- Design, synthesis and evaluation of small molecule CD4-mimics as entry inhibitors possessing broad spectrum anti-HIV-1 activity
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Since our first discovery of a CD4-mimic, NBD-556, which targets the Phe43 cavity of HIV-1 gp120, we and other groups made considerable progress in designing new CD4-mimics with viral entry-antagonist property. In our continued effort to make further progress we have synthesized twenty five new analogs based on our earlier reported viral entry antagonist, NBD-11021. These compounds were tested first in HIV-1 Env-pseudovirus based single-cycle infection assay as well as in a multi-cycle infection assay. Four of these new compounds showed much improved antiviral potency as well as cytotoxicity. We selected two of the best compounds 45A (NBD-14009) and 46A (NBD-14010) to test against a panel of 51 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates. These compounds showed noticeable breadth of antiviral potency with IC50of as low as 150 nM. These compounds also inhibited cell-to-cell fusion and cell-to-cell HIV-1 transmission. The study is expected to pave the way of designing more potent and selective HIV-1 entry inhibitors targeted to the Phe43 cavity of HIV-1 gp120.
- Curreli, Francesca,Belov, Dmitry S.,Ramesh, Ranjith R.,Patel, Naisargi,Altieri, Andrea,Kurkin, Alexander V.,Debnath, Asim K.
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- Importance of the azole moiety of cimetidine derivatives for the inhibition of human multidrug and toxin extrusion transporter 1 (hmate1)
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Herein, we describe the design and synthesis of cimetidine analogs, as well as their inhibitory activity toward the human multidrug and toxin extrusion transporter 1 (hMATE1), which is related to nephrotoxicity of drugs. Cimetidine is the histamine H2-receptor antagonist, but also inhibits hMATE1, which is known to cause renal impairment. We designed and synthesized cimetidine analogs to evaluate hMATE1 inhibitory activity to reveal whether the analogs could reduce the inhibition of hMATE1. The results showed that all analogs with an unsubstituted guanidino group exhibited hMATE1 inhibitory activity. On the other hand, there was a clear difference in the hMATE1 inhibitory activity for the other compounds. That is, compounds with a methylimidazole ring exhibited hMATE1 inhibition, while compounds with a phenyl ring did not. The results suggest that the ability to form hydrogen bonds at the azole moiety is strongly involved in the hMATE1 inhibition.
- Shinya, Susumu,Kawai, Kentaro,Tarui, Atsushi,Karuo, Yukiko,Sato, Kazuyuki,Matsuda, Masaya,Kitatani, Kazuyuki,Kobayashi, Naoki,Nabe, Takeshi,Otsuka, Masato,Omote, Masaaki
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p. 905 - 912
(2021/09/06)
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- Process for the manufacture of 4-methyl-5-hydroxymethyl-imidazole
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A process is provided for the manufacture of 4-lower-alkyl-5-hydroxymethyl-imidazole comprising reacting (4)-lower-alkyl imidazole with formaldehyde in an alkanol solvent having from 2 to 5 carbon atoms in the presence of a solid mild base suspended in the solvent.
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- Preparation of 5-hydroxymethylimidazoles
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A process for the manufacture of 5-hydroxymethylimidazoles by reaction of an imidazole with formaldehyde or an oligomer of formaldehyde in aqueous hydrochloric acid solution containing from 5 to 18% by weight of hydrogen chloride, at from 80° to 160° C., if desired in a closed system under pressure, followed by isolation in the form of its hydrochloride of the 5-hydroxymethylimidazole obtained.
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- Process for the production of hydroxymethylimidazoles
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This invention discloses a process for the production of hydroxymethylimidazoles which comprises reacting imidazolecarboxylic acids, their esters or inorganic salts with a formaldehyde agent in the presence of an alkali in an aqueous medium.
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- Process for producing 1-hydroxymethylimidazoles
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1-Hydroxymethylimidazoles which are unsubstituted or alkyl-substituted in the 2-position, their manufacture and their use as chemical intermediates, e.g. for other imidazole derivatives or for the drug cimetidine.
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- Preparation of 4-methyl-5-chloromethyl-imidazole
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4-Methyl-5-chloromethyl-imidazole is prepared in the form of its hydrochloride by direct chloromethylation of 4-methyl-imidazole, thus becoming readily available industrially as an intermediate.
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- Process for preparing 4-(hydroxymethyl)imidazole compounds
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An improved process for the preparation of 4-(hydroxymethyl)imidazoles by reducing 4-imidazolecarboxylic acid esters using an alkali metal or calcium in liquid ammonia with an additional proton source provided during the reaction or upon workup.
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- Process of reduction
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An electrochemical process for preparing 4-(hydroxymethyl)-imidazoles, which are useful as chemical intermediates.
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