibition kills the parasite at multiple stages of its life cycle and restores artemisinin sensitivity in parasites that have become resistant through mutation in Kelch K13. Here, we detail our efforts to develop noncovalent, macrocyclic peptide malaria proteasome inhibitors, guided by structural analysis and pharmacokinetic properties, leading to a potent, species-selective, metabolically stable inhibitor.

Dedicated to Professor E. J. Corey on the occasion of his 80th birthday Combining catalysts having different or similar properties is currently an important topic in catalysis development. [1] Various catalyst combinations, such as Lewis acid/Brønsted base, [2] Lewis acid/Lewis base, [3,4] Lewis acid/Brønsted acid, [5] Lewis acid/Lewis acid, [5] and transition metal/Lewis acid [6] have been developed to provide unique catalytic activities. Herein we describe a different class of combination catalysts, in which Brønsted base catalysis is assisted by a Lewis base catalyst ( Figure 1). A catalytic amount of Lewis basic bidentate phosphine oxide 1 effectively activated and modified the properties of Brønsted basic rare-earth metal aryloxide catalysts, switching the diastereoselectivity from syn to anti in the lanthanum-catalyzed direct Mannich-type reaction. The mechanistic studies, a preliminary trial in a catalytic asymmetric reaction, and the extension of the Lewis base/Brønsted base catalysis to Michael and nitroaldol reactions are also described.We recently reported an iPr-pybox/La(OAr 1 ) 3 (Ar 1 = 4-MeO-C 6 H 4 ) complex which catalyzed the syn-selective direct asymmetric Mannich-type reactions [7] of imines 2 [8] with trichloromethyl ketone 3 a, an ester donor equivalent (Table 1, entry 1). [9,10] During the mechanistic studies of the reaction, we found that the reaction did not proceed with either La(OAr 1 ) 3 alone (Table 1, entry 2,) or iPr-pybox alone (Table 1, entry 3). In addition, an electron-donating Me 2 N group appended to iPr-pybox, which is sterically similar to the standard iPr-pybox, significantly decreased the diastereoselectivity (Table 1, entry 4). On the basis of these results, we hypothesized that the pybox acts not only as a simple chiral ligand to provide a steric bias in the transition state, but also as a Lewis base to electronically modify the properties of the Brønsted basic La(OAr) 3 .[11] To test this hypothesis involving Lewis base assisted Brønsted base catalysis, we decided to search for a new catalyst system.

Treatment of tuberculosis (TB) currently takes at least 6 months. Latent Mycobacterium tuberculosis (Mtb) is phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill nonreplicating (NR) Mtb may shorten treatment when used in combination with conventional drugs. The Mtb proteasome (Mtb20S) could be such a target because its pharmacological inhibition kills NR Mtb and its genetic deletion renders Mtb unable to persist in mice. Here, we report a series of macrocyclic peptides that potently and selectively target the Mtb20S over human proteasomes, including macrocycle 6. The cocrystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by 6 dose dependently led to the accumulation of Pup-tagged GFP that is degradable but resistant to depupylation and death of nonreplicating Mtb under nitrosative stress. These results suggest that compounds of this class have the potential to develop as anti-TB therapeutics.