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Pharmaceuticals
Volume 18
Issue 12
10.3390/ph18121821
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

A Unified Approach to Synthesizing Four Linezolid Metabolites that May Cause Thrombocytopenia

by
Naoki Oikawa
1,*,
Natsu Inoue
1,
Shogo Ishii
1,
Takumi Goto
1,
Hiroaki Saito
1,
Fumihiro Kurosaki
2,
Takahiro Aoyama
2,
Yasuhiro Tsuji
2 and
Taketo Uchiyama
1,*
1
Laboratory of Medicinal Chemistry, School of Pharmacy, Nihon University, 7-7-1, Narashinodai, Funabashi Chiba, 274-8555, Japan
2
Laboratory of Clinical Pharmacometrics, School of Pharmacy, Nihon University, 7-7-1, Narashinodai, Funabashi Chiba, 274-8555, Japan
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2025, 18(12), 1821; https://doi.org/10.3390/ph18121821 (registering DOI)
Submission received: 29 October 2025 / Revised: 22 November 2025 / Accepted: 26 November 2025 / Published: 28 November 2025
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Background/Objectives: Linezolid is a first-in-class oxazolidinone antibiotic that exhibits activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. However, its clinical use is often restricted because of hematological toxicities, particularly thrombocytopenia, in patients with renal impairment. That side effect is thought to result from the systemic accumulation of pharmacologically inactive metabolites generated by oxidative degradation and ring-opening of the morpholine, but the details remain unclear. In this study, we established a novel synthetic route for four linezolid metabolites (PNU-142618, 142300, 142586 and 173558). Methods: The four major metabolites, which are secondary or tertiary amines, were synthesized using the aniline derivatives protected with a 2-nitrobenzensulfonyl (Ns) group. Results: Application of this Ns strategy enabled selective N-alkylation, enabling efficient synthesis of the target metabolites. The desired metabolites containing a carboxylic acid group were obtained as their sodium salts. This is the first report on the synthesis of PNU-142618 and 173558. Conclusions: The established synthetic pathway provides access to four linezolid metabolites. The results facilitated the provision of compounds necessary for comprehensive pharmacokinetic and toxicological studies.
Keywords: linezolid; metabolites; synthesis; PNU-142618; PNU-142300; PNU-142586; PNU-173558; Ns strategy linezolid; metabolites; synthesis; PNU-142618; PNU-142300; PNU-142586; PNU-173558; Ns strategy
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MDPI and ACS Style

Oikawa, N.; Inoue, N.; Ishii, S.; Goto, T.; Saito, H.; Kurosaki, F.; Aoyama, T.; Tsuji, Y.; Uchiyama, T. A Unified Approach to Synthesizing Four Linezolid Metabolites that May Cause Thrombocytopenia. Pharmaceuticals 2025, 18, 1821. https://doi.org/10.3390/ph18121821

AMA Style

Oikawa N, Inoue N, Ishii S, Goto T, Saito H, Kurosaki F, Aoyama T, Tsuji Y, Uchiyama T. A Unified Approach to Synthesizing Four Linezolid Metabolites that May Cause Thrombocytopenia. Pharmaceuticals. 2025; 18(12):1821. https://doi.org/10.3390/ph18121821

Chicago/Turabian Style

Oikawa, Naoki, Natsu Inoue, Shogo Ishii, Takumi Goto, Hiroaki Saito, Fumihiro Kurosaki, Takahiro Aoyama, Yasuhiro Tsuji, and Taketo Uchiyama. 2025. "A Unified Approach to Synthesizing Four Linezolid Metabolites that May Cause Thrombocytopenia" Pharmaceuticals 18, no. 12: 1821. https://doi.org/10.3390/ph18121821

APA Style

Oikawa, N., Inoue, N., Ishii, S., Goto, T., Saito, H., Kurosaki, F., Aoyama, T., Tsuji, Y., & Uchiyama, T. (2025). A Unified Approach to Synthesizing Four Linezolid Metabolites that May Cause Thrombocytopenia. Pharmaceuticals, 18(12), 1821. https://doi.org/10.3390/ph18121821

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