title: Design, synthesis and evaluation of novel pyrazolo-pyrimido[4,5-d]pyrimidine derivatives as potent antibacterial and biofilm inhibitors.
abstract: An efficient four-component reaction of 6-amino-1,3-dimethyluracil, N,N-dimethylformamide dimethylacetal, 1-phenyl-3-(4-substituted-phenyl)-4-formyl-1H-pyrazoles and aromatic amines was conducted in the presence of [Bmim]FeCl4ionic liquid as a promoting medium. This strategy provided a convenient route without any additional catalyst or metal salt under mild conditions. All the synthesized pyrazolo-pyrimido[4,5-d]pyrimidines derivatives were evaluated for their antibacterial, minimum bactericidal concentration (MBC), biofilm inhibition, intracellular ROS accumulation and protein leakage activities. The results revealed that among all the screened derivatives, the compounds 5c, 5i, 5l and 5m were quite promising with MIC values ranging between 3.9 and 15.6μg/mL, while the MBC values were 2-fold the antibacterial activity values. The biofilm inhibition activity revealed that the compounds 5l and 5m exhibited promising activity with IC50values ranging between 1.8 and 8.2μg/mL. It was observed that at a concentration of 0.5μg/mL, the compound 5l treated biofilms of Micrococcus luteus showed increased levels of intracellular ROS accumulation. Further, the protein leakage study revealed that the Micrococcus luteus cells treated with compound 5l caused membrane permeability which resulted in protein leakage and subsequent bacterial cell death.
authors.affiliation: Department of Chemistry, National Institute of Technology, Warangal 506 004, Telangana, India.
authors.forename: Lingala
authors.initials: L
authors.lastname: Suresh
authors.affiliation: Department of Chemistry, National Institute of Technology, Warangal 506 004, Telangana, India.
authors.forename: P
authors.initials: P
authors.lastname: Sagar Vijay Kumar
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500 007, Telangana, India.
authors.forename: Y
authors.initials: Y
authors.lastname: Poornachandra
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500 007, Telangana, India.
authors.forename: C
authors.initials: C
authors.lastname: Ganesh Kumar
authors.affiliation: Department of Chemistry, National Institute of Technology, Warangal 506 004, Telangana, India. Electronic address: gvpc2000@gmail.com.
authors.forename: G V P
authors.initials: GVP
authors.lastname: Chandramouli
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D011720:Pyrazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C031280:pyrazole
keywords: Antibacterial and biofilm inhibitors; Ionic liquid; Multicomponent reaction; Pyrazolo-pyrimido[4,5-d]pyrimidine