Structure-Activity Relationship Studies of Antimalarial Proteasome Inhibitors─Part II.

With increasing reports of resistance to artemisinins and artemisinin-combination therapies, targeting the proteasome is a promising strategy for antimalarial development. We recently reported a highly selective 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.

Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors.

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. , 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.

Macrocyclic Peptides that Selectively Inhibit the Proteasome.

Treatment of tuberculosis (TB) currently takes at least 6 months. Latent (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.

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

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.

Improvement of Asparagine Ethylenediamines as Anti-malarial -Selective Proteasome Inhibitors.

The proteasome (Pf20S) emerged as a target for antimalarials. Pf20S inhibitors are active at multiple stages of the parasite life cycle and synergize with artemisinins, suggesting that Pf20S inhibitors have potential to be prophylactic, therapeutic, and transmission blocking as well as are useful for combination therapy. We recently reported asparagine ethylenediamines (AsnEDAs) as immunoproteasome inhibitors and modified AsnEDAs as selective Pf20S inhibitors.

Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents.

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content.

1,2,5-Thiadiazolidin-3-one 1,1-dioxide-based heterocyclic sulfides are potent inhibitors of human tryptase.

We describe herein the design, synthesis, and in vitro biochemical evaluation of a series of potent, time-dependent inhibitors of the mast cell-derived serine protease tryptase. The inhibitors were readily obtained by attaching various heterocyclic thiols, as well as a basic primary specificity residue P(1), to the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold. The inhibitors were found to be devoid of any inhibitory activity toward a neutral (elastase) or cysteine (papain) protease, however they were also fairly efficient inhibitors of bovine trypsin.

Serendipitous discovery of an unexpected rearrangement leads to two new classes of potential protease inhibitors.

The pathogenesis of a range of human diseases arises from the aberrant activity of proteolytic enzymes. Agents capable of selectively modulating the activity of these enzymes are of potential therapeutic value. Thus, there is a continuing need for the design of scaffolds that can be used in the development of new classes of protease inhibitors.

Potential protease inhibitors based on a functionalized cyclic sulfamide scaffold.

Exploratory studies related to the design and synthesis of functionalized cyclic sulfamides (I) as potential inhibitors of proteolytic enzymes were carried out. The structural motif and three diversity sites embodied in the scaffold render it amenable to combinatorial parallel synthesis and the facile generation of lead discovery prospecting libraries. The scaffold was readily assembled starting with (DL) serine methyl ester, and a series of compounds was generated and screened against human leukocyte elastase.