Quinolylhydrazones as novel inhibitors of Plasmodium falciparum serine protease PfSUB1

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 16; pp. 5317 - 5321
• Main Authors: Gemma, Sandra, Giovani, Simone, Brindisi, Margherita, Tripaldi, Pierangela, Brogi, Simone, Savini, Luisa, Fiorini, Isabella, Novellino, Ettore, Butini, Stefania, Campiani, Giuseppe, Penzo, Maria, Blackman, Michael J.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2012; Elsevier
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; antimalarials; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Egress; erythrocytes; Hydrazones; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrazones - pharmacology; Life Sciences & Biomedicine; Malaria; mechanism of action; Medical sciences; merozoites; parasites; PfSUB1; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - metabolism; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Science & Technology; screening; Serine protease inhibitors; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; serine proteinases; Structure-Activity Relationship; structure-activity relationships; Subtilisins - antagonists & inhibitors; Subtilisins - metabolism; Serine protease inhibitors; Hydrazones; Egress; Malaria; PfSUB1; RELEASE; 4-AMINOQUINOLINES; IDENTIFICATION; INVASION; DRUG DEVELOPMENT; MALARIA PARASITE; RED-BLOOD-CELL; HOST ERYTHROCYTE; Protozoa; Antimalarial; Apicomplexa; Protozoal disease; Serine endopeptidases; Enzyme; Enzyme inhibitor; Parasitosis; Infection; Peptidases; Antiprotozoal agent; Plasmodium falciparum; Hydrolases; Parasiticide; Hydrazone; Protease inhibitor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.06.023

Plasmodium falciparum subtilisin-like protease 1 (PfSUB1) is a serine protease that plays key roles in the egress of the parasite from red blood cells and in preparing the released merozoites for the subsequent invasion of new erythrocytes. The development of potent and selective PfSUB1 inhibitors could pave the way to the discovery of potential antimalarial drugs endowed with an innovative mode of action and consequently able to overcome the current problems of resistance to established chemotherapies. Through the screening of a proprietary library of compounds against PfSUB1, we identified hydrazone 2 as a hit compound. Here we report a preliminary investigation of the structure–activity relationships for a class of PfSUB1 inhibitors related to our identified hit.