Novel acyl carbamates and acyl / diacyl ureas show in vitro efficacy against Toxoplasma gondii and Cryptosporidium parvum

Kun Li, Gregory M Grooms, Shahbaz M Khan, Anolan Garcia Hernandez, William H Witola, Jozef Stec

Research output: Contribution to journalArticlepeer-review

Abstract

Toxoplasma gondii and Cryptosporidium parvum are protozoan parasites that are highly prevalent and opportunistically infect humans worldwide, but for which completely effective and safe medications are lacking. Herein, we synthesized a series of novel small molecules bearing the diacyl urea scaffold and related structures, and screened them for in vitro cytotoxicity and antiparasitic activity against T. gondii and C. parvum. We identified one compound (GMG-1-09), and four compounds (JS-1-09, JS-2-20, JS-2-35 and JS-2-49) with efficacy against C. parvum and T. gondii, respectively, at low micromolar concentrations and showed appreciable selectivity in human host cells. Among the four compounds with efficacy against T. gondii, JS-1-09 representing the diacyl urea scaffold was the most effective, with an anti-Toxoplasma IC50 concentration (1.21 μM) that was nearly 53-fold lower than its cytotoxicity IC50 concentration, indicating that this compound has a good selectivity index. The other three compounds (JS-2-20, JS-2-35 and JS-2-49) were structurally more divergent from JS-1-09 as they represent the acyl urea and acyl carbamate scaffold. This appeared to correlate with their anti-Toxoplasma activity, suggesting that these compounds' potency can likely be enhanced by selective structural modifications. One compound, GMG-1-09 representing acyl carbamate scaffold, depicted in vitro efficacy against C. parvum with an IC50 concentration (32.24 μM) that was 14-fold lower than its cytotoxicity IC50 concentration in a human intestinal cell line. Together, our studies unveil a series of novel synthetic acyl/diacyl urea and acyl carbamate scaffold-based small molecule compounds with micromolar activity against T. gondii and C. parvum that can be explored further for the development of the much-needed novel anti-protozoal drugs.

Original languageEnglish (US)
Pages (from-to)80-90
Number of pages11
JournalInternational Journal for Parasitology: Drugs and Drug Resistance
Volume14
Early online dateAug 25 2020
DOIs
StatePublished - Dec 2020

Keywords

  • Acyl carbamate
  • Acyl urea
  • Cryptosporidium parvum
  • Diacyl urea
  • Drug discovery
  • Toxoplasma gondii

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)
  • Parasitology

Fingerprint Dive into the research topics of 'Novel acyl carbamates and acyl / diacyl ureas show in vitro efficacy against Toxoplasma gondii and Cryptosporidium parvum'. Together they form a unique fingerprint.

Cite this