Insights into novel benzo[h]quinoline-based 2-thioxothiazolidin-4-one and thiazol-4-one hybrids as potential antimicrobial, and antibiofilm candidates: Design, synthesis, molecular modeling, and in-silico ADME studies.
The findings strongly confirm the substituted benzo[h]quinoline core as a highly promising pharmacophore for the development of next-generation antimicrobial medicines effective against both free-floating planktonic cells and tough structured biofilms.
Abstract
The growing crisis of antimicrobial resistance urges the immediate development of new therapeutic pharmaceuticals that can overcome current resistance mechanisms, including biofilm formation. This study included the synthesis and strategic design of a novel set of quinoline-based scaffolds (3-11) to enhance interactions with the bacterial Peptide Deformylase (PDF) enzyme. The compounds underwent extensive in vitro biological assessment, comprising initial inhibition zone (IZ) screening, followed by quantitative minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests against a range of Gram-positive, Gram-negative, and fungal strains. The synthesized derivatives exhibited potent, primarily bactericidal activity, with compounds 4, 6, and 10 emerging as notably outstanding candidates. These three compounds exhibited significant activity against S. aureus (MIC = 7.8 μg/mL), demonstrating equivalent potency to the standard reference antibiotic. Additionally, the anti-biofilm efficacy of these leading candidates was assessed against S. aureus and S. typhi at sub-inhibitory doses. Compound 6 emerged as a prominent dual-action drug, demonstrating strong bactericidal activity and significant dose-dependent biofilm destruction. It exhibited considerable biofilm inhibition against both S. aureus (56.76%) and S. typhi (65.93%) even at substantially diluted sub-lethal concentrations (25% MBC). The findings strongly confirm the substituted benzo[h]quinoline core as a highly promising pharmacophore for the development of next-generation antimicrobial medicines effective against both free-floating planktonic cells and tough structured biofilms.
The emergence of antimicrobial resistance needs the development of new chemotherapeutic scaffolds. Pyrazole derivatives are recognized for their broad biological activity; however, further structural innovation is required to enhance antimicrobial efficacy and safety. Thus, new pyrazole-based candidates were designed and synthesized using 3-(4-chlorophenyl)-1-phenylpyrazol-4-yl-2-cyanoacryloyl chloride as a versatile precursor. A series of mono- and bidentate nucleophile-derived compounds was prepared and evaluated for antimicrobial activity against Gram-positive and Gram-negative bacteria and Candida albicans. Several derivatives exhibited potent antibacterial and antifungal activity, particularly against Gram-positive strains, with minimum inhibitory concentrations comparable to standard drugs. Most compounds showed low cytotoxicity toward HepG2 cells, which was further reduced upon antioxidant co-treatment. Notably, vitamin C and N-acetylcysteine showed synergistic enhancement of antimicrobial and antibiofilm effects. Molecular docking studies against dihydropteroate synthase (DHPS, PDB: 5U0V) revealed favorable binding interactions, with the thiophene-based derivative 10 displaying ligand efficiency comparable to the co-crystallized ligand 7VJ. Overall, these findings highlight pyrazole-based scaffolds as promising antimicrobial candidates with favorable biological profiles, providing a strong basis for further structural optimization.
E. El‐Helw, Selwan Hamed, A. El-ziaty et al.· Scientific Reports· 0 citations
A series of thiazolo[5,4-b]pyridine–based sulfonamide derivatives was designed and synthesized using a cyanoacetyl sulfonamide intermediate to access various heterocyclic frameworks. Their antimicrobial activity was evaluated
in vitro
against
Staphylococcus aureus
,
Escherichia coli
, and
Candida albicans
using agar diffusion and minimum inhibitory concentration (MIC) determination. Several compounds exhibited potent antibacterial activity with MIC values ranging from 3.125 to 12.5 μg/mL, where compounds
10
,
16
, and
21
showed broad-spectrum activity comparable to or superior to reference drugs. Structure–activity relationship (SAR) analysis indicated that electron-withdrawing and aromatic substituents enhanced antimicrobial potency. Molecular docking studies against dihydrofolate reductase (DHFR, PDB ID: 2W9S) supported the experimental results, revealing favorable binding interactions and high affinity of the most active compounds. These findings suggest that thiazolo[5,4-b]pyridine–sulfonamide hybrids represent promising scaffolds for the development of new antimicrobial agents.
Noof A. Alenazi· Arabian Journal of Chemistry· 0 citations
Bacterial pathogens inflict substantial crop losses and economic damage, threatening global food security. Although antibacterial agents are available, their application is constrained by drug resistance, environmental hazards, and inadequate sustainability. Development of novel and effective antimicrobial agents has become urgent imperative. A series of morpholine-containing 1,3,4-thiadiazole derivatives were designed and synthesized. Compound H6 exhibited the most potent inhibitory activity against Xanthomonas oryzaepv oryzae (Xoo), with EC50 of 1.21 μg/mL-significantly lower than bismerthiazol (EC50 = 64.71 μg/mL) and thiodiazole-copper (EC50 = 63.94 μg/mL). Mechanistic studies revealed H6 inhibits biofilm and extracellular polysaccharide formation, disrupts membrane integrity, induces ROS accumulation, and promotes lipid peroxidation. Transcriptomic analysis demonstrated significant downregulation of key virulence genes (vgrG, accC, MCP), indicating attenuated pathogenicity. These results underscore H6 as a promising bactericidal agent, demonstrating considerable potential in sustainable management of plant bacterial diseases.
Mengzhi Yang, Chengpeng Li, Yue Zhou et al.· Journal of Agricultural and...· 0 citations
The rapid emergence of antimicrobial resistance (AMR) posed a major global health threat and created an urgent need for new broad-spectrum antimicrobial agents. The quinolin-2-one scaffold emerged as a privileged structural motif in medicinal chemistry because it exhibited promising activity against a wide range of bacterial and fungal pathogens. Continuous optimization of this scaffold remained essential to address the increasing burden of resistance. This review summarized recent advances in quinolin-2-one derivatives reported from 2015 to 2025. It systematically examined synthetic approaches and revealed a growing shift toward greener and more sustainable methodologies. The review also analyzed the structure-activity relationships that governed antimicrobial potency, integrated findings from biological evaluations, discussed proposed mechanisms of action, including inhibition of DNA topoisomerases and disruption of cell wall biosynthesis, and assessed the available toxicity data for the reported compounds. Advantages, disadvantages and future perspectives Quinolin-2-one derivatives demonstrated considerable therapeutic promise as versatile antimicrobial scaffolds. However, current studies revealed several limitations, including poor aqueous solubility, insufficient preclinical ADMET characterization, and limited in vivo validation. Future investigations should address these pharmacokinetic and toxicological limitations to support the rational design of next-generation quinolin-2-one hybrids and improve their potential for clinical translation.
M. Khattab, Mai I Shahin, A. Taher et al.· Future Medicinal Chemistry· 0 citations
The synthesis of new bis-oxadiazole-bearing benzo[b]thiophene derivatives are reported as well as assessments of their antimicrobial and antitubercular activity through both in vitro and in silico approaches, identifying promising oxadiazole-based inhibitors.
Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global public health. Marine natural products provide a rich source of novel chemical entities for tackling MRSA infections. In this study, a series of halogenated 2-benzoylquinazolin-4(3H)-one derivatives (1−48) was designed and synthesized by innovatively integrating halogen pharmacophores with the biologically validated marine alkaloid penipanoid C. Anti-MRSA assays revealed that the introduction of iodine atoms significantly enhanced the activity of this class of compounds. Compound 48 (CHNQD-01748), bearing three iodine atoms, exhibited the most significant and selective antibacterial effect against the MRSA strain with an MIC value of 4 μg/mL against the reference MRSA strain (ATCC 43300) and 8−16 μg/mL against three clinical isolates. Further investigations revealed that 48 possessed a sustained antibacterial effect, potent biofilm-disrupting and biofilm-inhibitory activity, a long half-life, and a favorable preliminary safety profile in the models tested. An in vivo antibacterial assay demonstrated that 48 had vancomycin-comparable efficacy against localized MRSA skin infections yet provided superior suppression of systemic dissemination, inhibiting bacterial loads by >95% in the spleen, lung, and kidney. These findings showed the promising potential of 48 as a potent agent for the treatment of MRSA infections.
Peng-Jie Li, Ji-Xiu Gao, Hao-Ran Li et al.· Journal of Natural Products· 0 citations