Synthesis and Biological Evaluation of 4,7,9-trisubstituted Benzoxazepines As Antileishmanial Agents

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2024 Oct 30

PMID 39477128

Authors

Tara Man Kadayat

Stefan Kwiatkowski

Diana Ortiz

Gaurav Shoeran

Jared T Hammill

Ho Shin Kim

Joanna Cholewo

Scott M Landfear

R Kiplin Guy

Affiliations

Soon will be listed here.

Abstract

Herein we report a series of antileishmanial analogues derived from 4-[(3,5-dimethyl-4-isoxazolyl)acetyl]-9-[(1-methyl-3-piperidinyl)methoxy]-7-(5-methyl-2-thienyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1), which was identified through a previously reported high-throughput phenotypic screen. The analogue series was designed, synthesized, and evaluated for antileishmanial activity to establish pharmacophore elements and preliminary structure-activity relationships as key steps in validating the series for further optimization. This study led to identification of the early lead compound 46, which exhibited sub-micromolar proliferation inhibitory activity against intra-macrophage L. mexicana amastigotes, modest selectivity towards host macrophages (J774A.1 line), and good aqueous solubility.

References

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

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

Nagle A, Biggart A, Be C, Srinivas H, Hein A, Caridha D . Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases. J Med Chem. 2020; 63(19):10773-10781. PMC: 7549094. DOI: 10.1021/acs.jmedchem.0c00499. View

Sindermann H, Engel J . Development of miltefosine as an oral treatment for leishmaniasis. Trans R Soc Trop Med Hyg. 2006; 100 Suppl 1:S17-20. DOI: 10.1016/j.trstmh.2006.02.010. 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

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

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

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

10.

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

11.

Fino R, Lenhart D, Kalel V, Softley C, Napolitano V, Byrne R . Computer-Aided Design and Synthesis of a New Class of PEX14 Inhibitors: Substituted 2,3,4,5-Tetrahydrobenzo[F][1,4]oxazepines as Potential New Trypanocidal Agents. J Chem Inf Model. 2021; 61(10):5256-5268. DOI: 10.1021/acs.jcim.1c00472. View

12.

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

13.

Shafi S, Afrin F, Islamuddin M, Chouhan G, Ali I, Naaz F . β-Nitrostyrenes as Potential Anti-leishmanial Agents. Front Microbiol. 2016; 7:1379. PMC: 5007854. DOI: 10.3389/fmicb.2016.01379. View

14.

Popp T, Tallant C, Rogers C, Fedorov O, Brennan P, Muller S . Development of Selective CBP/P300 Benzoxazepine Bromodomain Inhibitors. J Med Chem. 2016; 59(19):8889-8912. DOI: 10.1021/acs.jmedchem.6b00774. View

15.

Hammill J, Sviripa V, Kril L, Ortiz D, Fargo C, Kim H . Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents. J Med Chem. 2021; 64(16):12152-12162. PMC: 8404201. DOI: 10.1021/acs.jmedchem.1c00813. View

16.

Alcantara L, Ferreira T, Gadelha F, Miguel D . Challenges in drug discovery targeting TriTryp diseases with an emphasis on leishmaniasis. Int J Parasitol Drugs Drug Resist. 2018; 8(3):430-439. PMC: 6195035. DOI: 10.1016/j.ijpddr.2018.09.006. View

17.

Fox B, Beck H, Roveto P, Kayser F, Cheng Q, Dou H . A selective prostaglandin E2 receptor subtype 2 (EP2) antagonist increases the macrophage-mediated clearance of amyloid-beta plaques. J Med Chem. 2015; 58(13):5256-73. DOI: 10.1021/acs.jmedchem.5b00567. View

18.

Kim H, Ortiz D, Kadayat T, Fargo C, Hammill J, Chen Y . Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides. J Med Chem. 2023; 66(11):7374-7386. PMC: 10259451. DOI: 10.1021/acs.jmedchem.3c00056. View

19.

Sharlow E, Close D, Shun T, Leimgruber S, Reed R, Mustata G . Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. PLoS Negl Trop Dis. 2009; 3(11):e540. PMC: 2765639. DOI: 10.1371/journal.pntd.0000540. View

20.

Hwang J, Smithson D, Zhu F, Holbrook G, Connelly M, Kaiser M . Optimization of chloronitrobenzamides (CNBs) as therapeutic leads for human African trypanosomiasis (HAT). J Med Chem. 2013; 56(7):2850-60. DOI: 10.1021/jm301687p. View