4-(1-Adamantyl)phenylalkylamines with potential antiproliferative activity

© 2016 Bentham Science Publishers. Background: In our previous publications we have described the synthesis of aminosubstituded diaryl adamantanes and their pharmacological evaluation in vitro and in vivo against many cancer cell lines. More recently, we have reported the synthesis of mono C2-Aryl substituted aminoadamantane derivatives that have moderate antiproliferative activity at low micromolar IC50 against a panel of four tumor cell lines. Methods: The synthesis and the pharmacological evaluation of 4-(1-Adamantyl) phenylalkylamines 1-4 is described in this work. The new derivatives present an aryl substitution at C-1 adamantane position and diverge from the methylene spacer between the phenyl ring and the amine heterocycle moiety. Results: Piperazines 1a (R:N-H) and 1b (R:N-Me) are more active than piperidine 1c. This difference indicates the importance of the presence of this nitrogen atom in 1a and 1b, which is at a distance of 3 atoms (two carbons and the piperazine nitrogen included) from the benzene ring. Adducts 2a,b are less active than the rest of the products, because neither the R:N-H nitrogen atom (compound 2a) nor the R:N-Me nitrogen (compound 2b) are in an optimum distance from the benzene ring. Derivatives 3a-c are almost as potent as the piperazines 1a and 1b, which means that also in this case, the distance of 2 atoms (PhβCH2αCH2N) is sufficient for antiproliferative activity. Products 4a-c have also significant activity, possibly due to the fact that the benzene moiety is attached to the nitrogen atom via a three methylene linker. Piperidine 4c is the most potent compound, showing that the nitrogen atom of these cyclic amines, which is near to benzene ring, is important for the pharmacological action. Conclusion: The comparison of the pharmacological results of the present work in relation to our previous publication shows that C-1 substitution in adamantane skeleton with aminoaryl or aminoalkyl groups enhances the antiproliferative activity towards to C-2 substitution. Our approach shows that the optimization of the antiproliferative activity is the incorporation of the p-Aminoalkylphenyl side chain at C-1 adamantane position.status: publishe

Synthesis of Adamantane Aminoethers with Antitubercular Potential

Background: Intrigued by the fact that aminoadamantane derivatives, bearing the active 1,2-ethylenediamine moiety, are promising antitubercular agents, we report herein the synthesis and the antitubercular evaluation of N,N'-substituded-4,4'-[adamantane-2,2-diyl]bis(phe-noxyalkylamines) 1a-g, N,N'-substituded-4,4'-[adamantane-1,3-diyl]bis(phenoxyalkylamines) 2a-f, N,N'-substituded-[4-(1-adamantyl)phenoxy]alkylamines 3a-d and N,N'-substituded-[4-(2-adamantyl)phenoxy]alkylamines 4a, b. Method: A substituted diarylmethane moiety was introduced on the adamantane skeleton of the new derivatives. The synthesis of the above compounds involved the nucleophilic attack of the corresponding phenoxide, to the appropriate aminoalkylchloride hydrochloride under heating. Results: The double substituted adamantane derivatives with an aminoether side chain exhibit significant activity against Mycobacterium tuberculosis. Conclusion: The length and the nature of the amino end of the side chain influence the antitubercular activity. The double phenolic substitution of the adamantane scaffold and the aminoether side chain with a three-methylene spacer between the phenoxy group and the nitrogen atom present the better results. (analogues 1f, g and 2e, f). These findings merit further investigation aiming at the design of more potent adamantane antituberculars, bearing a number of different substituents on the diarylmethane pharmacophore, which will also be translocated to other posititions on the adamantane ring

Design and synthesis of bioactive adamantane spiro heterocycles.

Spiro[aziridine-2,2'-adamantanes] 1 and 2, spiro[azetidine-2,2'-adamantanes] 3 and 5, spiro[azetidine-3,2'-adamantane] 13, spiro[piperidine-4,2'-adamantanes] 25 and 27, and spiro barbituric analog 18 were synthesized and tested for their anti-influenza A virus properties and for trypanocidal activity. The effect of ring size on potency was investigated. Piperidine 25 showed significant anti-influenza A virus activity, being 12-fold more active than amantadine, about 2-fold more active than rimantadine, and 54-fold more potent than ribavirin. It also proved to be the most active of the compounds tested against bloodstream forms of the African trypanosome, Trypanosoma brucei, being 1.5 times more potent than rimantadine and at least 25 times more active than amantadine

Conformationally Constrained Adamantaneoxazolines of Pharmacological Interest

New conformationally constrained adamantane 2-oxazoline building blocks 1-4 were synthesized and their antimicrotubule and antitrypanosomal potency was investigated. Although most of the new compounds affect tubulin polymerization, this does not make a major contribution to trypanocidal activity. © 2008 The Japan Institute of Heterocyclic Chemistry

New Adamantane Phenylalkylamines with σ‑Receptor Binding Affinity and Anticancer Activity, Associated with Putative Antagonism of Neuropathic Pain

The synthesis of the adamantane phenylalkylamines <b>2a</b>–<b>d</b>, <b>3a</b>–<b>c</b>, and <b>4a</b>–<b>e</b> is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The σ₁, σ₂, and sodium channel binding affinities of compounds <b>2a</b>, <b>3a</b>, <b>4a</b>, and <b>4c</b>–<b>e</b> were investigated. The most interesting analogue, <b>4a</b>, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with <b>4a</b>. Finally, encouraging results were observed with <b>4a</b> in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound