Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents

Abstract

Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease β-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 μM and 0.099 μM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.

Potent antiplasmodial extracts and fractions from Terminalia mantaly and Terminalia superba

“…Moreover, studies on their potential mechanisms of action revealed that phenolic compounds and derivatives are very active as enzymes inhibitors. Examples of such enzymes inhibited by phenolic compounds and derivatives are aspartic proteases, xanthine oxidase, 1,5-lipoxygenase, α-glucosidase, glucose-6-phosphate dehydrogenase, carbonic anhydrase and glutathione- S -transferase [ 26 , 30 , 31 ]. It is noteworthy that nowadays some of the abovementioned enzymes including aspartic proteases, glutathione- S -transferase are clearly identified as potential new targets for drug discovery against malaria and several others metabolic dysfunctions of public health significance including cancer, obesity, epilepsy and gout.…”

Synthesis and Antiplasmodial Activity of Novel Bioinspired Imidazolidinedione Derivatives

“…Meyers et al [ 21 ] identified spiropiperidine hydantoins as new leads for antimalarial drug discovery. Lead compound CWHM-123 (8-(5-chloro-2-hydroxybenzyl)-3-ethyl-1-isopentyl-1,3,8-triazaspiro[4.5]decane-2,4-dione) and its 4,5 dichloro analogue, CWHM-505, are potent antimalarials (IC 50 values against Plasmodium falciparum 3D7 of 0.310 μM and 0.099 μM) and the former features equivalent potency on the chloroquine-resistant Dd2 strain.…”

Synthesis and Antimalarial Activity of 1,4-Disubstituted Piperidine Derivatives

“…Studies have shown that compounds with piperidine rings [4,8,[21][22][23][24][25][26] have good selectivity and activity for the P. falciparum strain. This prompted us to assess their antiplasmodial activity against the chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of P. falciparum as well as their cytotoxic activity against HUVEC cells (Tables 3 and 4).…”

“…The 4-arylaminopiperidine is a structural moiety found in many alkaloids [4][5][6][7][8][9][10][11] and pharmaceutical products such as fentanyl and structurally-related analgesic opioids or H1-antihistamines agents such as bamipine [12][13][14][15][16][17] and neurokinin 1 (NK1) receptor antagonists [18][19][20]. Studies have shown that compounds with piperidine rings [4,8,[21][22][23][24][25][26] have good selectivity and activity for the P. falciparum strain.…”

“…Research is being pursued for the discovery of new antimalarials with less side effects, a faster onset of action and a better rate of response [4,8,[21][22][23][24][25][26]. In the process of searching for new small molecules interacting with the P. falciparum strain, we have identified the target compounds A with various R1, R2 and R3 substituents ( Figure 1).…”