Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2023 May 22

PMID 37216489

Authors

Ho Shin Kim

Diana Ortiz

Tara Man Kadayat

Corinne M Fargo

Jared T Hammill

Yizhe Chen

Amy L Rice

Kristin L Begley

Gaurav Shoeran

William Pistel

Phillip A Yates

Marco A Sanchez

Scott M Landfear

R Kiplin Guy

Affiliations

Soon will be listed here.

Abstract

Leishmaniasis, a neglected tropical disease caused by species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides () that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead exhibited an 80% oral bioavailability and potently blocked proliferation of in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.

Citing Articles

Synthesis and biological evaluation of 4,7,9-trisubstituted benzoxazepines as antileishmanial agents.

Kadayat T, Kwiatkowski S, Ortiz D, Shoeran G, Hammill J, Kim H Bioorg Med Chem Lett. 2024; 114:130003.

PMID: 39477128 PMC: 11623309. DOI: 10.1016/j.bmcl.2024.130003.

References

Hwang J, Smithson D, Holbrook G, Zhu F, Connelly M, Kaiser M . Optimization of the electrophile of chloronitrobenzamide leads active against Trypanosoma brucei. Bioorg Med Chem Lett. 2013; 23(14):4127-31. DOI: 10.1016/j.bmcl.2013.05.049. View

Johnson T, Gallego R, Edwards M . Lipophilic Efficiency as an Important Metric in Drug Design. J Med Chem. 2018; 61(15):6401-6420. DOI: 10.1021/acs.jmedchem.8b00077. View

McGwire B, Satoskar A . Leishmaniasis: clinical syndromes and treatment. QJM. 2013; 107(1):7-14. PMC: 3869292. DOI: 10.1093/qjmed/hct116. View

Sundar S, Singh A, Rai M, Prajapati V, Singh A, Ostyn B . Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clin Infect Dis. 2012; 55(4):543-50. DOI: 10.1093/cid/cis474. View

Mowbray C, Braillard S, Glossop P, Whitlock G, Jacobs R, Speake J . DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis. J Med Chem. 2021; 64(21):16159-16176. PMC: 8591608. DOI: 10.1021/acs.jmedchem.1c01437. View

Aruleba R, Carter K, Brombacher F, Hurdayal R . Can We Harness Immune Responses to Improve Drug Treatment in Leishmaniasis?. Microorganisms. 2020; 8(7). PMC: 7409143. DOI: 10.3390/microorganisms8071069. View

Ponte-Sucre A, Gamarro F, Dujardin J, Barrett M, Lopez-Velez R, Garcia-Hernandez R . Drug resistance and treatment failure in leishmaniasis: A 21st century challenge. PLoS Negl Trop Dis. 2017; 11(12):e0006052. PMC: 5730103. DOI: 10.1371/journal.pntd.0006052. View

Patterson S, Fairlamb A . Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis. Curr Med Chem. 2018; 26(23):4454-4475. DOI: 10.2174/0929867325666180426164352. View

Sunyoto T, Potet J, Boelaert M . Why miltefosine-a life-saving drug for leishmaniasis-is unavailable to people who need it the most. BMJ Glob Health. 2018; 3(3):e000709. PMC: 5935166. DOI: 10.1136/bmjgh-2018-000709. View

10.

Sundar S, Jha T, Thakur C, Sinha P, Bhattacharya S . Injectable paromomycin for Visceral leishmaniasis in India. N Engl J Med. 2007; 356(25):2571-81. DOI: 10.1056/NEJMoa066536. View

11.

Gupta S, Yardley V, Vishwakarma P, Shivahare R, Sharma B, Launay D . Nitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasis. J Antimicrob Chemother. 2014; 70(2):518-27. DOI: 10.1093/jac/dku422. View

12.

Nagle A, Khare S, Kumar A, Supek F, Buchynskyy A, Mathison C . Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis. Chem Rev. 2014; 114(22):11305-47. PMC: 4633805. DOI: 10.1021/cr500365f. View

13.

Ortiz D, Guiguemde W, Hammill J, Carrillo A, Chen Y, Connelly M . Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. PLoS Negl Trop Dis. 2017; 11(12):e0006157. PMC: 5764437. DOI: 10.1371/journal.pntd.0006157. View

14.

Patrick D, Gillespie J, McQueen J, Hulverson M, Ranade R, Creason S . Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis. J Med Chem. 2016; 60(3):957-971. PMC: 5362113. DOI: 10.1021/acs.jmedchem.6b01163. View

15.

Thompson A, OConnor P, Marshall A, Yardley V, Maes L, Gupta S . 7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis. J Med Chem. 2017; 60(10):4212-4233. PMC: 7722354. DOI: 10.1021/acs.jmedchem.7b00034. View

16.

Patrick D, Wenzler T, Yang S, Weiser P, Wang M, Brun R . Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense. Bioorg Med Chem. 2016; 24(11):2451-2465. PMC: 4862372. DOI: 10.1016/j.bmc.2016.04.006. View

17.

Freeman-Cook K, Hoffman R, Johnson T . Lipophilic efficiency: the most important efficiency metric in medicinal chemistry. Future Med Chem. 2013; 5(2):113-5. DOI: 10.4155/fmc.12.208. View

18.

Cleghorn L, Albrecht S, Stojanovski L, Simeons F, Norval S, Kime R . Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei. J Med Chem. 2015; 58(19):7695-706. PMC: 4601051. DOI: 10.1021/acs.jmedchem.5b00596. View

19.

Van Bocxlaer K, Caridha D, Black C, Vesely B, Leed S, Sciotti R . Novel benzoxaborole, nitroimidazole and aminopyrazoles with activity against experimental cutaneous leishmaniasis. Int J Parasitol Drugs Drug Resist. 2019; 11:129-138. PMC: 6904836. DOI: 10.1016/j.ijpddr.2019.02.002. View

20.

Thompson A, OConnor P, Marshall A, Blaser A, Yardley V, Maes L . Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis. J Med Chem. 2018; 61(6):2329-2352. PMC: 5867678. DOI: 10.1021/acs.jmedchem.7b01581. View