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

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

doi:10.3390/molecules22101797

Cited by 8 publications

(3 citation statements)

References 32 publications

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“…It brought a slight improvement in activity. From our experience, propyl esters tend to favorably influence antimycobacterial activity of pyrazine derivatives . Hegde and colleagues have recently published an article on PAS prodrugs (as an attempt to increase oral bioavailability) and analogues (as an attempt to slow down the rapid clearance by NAT-1), where they reported the synthesis and biological evaluation of methyl, ethyl, and isopropyl esters of PAS, but not propyl esters .…”

Section: Resultsmentioning

confidence: 99%

Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid

et al. 2022

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Apart from the SARS-CoV-2 virus, tuberculosis remains the leading cause of death from a single infectious agent according to the World Health Organization. As part of our longterm research, we prepared a series of hybrid compounds combining pyrazinamide, a first-line antitubercular agent, and 4aminosalicylic acid (PAS), a second-line agent. Compound 11 was found to be the most potent, with a broad spectrum of antimycobacterial activity and selectivity toward mycobacterial strains over other pathogens. It also retained its in vitro activity against multiple-drug-resistant mycobacterial strains. Several structural modifications were attempted to improve the in vitro antimycobacterial activity. The δ-lactone form of compound 11 (11′) had more potent in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compound 11 was advanced for in vivo studies, where it was proved to be nontoxic in Galleria mellonella and zebrafish models, and it reduced the number of colonyforming units in spleens in the murine model of tuberculosis. Biochemical studies showed that compound 11 targets mycobacterial dihydrofolate reductases (DHFR). An in silico docking study combined with molecular dynamics identified a viable binding mode of compound 11 in mycobacterial DHFR. The lactone 11′ opens in human plasma to its parent compound 11 (t 1/2 = 21.4 min). Compound 11 was metabolized by human liver fraction by slow hydrolysis of the amidic bond (t 1/2 = 187 min) to yield PAS and its starting 6-chloropyrazinoic acid. The long t 1/2 of compound 11 overcomes the main drawback of PAS (short t 1/2 necessitating frequent administration of high doses of PAS).

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Section: Resultsmentioning

confidence: 99%

Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid

et al. 2022

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“…In procedure A, the first step was a Fisher esterification in the presence of H 2 SO 4 and methanol to afford the corresponding methyl ester. The second step was the aminolysis of the obtained ester by corresponding benzylamine using microwave irradiation [19]. In procedure B, the starting acid was treated with the coupling agent 1,1′-carbonyldiimidazole (CDI) in anhydrous dimethyl sulfoxide (DMSO) [20].…”

Section: Resultsmentioning

confidence: 99%

“…Synthesis of N -substituted 3-aminopyrazine-2-amides. Procedure A: I) H 2 SO 4 , methanol, 48 h, rt; II) substituted benzylamine, NH 4 Cl, methanol, MW: 130 °C, 40 min, 90 W [19]; Procedure B: III) 1. CDI, DMSO; 2. benzylamine/alkylamine/aniline, MW: 120 °C, 30 min, 100 W [20].…”

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Derivatives of 3-Aminopyrazine-2-carboxamides: Synthesis, Antimicrobial Evaluation, and in Vitro Cytotoxicity

et al. 2019

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We report the design, synthesis, and in vitro antimicrobial activity of a series of N-substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino-N-(2,4-dimethoxyphenyl)pyrazine-2-carboxamide (17, MIC = 12.5 µg/mL, 46 µM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans. The four most active compounds (compounds 10, 16, 17, 20) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.

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Antitubercular Agents

Aldrich¹,

Wallis²,

Hegde³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Mycobacterium tuberculosis remains the leading cause of death due to infection in humans. Although antibiotics are available to treat drug‐sensitive M. tuberculosis infections, the increasing incidence of drug‐resistant strains is threatening our ability to gain hold of this pandemic. In addition, recent research has highlighted that even the current standard of care antibiotics face multiple obstacles for reaching therapeutic concentrations at the site of infection. In this article, we detail the current standard of care for clinical tuberculosis (TB) disease, the chemistry, mechanisms of action, and mechanisms of resistance for the antibiotics used clinically to treat TB, the growing problem of antibiotic resistance, and other challenges associated with TB treatment, and host‐directed therapies as an additional approach to treatment. This article is meant to serve as the foundation to build from as the field addresses the dire need for continued development of new therapeutic strategies to treat TB.

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

Cited by 8 publications

References 32 publications

Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid

Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid

Derivatives of 3-Aminopyrazine-2-carboxamides: Synthesis, Antimicrobial Evaluation, and in Vitro Cytotoxicity

Antitubercular Agents

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