Clotrimazole Scaffold as an Innovative Pharmacophore Towards Potent Antimalarial Agents: Design, Synthesis, and Biological and Structure–Activity Relationship Studies

• Published in: Journal of medicinal chemistry Vol. 51; no. 5; pp. 1278 - 1294
• Main Authors: Gemma, Sandra, Campiani, Giuseppe, Butini, Stefania, Kukreja, Gagan, Coccone, Salvatore Sanna, Joshi, Bhupendra P, Persico, Marco, Nacci, Vito, Fiorini, Isabella, Novellino, Ettore, Fattorusso, Ernesto, Taglialatela-Scafati, Orazio, Savini, Luisa, Taramelli, Donatella, Basilico, Nicoletta, Parapini, Silvia, Morace, Giulia, Yardley, Vanessa, Croft, Simon, Coletta, Massimiliano, Marini, Stefano, Fattorusso, Caterina
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.03.2008; Amer Chemical Soc
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Antifungal Agents - toxicity; Antimalarials - chemical synthesis; Antimalarials - pharmacology; Antimalarials - toxicity; Antiparasitic agents; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Clotrimazole - analogs & derivatives; Clotrimazole - chemical synthesis; Clotrimazole - pharmacology; Clotrimazole - toxicity; Cytochrome P-450 Enzyme Inhibitors; Drug Design; Female; Ferric Compounds - chemistry; Heme - chemistry; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Mice; Models, Molecular; Oxidoreductases - antagonists & inhibitors; Parasitic Sensitivity Tests; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plasmodium berghei - drug effects; Plasmodium chabaudi - drug effects; Plasmodium falciparum - drug effects; Protoporphyrins - chemistry; Science & Technology; Stereoisomerism; Sterol 14-Demethylase; Structure-Activity Relationship; OXIDATIVE STRESS; IN-VITRO; INHIBITION; HEME; PLASMODIUM-FALCIPARUM; RESISTANCE; SIMULATIONS; MALARIA PARASITES; CHLOROQUINE; GRIGNARD-REAGENTS; Antimalarial; Imidazole derivatives; Modeling; Pyrrolidine derivatives; Antiprotozoal agent; Antifungal agent; Plasmodium berghei; Structure activity relation; Chlorine Organic compounds; Molecular model; Semiempirical method; Chemical synthesis; Protozoa; Apicomplexa; Rodentia; Theoretical study; In vitro; Plasmodium chabaudi; In vivo; Vertebrata; Mammalia; Mouse; Animal; Parasiticide; AM1 method; Clotrimazole
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm701247k

We describe herein the design, synthesis, biological evaluation, and structure–activity relationship (SAR) studies of an innovative class of antimalarial agents based on a polyaromatic pharmacophore structurally related to clotrimazole and easy to synthesize by low-cost synthetic procedures. SAR studies delineated a number of structural features able to modulate the in vitro and in vivo antimalarial activity. A selected set of antimalarials was further biologically investigated and displayed low in vitro toxicity on a panel of human and murine cell lines. In vitro, the novel compounds proved to be selective for free heme, as demonstrated in the β-hematin inhibitory activity assay, and did not show inhibitory activity against 14-α-lanosterol demethylase (a fungal P450 cytochrome). Compounds 2, 4e, and 4n exhibited in vivo activity against P. chabaudi after oral administration and thus represent promising antimalarial agents for further preclinical development.