Ureidopyrazine Derivatives: Synthesis and Biological Evaluation as Anti-Infectives and Abiotic Elicitors.

Petr Kastner,Martin Doležal,Ondřej Janďourek,Jan Zitko,Zuzana Kovalíková,Ghada Bouz,Pavlína Niklová,Lenka Tůmová,Pavla Paterová,Jiří Janoušek,Martin Juhás

doi:10.3390/molecules22101797

Petr Kastner, Martin Doležal

Open Access

https://doi.org/10.3390/molecules22101797

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Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become a frequently deadly infection due to increasing antimicrobial resistance. This serious issue has driven efforts worldwide to discover new drugs effective against Mtb. One research area is the synthesis and evaluation of pyrazinamide derivatives as potential anti-TB drugs. In this paper we report the synthesis and biological evaluations of a series of ureidopyrazines. Compounds were synthesized by reacting alkyl/aryl isocyanates with aminopyrazine or with propyl 5-aminopyrazine-2-carboxylate. Reactions were performed in pressurized vials using a CEM Discover microwave reactor with a focused field. Purity and chemical structures of products were assessed, and the final compounds were tested in vitro for their antimycobacterial, antibacterial, and antifungal activities. Propyl 5-(3-phenylureido)pyrazine-2-carboxylate (compound 4, MICMtb = 1.56 μg/mL, 5.19 μM) and propyl 5-(3-(4-methoxyphenyl)ureido)pyrazine-2-carboxylate (compound 6, MICMtb = 6.25 μg/mL, 18.91 μM) had high antimycobacterial activity against Mtb H37Rv with no in vitro cytotoxicity on HepG2 cell line. Therefore 4 and 6 are suitable for further structural modifications that might improve their biological activity and physicochemical properties. Based on the structural similarity to 1-(2-chloropyridin-4-yl)-3-phenylurea, a known plant growth regulator, two selected compounds were evaluated for similar activity as abiotic elicitors.

Highlights

Tuberculosis (TB) is a common infection that had been successfully treated with appropriate first line anti-TB drugs, including isoniazid (INH), rifampicin, pyrazinamide (PZA), and ethambutol [1].Yet in the last few years, this curable infection has become a frequently deadly illness due to the raising issue of antimicrobial resistance (AMR) [1]
AMR includes multi-drug resistant TB (MDR-TB), when the bacteria is resistant to both INH and rifampicin, and extensively drug resistant TB (XDR-TB), when the bacteria is resistant to INH, rifampicin, fluoroquinolones, and one of the three parenteral second line drugs [2]
We focus on the design, synthesis, and anti-infective evaluation of ureidopyrazine

Summary

Introduction

In the last few years, this curable infection has become a frequently deadly illness due to the raising issue of antimicrobial resistance (AMR) [1]. AMR includes multi-drug resistant TB (MDR-TB), when the bacteria is resistant to both INH and rifampicin, and extensively drug resistant TB (XDR-TB), when the bacteria is resistant to INH, rifampicin, fluoroquinolones, and one of the three parenteral second line drugs (amikacin, kanamycin, or capreomycin) [2]. Despite the fact that the annual number of deaths due to TB has fallen from the year 2000 till today, TB remains one of the top ten causes of death worldwide and the leading cause of death from infectious diseases [3]. Health Organization (WHO) annual report, there were 10.4 million new cases of TB worldwide in. The number of deaths attributed to TB in that year

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