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Human rhinoviruses (HRVs) are the most common cause of viral respiratory infections and their complications. So far, no anti-viral agent has been approved for prevention or treatment of HRV infections. Pursuing our researches on small molecules with anti-rhinovirus activity, in this paper we describe the synthesis and in vitro anti-HRV 1B and 14 properties of new [2-(2H-chromen-3-yl)vinyl]pyridines and 3-[2-(pyridinyl)vinyl]-4H-chromen-4-ones. Generally, the synthesized compounds interfered with the replication of both serotypes at the micromolar or submicromolar concentrations. Preliminary results on their mechanism of action, performed on selected (E)-2-[2-(2H-chromen-3-yl)vinyl]pyridine, indicate an interference with the early step(s) of HRV 1B and 14 replication, probably at the uncoating level.

As part of an effort to generate broad-spectrum inhibitors of rhinovirus replication, novel series of (E)-3-[(E)-3-phenylallylidene]chroman-4-ones 1a-e, (E)-3-(3-phenylprop-2-yn-1-ylidene)chroman-4-ones 2a and 2b, (Z)-3-[(E)-3-phenylallylidene]chromans 3a-e, and (E)-3-(3-phenylprop-1-en-1-yl)-2H-chromenes 4a-d were designed and synthesized. All the compounds were tested in vitro for their efficacy against infection by human rhinovirus (HRV) 1B and 14, two representative serotypes for rhinovirus group B and A, respectively. Most of the analogues were found to be potent and selective inhibitors of both HRVs, although HRV 1B was generally more susceptible than HRV 14. Mechanism of action studies of (E)-6-chloro-3-(3-phenylprop-1-en-1-yl)-2H-chromene 4b, the most potent compound on HRV 1B infection, suggested that 4b behaves as a capsid-binder probably acting at the uncoating level.

Midodrine hydrochloride is a peripheral alpha(1)-adrenoreceptor agonist that induces venous and arterial vasoconstriction. Midodrine, after oral or intravenous administration, undergoes enzymatic hydrolysis and releases deglymidodrine, a pharmacologically active metabolite. Midodrine and deglymidodrine have a chiral carbon in the 2-position. To investigate the bioactivity of racemates and enantiomers of the drug and metabolite, three chromatographic chiral stationary phases, Chiralcel OD-H, Chiralcel OD-R, and alpha(1)-AGP, were evaluated for enantiomeric resolution. Good enantioseparation of midodrine racemate was obtained using the Chiralcel OD-H column. This stationary phase was then used to collect separately the midodrine enantiomers. By alkaline hydrolysis of rac-midodrine and each separated enantiomer, rac-deglymidodrine and its enantiomers were prepared. The control of the enantiomeric purity was carried out by alpha(1)-AGP stationary phase, while the hydrolysis of rac-midodrine and its enantiomers was controlled by capillary electrophoresis using trimethyl-beta-cyclodextrin as chiral selector. The pharmacological activity of the two racemates and the two enantiomeric pairs was tested in vitro on a strip of rabbit descending thoracic aorta. The tests continued that the activity of the drug and metabolite is due only to the (-)-enantiomer because neither of the (+)-enantiomers is active.

La progettazione e sintesi di nuovi antivirali strutturalmente correlati a flavanoidi e flavonoidi sia naturali che sintetici e lo studio della relativa attività anti-picornavirus dei 4H-cromen-4-oni e 2H-cromeni ha portato ad identificare l’(E)-3-stiril-2H-cromene come un inibitore potente, selettivo e ad ampio spettro d’azione nei confronti dei rhinovirus umani (HRV). l’(E)-3-stiril-2H-cromene è stato perciò selezionato come hit compound sul quale effettuare uno studio sistematico di ottimizzazione della struttura. Sono stati quindi progettati e sintetizzati un ampio numero di arilalchil cromeni, cromanoni e cromoni che sono stati saggiati in vitro nei confronti dei sierotipi 14 e 1B di HRV, scelti come rappresentati rispettivamente dei gruppi A e B di HRV. L’estensione dello screening ad altri virus ad RNA conferma la bassa citotossicità e la selettività dell’azione anti-HRV. Sono stati così selezionati i composti più potenti, ad ampio spettro d’azione anti-HRV e con alto indice terapeutico per valutarne il meccanismo d’azione. I risultati ottenuti sia sulla particella virale che sulla moltiplicazione virale suggeriscono che tutti i composti selezionati si comportano da capsid-binder, interferendo con le prime fasi dell’infezione virale, ma mentre l’(E)-3-stiril-2H-cromene agisce sull’adsorbimento del virus al recettore cellulare gli altri composti studiati non interferiscono in questa fase ma solo sul processo di uncoating. Il risultato è di notevole interesse dal momento che l’utilizzo di combinazioni di farmaci che agiscono su fasi successive della replicazione virale potrebbe essere utile per superare il problema delle mutazioni virali che rendono rapidamente inefficace la monoterapia.