Sapna Saini, G Lakshma Reddy, Anjali Gangwar, Harpreet Kour, Gajanan G Nadre, Ramajayan Pandian, Sunny Pal, Utpal Nandi, Rashmi Sharma, Sanghapal D Sawant
{"title":"硝基呋喃基-吡唑嘧啶杂化偶联物对金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌的有效抗菌药物的发现和生物学评价。","authors":"Sapna Saini, G Lakshma Reddy, Anjali Gangwar, Harpreet Kour, Gajanan G Nadre, Ramajayan Pandian, Sunny Pal, Utpal Nandi, Rashmi Sharma, Sanghapal D Sawant","doi":"10.1039/d4md00826j","DOIUrl":null,"url":null,"abstract":"<p><p>Nitrofuran and pyrazolopyrimidine-based compounds possess a broad antimicrobial spectrum including Gram-positive and Gram-negative bacteria. In the present work, a series of conjugates of these scaffolds was synthesized and evaluated for antimicrobial activity against <i>Staphylococcus aureus</i> and methicillin-resistant <i>S. aureus</i> (MRSA). Many compounds showed MIC values of ≤2 μg ml<sup>-1</sup>, with compound 35 demonstrating excellent activity (MICs: 0.7 and 0.15 μg ml<sup>-1</sup> against <i>S. aureus</i> and MRSA, respectively) and safety up to 50 μg ml<sup>-1</sup> in HepG2 cells. Compound 35 also exhibited no hemolytic activity, biofilm eradication, and effectiveness against efflux-pump-overexpressing strains (NorA, TetK, MsrA) without resistance development. It showed synergistic effects with vancomycin (<i>S. aureus</i>) and rifampicin (MRSA). Mechanistic studies revealed that compound 35 exhibits good membrane-targeting abilities, as evidenced by DAPI/PI staining and scanning electron microscopy (SEM). In an intracellular model, it reduced bacterial load efficiently in both <i>S. aureus</i> and MRSA strains. With a strong <i>in vitro</i> profile, compound 35 demonstrated favorable oral pharmacokinetics at 30 mg kg<sup>-1</sup> and potent <i>in vivo</i> anti-MRSA activity, highlighting its potential against antibiotic-resistant infections.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1000,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740095/pdf/","citationCount":"0","resultStr":"{\"title\":\"Discovery and biological evaluation of nitrofuranyl-pyrazolopyrimidine hybrid conjugates as potent antimicrobial agents targeting <i>Staphylococcus aureus</i> and methicillin-resistant <i>S. aureus</i>.\",\"authors\":\"Sapna Saini, G Lakshma Reddy, Anjali Gangwar, Harpreet Kour, Gajanan G Nadre, Ramajayan Pandian, Sunny Pal, Utpal Nandi, Rashmi Sharma, Sanghapal D Sawant\",\"doi\":\"10.1039/d4md00826j\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Nitrofuran and pyrazolopyrimidine-based compounds possess a broad antimicrobial spectrum including Gram-positive and Gram-negative bacteria. In the present work, a series of conjugates of these scaffolds was synthesized and evaluated for antimicrobial activity against <i>Staphylococcus aureus</i> and methicillin-resistant <i>S. aureus</i> (MRSA). Many compounds showed MIC values of ≤2 μg ml<sup>-1</sup>, with compound 35 demonstrating excellent activity (MICs: 0.7 and 0.15 μg ml<sup>-1</sup> against <i>S. aureus</i> and MRSA, respectively) and safety up to 50 μg ml<sup>-1</sup> in HepG2 cells. Compound 35 also exhibited no hemolytic activity, biofilm eradication, and effectiveness against efflux-pump-overexpressing strains (NorA, TetK, MsrA) without resistance development. It showed synergistic effects with vancomycin (<i>S. aureus</i>) and rifampicin (MRSA). Mechanistic studies revealed that compound 35 exhibits good membrane-targeting abilities, as evidenced by DAPI/PI staining and scanning electron microscopy (SEM). In an intracellular model, it reduced bacterial load efficiently in both <i>S. aureus</i> and MRSA strains. 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Discovery and biological evaluation of nitrofuranyl-pyrazolopyrimidine hybrid conjugates as potent antimicrobial agents targeting Staphylococcus aureus and methicillin-resistant S. aureus.
Nitrofuran and pyrazolopyrimidine-based compounds possess a broad antimicrobial spectrum including Gram-positive and Gram-negative bacteria. In the present work, a series of conjugates of these scaffolds was synthesized and evaluated for antimicrobial activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Many compounds showed MIC values of ≤2 μg ml-1, with compound 35 demonstrating excellent activity (MICs: 0.7 and 0.15 μg ml-1 against S. aureus and MRSA, respectively) and safety up to 50 μg ml-1 in HepG2 cells. Compound 35 also exhibited no hemolytic activity, biofilm eradication, and effectiveness against efflux-pump-overexpressing strains (NorA, TetK, MsrA) without resistance development. It showed synergistic effects with vancomycin (S. aureus) and rifampicin (MRSA). Mechanistic studies revealed that compound 35 exhibits good membrane-targeting abilities, as evidenced by DAPI/PI staining and scanning electron microscopy (SEM). In an intracellular model, it reduced bacterial load efficiently in both S. aureus and MRSA strains. With a strong in vitro profile, compound 35 demonstrated favorable oral pharmacokinetics at 30 mg kg-1 and potent in vivo anti-MRSA activity, highlighting its potential against antibiotic-resistant infections.