Design and synthesis of bioactive 1,2-annulated adamantane derivatives

Abstract

Adamantanopyrrolidines 8, 9 and 10, adamantanopyrrolidines 16 and 18, adamantanoxazolone 20, adamantanopyrazolone 23, adamantanopyrazolothione 24 and adamantanocyclopentanamine 32 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. Pyrrolidine 16 proved to be the most active of the compounds tested against influenza A virus, being 4-fold more active than amantadine, equipotent to rimantadine and 19-fold more potent than ribavirin. Oxazolone 20 showed significant trypanocidal activity against bloodstream forms of the African trypanosome, Trypanosoma brucei, being approximately 3 times more potent than rimantadine and almost 50-fold more active than amantadine.

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

“…Representing another recently studied class of aminoadamantanes designed and screened as antivirals, 1,2-annulated ring systems have also been studied. 152 The potency of 88 along with a marked decrease in activity when N -alkylated (compared to amantadine, anti- Influenza A (H3N2) activity of 88 was 4.3-fold while the N -ethyl derivative was less potent than amantadine) confirmed the SAR from previous publications. Focusing on adamantyl piperidines, the differences in potency of 1,2-annulated piperidines 91 and 92 are striking.…”

“…154 Out of a series of adamantane-2-oxazolines tested, only 193 displayed significant activity, and since this class of adamantyl-heterocycles has an effect on microtubule association that does not correlate with their trypanocidal potency, the effect on tubulin polymerization obviously is not contributing to anti-trypanosomal activity. 357 4,5-Dihydroimidazole 194 , 358 adamantane oxazolone 196 , and adamantane cyclopentane amine 197 152 also are examples for adamantyl substituted heterocyles with trypanocidal activity at comparable potency in the in vitro test. Combining the guanylhydrazone pharmacophore, which is known to be a S-adenosylmethionine decarboxylase inhibitor and a trypanocidal motif by itself, with lipophilically substituted adamantane moieties, a synergistic effect of lipophilicity at C1 of the adamantane scaffold and the C2 functionality could be observed in compounds 195 , 359 199 , and 200 .…”

Discovery of Spiro-Piperidine Inhibitors and Their Modulation of the Dynamics of the M2 Proton Channel from Influenza A Virus

“…Similar structure–activity relations were also found in adamantane analogues, where methylation and ethylation of the amine group of all heterocycles caused a reduction of anti-influenza A virus activity. 17,19–22,25 …”

Another ten stories in antiviral drug discovery (part C): “Old” and “new” antivirals, strategies, and perspectives

“…88 Whether amantadine (which is also known for its beneficial effects on the course of Parkinson's disease), or adamantanamine derivatives in general, may have a role to play in the treatment of chronic HCV infections, e.g. in combination with ribavirin and/or pegylated interferon, [89][90][91][92][93][94][95] is an attractive but debated possibility, that until today has remained controversial.…”

“…In addition, derivatives from adamantane, such as spiro[piperidine-4,2 0 -adamantane] 87 and adamantanoxazolone 88 and related compounds (such as bananins) 84 should be further explored not only for their activity against influenza A viruses, but also other viruses [whether or not depending on H 1 ion channel function (as in the case of HCV) for their replication], and for their potential trypanocidal activity (as has been demonstrated for adamantanoxazolone against T. brucei. 88 Whether amantadine (which is also known for its beneficial effects on the course of Parkinson's disease), or adamantanamine derivatives in general, may have a role to play in the treatment of chronic HCV infections, e.g.…”