The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum

Abstract

<p>Influenza A viruses can cause a serious future threat due to frequent mutations. Amantadine and rimantadine inhibit influenza A M2 wild-type (WT) viruses by binding and blocking M2 WT channel-mediated proton current. The resistant to the drugs amantadine and rimantadine influenza A viruses bearing the S31N mutant in the M2 proton channel can be inhibited by <span style="color:rgb( 33 , 33 , 33 )">amantadine – aryl conjugates, in which amantadine and an aryl group are linked through a methylene, which block M2 S31N channel</span>-mediated proton current<span style="color:rgb( 33 , 33 , 33 )">. </span>However, the M2 amantadine / rimantadine resistant viruses bearing one of the four mutations L26F, V27A, A30T, G34E in residues that line the M2 protein pore pose an additional concern for public health.</p><p> </p><p>Here, we designed 33 compounds based on the structure of three previously published and potent amantadine-aryl conjugates against M2 S31N virus, by replacing amantadine with 16 amantadine variants. The compounds were tested against M2 WT and the five M2 amantadine-resistant viruses aiming at identifying inhibitors against multiple M2 mutant – amantadine resistant viruses.</p><p> </p><p>We identified 16 compounds that inhibited <em>in vitro</em> two influenza A viruses with M2 WT or L26F channels. Additionally, compounds <strong>21</strong> or<strong> 32 </strong>or<strong> 33</strong>, which are conjugates of the rimantadine variant with CMe₂ (instead of CHMe in rimantadine) or the diamantylamine or the 4-(1-adamantyl)benzenamine with the 2-hydroxy-4-methoxyphenyl aryl group, were <em>in vitro</em> inhibitors against three influenza A viruses with M2 WT or L26F or S31N, while compound <strong>21</strong> inhibited<em> </em>also <em>in vitro</em> the M2 G34E virus and <strong>32</strong> inhibited also <em>in vitro</em> the M2 A30T virus. For these compounds we performed <span style="color:black">a preliminary </span><a href="https://en.wikipedia.org/wiki/Drug_metabolism" target="_blank" rel="nofollow noopener noreferrer">drug metabolism</a> and <a href="https://en.wikipedia.org/wiki/Pharmacokinetics" target="_blank" rel="nofollow noopener noreferrer">pharmacokinetics</a> study. Also, using electrophysiology, we showed that compound <strong>21 </strong>was<strong> </strong>an efficient blocker of the M2 WT and M2 L26F channels, compound <strong>32 </strong>blocked efficiently the M2 WT channel and compound <strong>33</strong> blocked the M2 WT, L26F and V27A channels.</p><p> </p>