Diaryl Ureas As an Antiprotozoal Chemotype

Overview

Journal ACS Infect Dis

Specialties Infectious Diseases
Microbiology
Pharmacology

Date 2021 May 10

PMID 33971090

Authors

Derek A Leas

Austin G Sanford

Jianbo Wu

Monica Cal

Marcel Kaiser

Sergio Wittlin

Ryan M Hemsley

Elyssa B Darner

LeeAnna M Lui

Paul H Davis

Jonathan L Vennerstrom

Affiliations

Soon will be listed here.

Abstract

We now describe the physicochemical profiling, ADME, and antiparasitic activity of eight ,-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD values ranged from 2.5 to 4.5; kinetic aq. solubilities were ≤6.3 μg/mL, and plasma protein binding ranged from 95 to 99%. All of the compounds had low intrinsic clearance values in human, but not mouse, liver microsomes. Although no ,-diarylurea had submicromolar potency against , two had submicromolar potencies against and , and five had submicromolar potencies against . appeared to be the most susceptible to growth inhibition by this compound series. Most of the ,-diarylureas had antiprotozoal selectivities ≥10. One ,-diarylurea had demonstrable activity in mouse models of malaria and toxoplasmosis.

References

Rao S, Barrett M, Dranoff G, Faraday C, Gimpelewicz C, Hailu A . Drug Discovery for Kinetoplastid Diseases: Future Directions. ACS Infect Dis. 2018; 5(2):152-157. DOI: 10.1021/acsinfecdis.8b00298. View

Torres-Guerrero E, Quintanilla-Cedillo M, Ruiz-Esmenjaud J, Arenas R . Leishmaniasis: a review. F1000Res. 2017; 6:750. PMC: 5464238. DOI: 10.12688/f1000research.11120.1. View

Alterio V, Cadoni R, Esposito D, Vullo D, Di Fiore A, Monti S . Benzoxaborole as a new chemotype for carbonic anhydrase inhibition. Chem Commun (Camb). 2016; 52(80):11983-11986. DOI: 10.1039/c6cc06399c. View

Eaton M, Weiss L, Kim K . Cyclic nucleotide kinases and tachyzoite-bradyzoite transition in Toxoplasma gondii. Int J Parasitol. 2005; 36(1):107-14. PMC: 3109623. DOI: 10.1016/j.ijpara.2005.08.014. View

Wu J, Wang C, Leas D, Vargas M, White K, Shackleford D . Progress in antischistosomal N,N'-diaryl urea SAR. Bioorg Med Chem Lett. 2018; 28(3):244-248. PMC: 6026081. DOI: 10.1016/j.bmcl.2017.12.064. View

Kortagere S, Mui E, McLeod R, Welsh W . Rapid discovery of inhibitors of Toxoplasma gondii using hybrid structure-based computational approach. J Comput Aided Mol Des. 2011; 25(5):403-11. DOI: 10.1007/s10822-011-9420-6. View

Orhan I, Sener B, Kaiser M, Brun R, Tasdemir D . Inhibitory activity of marine sponge-derived natural products against parasitic protozoa. Mar Drugs. 2010; 8(1):47-58. PMC: 2817922. DOI: 10.3390/md8010047. View

Bevan C, Lloyd R . A high-throughput screening method for the determination of aqueous drug solubility using laser nephelometry in microtiter plates. Anal Chem. 2000; 72(8):1781-7. DOI: 10.1021/ac9912247. View

Anderson J, Sarantakis D, Terpinski J, Kumar T, Tsai H, Kuo M . Novel diaryl ureas with efficacy in a mouse model of malaria. Bioorg Med Chem Lett. 2013; 23(4):1022-5. PMC: 3746744. DOI: 10.1016/j.bmcl.2012.12.022. View

10.

Tonoli D, Furstenberger C, Boccard J, Hochstrasser D, Jeanneret F, Odermatt A . Steroidomic Footprinting Based on Ultra-High Performance Liquid Chromatography Coupled with Qualitative and Quantitative High-Resolution Mass Spectrometry for the Evaluation of Endocrine Disrupting Chemicals in H295R Cells. Chem Res Toxicol. 2015; 28(5):955-66. DOI: 10.1021/tx5005369. View

11.

Coteron J, Marco M, Esquivias J, Deng X, White K, White J . Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem. 2011; 54(15):5540-61. PMC: 3156099. DOI: 10.1021/jm200592f. View

12.

Popiel I, Gold M, Booth K . Quantification of Toxoplasma gondii bradyzoites. J Parasitol. 1996; 82(2):330-2. View

13.

Dong Y, Chollet J, Matile H, Charman S, Chiu F, Charman W . Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes. J Med Chem. 2005; 48(15):4953-61. DOI: 10.1021/jm049040u. View

14.

Sanford A, Schulze T, Potluri L, Hemsley R, Larson J, Judge A . Novel Toxoplasma gondii inhibitor chemotypes. Parasitol Int. 2017; 67(2):107-111. PMC: 5809185. DOI: 10.1016/j.parint.2017.10.010. View

15.

Ridley R, Matile H, JAQUET C, Dorn A, HOFHEINZ W, Leupin W . Antimalarial activity of the bisquinoline trans-N1,N2-bis (7-chloroquinolin-4-yl)cyclohexane-1,2-diamine: comparison of two stereoisomers and detailed evaluation of the S,S enantiomer, Ro 47-7737. Antimicrob Agents Chemother. 1997; 41(3):677-86. PMC: 163771. DOI: 10.1128/AAC.41.3.677. View

16.

Ingram-Sieber K, Cowan N, Panic G, Vargas M, Mansour N, Bickle Q . Orally active antischistosomal early leads identified from the open access malaria box. PLoS Negl Trop Dis. 2014; 8(1):e2610. PMC: 3886923. DOI: 10.1371/journal.pntd.0002610. View

17.

Cowan N, Datwyler P, Ernst B, Wang C, Vennerstrom J, Spangenberg T . Activities of N,N'-Diarylurea MMV665852 analogs against Schistosoma mansoni. Antimicrob Agents Chemother. 2015; 59(4):1935-41. PMC: 4356791. DOI: 10.1128/AAC.04463-14. View

18.

Zhang Y, Anderson M, Weisman J, Lu M, Choy C, Boyd V . Evaluation of Diarylureas for Activity Against Plasmodium falciparum. ACS Med Chem Lett. 2011; 1(9):460-465. PMC: 3019604. DOI: 10.1021/ml100083c. View

19.

McFarland M, Zach S, Wang X, Potluri L, Neville A, Vennerstrom J . Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity. Antimicrob Agents Chemother. 2016; 60(12):7017-7034. PMC: 5118980. DOI: 10.1128/AAC.01176-16. View

20.

Lombardo F, Shalaeva M, Tupper K, Gao F . ElogD(oct): a tool for lipophilicity determination in drug discovery. 2. Basic and neutral compounds. J Med Chem. 2001; 44(15):2490-7. DOI: 10.1021/jm0100990. View