Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Optimization of the 2,4-substituents

Aboushady, Dina; Rasheed, Sari; Herrmann, Jennifer; Maher, Ahmed; El‐Hossary, Ebaa M.; Ibrahim, Eslam S.; Abadi, Ashraf H.; Engel, Matthias; Müller, Rolf; Abdel‐Halim, Mohammad; Hamed, Mostafa M.

doi:10.1016/j.bioorg.2021.105422

Cited by 8 publications

(5 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antimicrobial activity studies were performed against the following test strains: Acinetobacter baumannii DSM-30008, Escherichia coli JW0451-2 (ΔacrB), E. coli BW25113, Staphylococcus aureus Newman, Mycobacterium smegmatis mc2155, Pseudomonas aeruginosa PA14, Bacillus subtilis DSM-10, Citrobacter freundii DSM-30039, Mucor hiemalis DSM-2656, Candida albicans DSM-1665, Cryptococcus neoformans DSM-11959 and Pichia anomala DSM-6766. Minimum inhibitory concentrations (MICs) were determined according to standard procedures [1]. Serial dilutions of pamamycins, dissolved in DMSO, ranging from 1 to 128 µM were prepared in sterile 96-well plates, and the bacterial suspension was added.…”

Section: Isolation and Purification Of Pamamycinsmentioning

confidence: 99%

Discovery and overproduction of novel highly bioactive pamamycins through transcriptional engineering of the biosynthetic gene cluster

Eckert,

Rebets,

Horbal

et al. 2023

Microb Cell Fact

Self Cite

View full text Add to dashboard Cite

Background Pamamycins are a family of highly bioactive macrodiolide polyketides produced by Streptomyces alboniger as a complex mixture of derivatives with molecular weights ranging from 579 to 705 Daltons. The large derivatives are produced as a minor fraction, which has prevented their isolation and thus studies of chemical and biological properties. Results Herein, we describe the transcriptional engineering of the pamamycin biosynthetic gene cluster (pam BGC), which resulted in the shift in production profile toward high molecular weight derivatives. The pam BGC library was constructed by inserting randomized promoter sequences in front of key biosynthetic operons. The library was expressed in Streptomyces albus strain with improved resistance to pamamycins to overcome sensitivity-related host limitations. Clones with modified pamamycin profiles were selected and the properties of engineered pam BGC were studied in detail. The production level and composition of the mixture of pamamycins was found to depend on balance in expression of the corresponding biosynthetic genes. This approach enabled the isolation of known pamamycins and the discovery of three novel derivatives with molecular weights of 663 Da and higher. One of them, homopamamycin 677A, is the largest described representative of this family of natural products with an elucidated structure. The new pamamycin 663A shows extraordinary activity (IC50 2 nM) against hepatocyte cancer cells as well as strong activity (in the one-digit micromolar range) against a range of Gram-positive pathogenic bacteria. Conclusion By employing transcriptional gene cluster refactoring, we not only enhanced the production of known pamamycins but also discovered novel derivatives exhibiting promising biological activities. This approach has the potential for broader application in various biosynthetic gene clusters, creating a sustainable supply and discovery platform for bioactive natural products.

show abstract

Section: Isolation and Purification Of Pamamycinsmentioning

confidence: 99%

Discovery and overproduction of novel highly bioactive pamamycins through transcriptional engineering of the biosynthetic gene cluster

Eckert,

Rebets,

Horbal

et al. 2023

Microb Cell Fact

Self Cite

View full text Add to dashboard Cite

show abstract

“…[18] We, among others, have previously reported a novel class of quinazoline derivatives (V) with broad-spectrum antibacterial activity. [19][20][21] Herein, we applied a diversity-oriented synthesis (DOS) approach through skeletal (scaffold) modification to design novel molecules with promising antibacterial activity. [22,23] To this end, we aimed to dissect the quinazoline scaffold (V) to the 5-arylpyrimidine core (VI), keeping a butylamino chain at positions 2 and 4 that showed high potency within the quinazoline series.…”

Section: Introductionmentioning

confidence: 99%

“…[22,23] To this end, we aimed to dissect the quinazoline scaffold (V) to the 5-arylpyrimidine core (VI), keeping a butylamino chain at positions 2 and 4 that showed high potency within the quinazoline series. [20,21] Structural modifications included the 5-aryl moiety besides the bioisosteric replacement of the linker heteroatom (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Development and evaluation of 2,4‐disubstituted‐5‐aryl pyrimidine derivatives as antibacterial agents

Khalifa,

Rasheed,

Haupenthal

et al. 2024

Archiv der Pharmazie

Self Cite

View full text Add to dashboard Cite

Designing novel candidates as potential antibacterial scaffolds has become crucial due to the lack of new antibiotics entering the market and the persistent rise in multidrug resistance. Here, we describe a new class of potent antibacterial agents based on a 5‐aryl‐N2,N4‐dibutylpyrimidine‐2,4‐diamine scaffold. Structural optimization focused on the 5‐aryl moiety and the bioisosteric replacement of the side chain linker atom. Screening of the synthesized compounds focused on a panel of bacterial strains, including gram‐positive Staphylococcus aureus strains (Newman MSSA, methicillin‐ and vancomycin‐resistant), and the gram‐negative Escherichia coli (ΔAcrB strain). Several compounds showed broad‐spectrum antibacterial activity with compound 12, bearing a 4‐chlorophenyl substituent, being the most potent among this series of compounds. This frontrunner compound revealed a minimum inhibitory concentration (MIC) value of 1 µg/mL against the S. aureus strain (Mu50 methicillin‐resistant S. aureus/vancomycin‐intermediate S. aureus) and an MIC of 2 µg/mL against other tested strains. The most potent derivatives were further tested against a wider panel of bacteria and evaluated for their cytotoxicity, revealing further potent activities toward Streptococcus pneumoniae, Enterococcus faecium, and Enterococcus faecalis. To explore the mode of action, compound 12 was tested in a macromolecule inhibition assay. The obtained data were supported by the safety profile of compound 12, which possessed an IC50 of 12.3 µg/mL against HepG2 cells. The current results hold good potential for a new class of extended‐spectrum antibacterial agents.

show abstract

“…In a biofilm, bacteria and microorganisms are protected by extracellular polymers (EPS) produced by themselves. , This powerful barrier hinders the penetration of various antibacterial agents . To resist biofilm, the current main method is to increase the dosage of antibiotics. − Still, the extensive use of antibiotics will lead to the emergence of a large number of drug-resistant bacteria. Additionally, heavy use of antibiotics can produce toxicity. − Therefore, there is an urgent need to develop a new strategy to combat bacteria and biofilm infections …”

Section: Introductionmentioning

confidence: 99%

High-Efficiency Near-Infrared Light Responsive Antibacterial System for Synergistic Ablation of Bacteria and Biofilm

Xie

et al. 2022

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

Bacterial infection is seriously threatening human health, and the design of high-efficiency and good biocompatibility antibacterial agents is an urgent problem to be solved. However, with the emergence of drug-resistant bacteria, the existing antibacterial agents have low killing efficiency, and the formation of biofilms has further weakened the therapeutic effect. Herein, we constructed an efficient antibacterial system mediated by nearinfrared light for synergistic antibacterial and biofilm dissipation. Specifically, the ZnO/Ti 3 C 2 T x with heterojunction was synthesized by hydrothermal growth of ZnO on the surface of lamellar Ti 3 C 2 T x -MXene. The prepared ZnO/Ti 3 C 2 T x had better photothermal ability than ZnO and Ti 3 C 2 T x , respectively. The local thermal effect can not only destroy the integrity of the bacterial membrane but also promote the release of Zn 2+ ions and further improve the antibacterial performance. ZnO/Ti 3 C 2 T x achieved a 100% sterilization rate (better than either ZnO or Ti 3 C 2 T x ) at 150 μg mL −1 . The biofilm dissipation experiment further proved its excellent biofilm ablation effect. More importantly, the results of in vitro cell culture and animal experiments have demonstrated its good biological safety. In summary, this new type of nanomaterial shows strong local chemical photothermal sterilization ability and has great potential to replace traditional antibacterial agents.

show abstract

Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Optimization of the 2,4-substituents

Cited by 8 publications

References 25 publications

Discovery and overproduction of novel highly bioactive pamamycins through transcriptional engineering of the biosynthetic gene cluster

Discovery and overproduction of novel highly bioactive pamamycins through transcriptional engineering of the biosynthetic gene cluster

Development and evaluation of 2,4‐disubstituted‐5‐aryl pyrimidine derivatives as antibacterial agents

High-Efficiency Near-Infrared Light Responsive Antibacterial System for Synergistic Ablation of Bacteria and Biofilm

Contact Info

Product

Resources

About