Integrated experimental and computational investigation of 4-quinolone hybrids as promising antihistaminic candidates for allergic asthma

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Background Histamine plays a critical role as a mediator in allergic asthma. To target this pathway, a series of 4-quinolone hybrids was designed by combining two pharmacophores, quinolone and piperazine, to inhibit histaminic activity effectively. Materials and methods A total of thirty-five novel quinolone derivatives were synthesized via five-step reaction and characterized using IR and ¹H NMR spectroscopy. Their antihistaminic activity ( ex-vivo ) was evaluated on Gallus gallus ileum, followed by in-vivo bronchodilatory studies in guinea pigs. Computational analyses, including molecular docking, DFT, TDDFT, and ADMET predictions, were performed to assess ligand–protein interactions, electronic properties, and pharmacokinetic behavior. Results Compounds 6c, 8e, and 10d exhibited potent antispasmodic ( ex-vivo ) and bronchodilatory ( in-vivo ) activities, showing protection rates of 32.8%, 35.6%, and 40.5%, respectively, comparable to the standard drug azelastine (42.5%). DFT analysis revealed that compound 8e possessed the lowest HOMO–LUMO gap (4.577 eV), indicating greater reactivity and stability. TDDFT spectra showed absorption maxima at 287.07 nm (6c), 271.9 nm (8e), and 270.3 nm (10d). ADMET studies predicted good oral permeability for compounds 8e (1.277 log Papp) and 10d (1.399 log Papp) with no significant toxicity up to 5000 mg/kg. Conclusion Most antihistaminic drugs lack bronchodilatory activity and are therefore not preferred for treating allergic asthma, whereas the 4-quinolone hybrids 8e and 10d were identified as potent antihistaminic agents with enhanced bronchodilatory activity and improved stability. Furthermore, in-silico studies suggested that both compounds possess favorable safety and tolerability profiles. However, further experimental studies and clinical trials are necessary to confirm their therapeutic potential in allergic asthma.