Repurposing human PDE4 inhibitors for neglected tropical diseases: Design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors

Abstract

A medicinal chemistry exploration of the human phosphodiesterase 4 (hPDE4) inhibitor cilomilast (1) was undertaken in order to identify inhibitors of phosphodiesterase B1 of Trypanosoma brucei (TbrPDEB1). T. brucei is the parasite which causes African sleeping sickness, a neglected tropical disease that affects thousands each year, and TbrPDEB1 has been shown to be an essential target of therapeutic relevance. Noting that 1 is a weak inhibitor of TbrPDEB1, we report the design and synthesis of analogs of this compound, culminating in 12b, a sub-micromolar inhibitor of TbrPDEB1 that shows modest inhibition of T. brucei proliferation.

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect

“…SAR study demonstrated that the presence of pyrazolopyridine 7-substituent can engender potency for the inhibition of PDE 4, and the isosteric imidazopyridine substitution made for the pyrazolopyridine subunit increases the well-balanced dual of PDE 3 and PDE 4. As a member of PDEs, Trypanosoma brucei PDB1 (TbrPDEB1) was described as a crucial target for the therapy of Human African trypanosomiasis [134,135], which was a parasitic disease caused by the protozoan pathogen T. brucei. Orrling and colleagues [136] explored catechol pyrazolinones as trypanocidals inspired from the structural motif rolipram.…”

Repurposing Human PDE4 Inhibitors for Neglected Tropical Diseases. Evaluation of Analogs of the Human PDE4 Inhibitor GSK‐256066 as Inhibitors of PDEB1 of Trypanosoma brucei

“…One of the advantages of this approach is the ability to launch optimization studies for new inhibitors with minimal upfront screening efforts. Indeed, our efforts to re‐optimize chemotypes related to piclamilast , cilomilast , and now GSK‐256066 for improved potency against TbrPDEB1 were launched by a broad assessment of 20 existing human PDE inhibitors . In this report, the SAR of the GSK‐256066 chemotype was elaborated in a rapid fashion and provided improved analogs such as 10a , 17a , 17t , 19a , 19c, and 24d .…”

Ensemble‐based ADME–Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

“…[5] In view of that, and in the absence of an effective vaccine, there is a continuous interest in the identification of new drug targets and the development of new drug candidates for the treatment of this disease. [10] Nevertheless, to the best of our knowledge, only a few reports describe the identification of novel CPBs inhibitors, [6,11,12] such as natural compounds (e.g., morelloflavones), [13] metal complexes, [14] and electrophilic warhead-based compounds (α-ketoheterocycles, thiosemicarbazones, semicarbazones, nitriles, aziridinyl peptides) [15][16][17] that covalently bind the cysteine thiolate of the active site, thereby inactivating the enzyme. [7,8] It is well known that the parasite cysteine proteases (CPs) are druggable targets as they are considered crucial for the survival and infectivity of Leishmania in its human host.…”