O. V. Ardashov

Synthesis and analgesic activity of new compounds combining azaadamantane and monoterpene moieties

Synthesis of new compounds that combine the diazaadamantane and monoterpenoid moieties was carried out based on the reaction between dimethylbispidinone and monoterpene-derived aldehydes. Investigation of the analgesic activity of the obtained products revealed that compound 5a synthesized from (−)-myrtenal had a higher efficacy compared with the reference drug, diclofenac sodium, in the acetic acid-induced writhing and hot plate tests. Compound 5a exhibits a low acute toxicity and does not cause damage to the gastric mucosa, and its analgesic effect is, at least partially, mediated by the cannabinoid system involving CB1 receptors.

Antiparkinsonian activity of some 9-N-, O-, S- and C-derivatives of 3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol

Earlier it was found, that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (1) possess high antiparkinsonian activity. The N-, O-, S- and C-derivatives at the C-9 position of diol 1 were synthesized in this work. The antiparkinsonian activity of these compounds was studied in MPTP mice models. As a rule, the introduction of substituents containing nitrogen atoms at the C-9 position led to a considerable decrease or loss of antiparkinsonian activity. A derivative of 2-aminoadamantane 8 significantly decreased the locomotor activity time, thus enhancing the symptoms of the parkinsonian syndrome. However the introduction of butyl or propylthio substituents at the C-9 position of diol 1 did not diminish the antiparkinsonian activity comparing to parent compound. This information is important when choosing a route for immobilization of compound 1 to find possible targets.

Synthesis and analgesic activity of new α-truxillic acid derivatives with monoterpenoid fragments

Novel derivatives of α-truxillic acid with a camphor framework were synthesized and evaluated for their in vivo analgesic activity. α-Truxillic acid derivatives were prepared via solvent-free photocatalyzed [2+2] cyclodimerization of (E)-cinnamic acid. Target compounds were obtained through the substitution of –Cl or –OH groups in α-truxillic acid. The chemical structures of the synthesized compounds were elucidated by 1H, 13C-NMR, and mass spectrometry. Their analgesic activities were evaluated by the acetic acid-induced writhing test and the hot plate method. Compounds 7b and 7f containing the cyclobutane unit and natural fragments at 10xa0mg/kg exhibited analgesic activity in the acetic acid-induced writhing test, while α-truxillic acid (10xa0mg/kg, per os) did not show analgesic activity in the test. Intermediate 2 caused a decrease in the writhing with pain inhibition of 28xa0%. In the hot plate test, borneol showed high analgesic activity with pain inhibition of 60xa0%.

Hydrogenation and conformational analysis of (1R,2R,6S)-3-methyl-6-(1-methylethenyl)cyclohex-3-ene-1,2-diol

Hydrogenation of (1R,2R,6S)-3-methyl-6-(1-methylethenyl)cyclohex-3-ene-1,2-diol was studied. Nickel chloride-sodium tetrahydridoborate system turned out to selectively reduce the double bond in the isopropenyl group. The results of conformational analysis of (1R,2R,6S)-3-methyl-6-(1-methylethenyl)cyclohex-3-ene-1,2-diol and its partly and completely hydrogenated derivatives were in a good agreement with the NMR data.

Synthesis and analgesic activity of monoterpenoid-derived alkyl-substituted chiral hexahydro-2H-chromenes

A set of new 2-alkyl-substituted 4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diols was obtained by reactions of monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol with aliphatic aldehydes in the presence of montmorillonite clay K10. Synthesized compounds were evaluated for their analgesic activity in vivo using the acetic acid-induced writhing test and the hot-plate test. Five compounds showed a significant analgesic activity in the acetic acid-induced writhing test; two of them also demonstrated analgesic activity in the hot-plate test. These compounds seem to be most promising for further development.

Evolution of anti-parkinsonian activity of monoterpenoid (1 R ,2 R ,6 S )−3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol in various in vivo models

Abstract It has been found recently that monoterpenoid (1R,2R,6S)‐3‐methyl‐6‐(prop‐1‐en‐2‐yl)cyclohex‐3‐ene‐1,2‐diol (Diol) demonstrates high antiparkinsonian activity in some animal models. We carried out an extended study of the antiparkinsonian activity of Diol in a set of relevant animal models. Diol (20 mg/kg) exhibited an anticataleptogenic effect in the haloperidol‐induced catalepsy model and restored motor activity in animals in the reserpine‐induced model of oligokinesia. The ability of Diol singly administered before MPTP injection to reduce rigidity comparable to that of activity of L‐DOPA (100 mg/kg) was found using the model of Parkinsonian syndrome (PS) induced by single injection of MPTP (30 mg/kg) to C57BL/6 mice. In the model of PS induced by subchronic administration of MPTP (4 × 20 mg/kg), Diol at a dose of 20 mg/kg reduced rigidity with effectiveness comparable to that of L‐DOPA, while being superior to L‐DOPA in terms of its effect on motor activity. It was found using the model of PS induced by systemic administration of rotenone that subchronic daily oral administration of Diol prior to rotenone injection reduced severity of PS in rats. Assessment of the effects of chronic administration of Diol (20 mg/kg) and L‐DOPA to animals with 6‐OHDA‐induced PS showed that administration of Diol alleviated the symptoms of sensorimotor deficit in right limbs in rats. Thus, the potent antiparkinsonian activity of Diol was demonstrated in all the used rodent models experiments. Diol (20 mg/kg) is as effective as the comparator agent L‐DOPA administered at doses of 50–100 mg/kg.

Synthesis of 10-Carbonyl and 10-Carboxylic Derivatives of para -Mentha-1,8-Diene-5,6-Diol

The synthesis of 10-carbonyl and 10-carboxylic derivatives of para-mentha-1,8-diene-5,6-diol (1) that exhibited high anti-Parkinson’s activity was described. The synthesis of these compounds was an important programmatic component in a study of the metabolism of 1.

Synthesis and Analgesic Activity of 4,7-Dimethyl-3,4,4a,5,8,8a-Hexahydro-2H-Chromen-4,8-Diols Containing Thiophene Substituents

Hexahydro-2H-chromenes with thiophene fragments were synthesized via reactions of a p-menthane monoterpenoid diol with several thiophenecarboxaldehydes. Most of the synthesized compounds with an additional thiophene fragment displayed analgesic activity in vivo tests at a dose of 10 mg/kg. It was found that the activity in either an acetate-writhing test or a hot-plate test depended on the type and location of substituent in the heteroaromatic ring.

Synthesis and structure determination of diastereoisomeric (1R,2R,6S)-6-(3-{[(1RS)-1-(1-adamantyl)ethyl]amino}prop-1-en-2-yl)-3-methylcyclohex-3-ene-1,2-diols

Epimeric (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol derivatives containing a rimantadine residue have been synthesized, and their steric structure has been determined using NOESY technique and DFT quantum chemical calculations.