Discovery of novel series of 4-quinolone hybrids as multi-targeting agent: Design, synthesis and H1-antihistaminic activity to treat allergic asthma.

• The multi-targeted 4-quinolone hybrids are designed, synthesized and characterized for the treatment of allergic asthma. • Asthma-associated antihistaminic activity, COX-2, LOX and PED-4 inhibitory activity have been performed to identify the potentiators. • In-silico physicochemical and pharmacokinetic parameters are analysed by Pass software and oral toxicity has been performed according to OECD-420 guidelines (in-vivo). • A 4-quinolone hybrid is found to be pharmacologically more effective and safer than standard (Azelastine hydrochloride). The multi-targeted hybrids can promise tools to fight against multifaceted diseases like allergic asthma by blocking the various mediators which are associated with allergic asthma. Therefore, the multi-targeted therapeutic hybrids have been designed from the combination of two bioactive pharmacophores like quinolone and piperazines. These hybrids have been synthesized and characterized by sophisticated spectroscopic techniques (1HNMR and 13CNMR). Histamine is a more prominent mediator for the progression of allergic asthma. Therefore, all 40 hybrids were screened for their H 1 -antihistaminic activity (in vitro) by histamine-induced contraction in the GPI model. The most active compounds 26c, 28a and 30c were elected for bronchodilatory activity. The two compounds 26c and 28a were found to be more active with 48.72% and 42.62% with significant bronchoprotection (in-vivo) against histamine contraction respectively. Other targets have been predicted for the best compounds by in silico target prediction study using pass online tool. Pass predicted different targets among them. We have selected major associated targets of allergic asthma. Best compounds have been evaluated against other selective targets like prostaglandin-endoperoxide synthase-2 (COX-2), lipoxygenases (LOX) and phosphodiesterase-4 (PDE-4). Both compounds (26c and 28a) manifested good COX-2, LOX and PED-4 inhibitory activities. In silico predictions of pharmacokinetic and oral toxicity parameters were also implemented for the best compounds. In addition to the above, single acute toxicity study for the best compound (26c) has been accomplished at the dose of 300 mg/kgbw to the identification of the Off-target adverse effects. No signs of toxicity and mortality were exhibited during the experiment as per guidelines OCED-420. [Display omitted] [ABSTRACT FROM AUTHOR]