New derivatives of 7-amino-2,3-polymethylenindole with anti-inflammatory activity

Thirty-four new N-acylderivatives of 7-amino-2,3-polymethyleneinoles (I) and (II) were prepared and tested, together with a few analogues previously obtained, against carrageenan edema in the rat. Several compounds, at a dose of 1 mmole/kg, exhibit good inhibitory activity, that in some cases is superior to that displayed by indomethacin at a dose of 5 mg/kg. With only one exception, activity is confined to compounds of formula (I) and, generally, derivatives of 2,3-hexamethyleneindole are more active than those of lower homologues.     

Analgesic and anti-inflammatory activity of 10-amino-11H-indeno [1,2-b] quinolin-11-one derivatives

Ten novel derivatives of 11H-indeno [1,2-b] quinolin-11-one (1-10) were synthesized and pharmacologically screened. All compounds showed analgesic activity. Anti-inflammatory activity was found only for alkylamine derivatives 1-6. The most active 10-ethylamine derivative 2 showed also ulcerogenic properties. The LD50/UD50 and UD50/ED50 values for compound 2 were less satisfactory than those for ibuprofen.     

Analgesic and anti-inflammatory activity of podophyllotoxin derivatives

Abstract

Context: Podophyllotoxin is a natural product that inhibits the polymerization of tubulin and has served as a prototype for the development of diverse antitumor agents in clinical use, such as etoposide, teniposide and etopophos. Reumacon, another semisynthetic derivative, reached its clinical phase for the treatment of rheumatoid arthritis.

Objective: This study investigated the analgesic and anti-inflammatory properties of three compound derivatives from podophyllotoxin.

Materials and methods: During a phytochemical study performed on Juniperus thurifera Linne (Cupressaceae) leaves, among other products, several cyclolignans, such as podophyllotoxin, deoxypodophyllotoxin, deoxypicropodophyllotoxin and thuriferic acid were isolated. These compounds, obtained afterwards through semisynthesis, were assayed as analgesic and anti-inflammatory agents. Additionally, the cytotoxic activity of thuriferic acid was evaluated in three cancer cell lines, P-388, A-549 and HT-29, and these data were compared with previous cytotoxicity results obtained for the other three compounds.

Results: Analgesic activity results showed that deoxypicropodophyllin is as effective as deoxypodophyllotoxin to inhibit nociceptive perception induced by acetic acid in mice (77.8%?±?4.1% and 71.3%?±?6.5%, respectively), while its cytotoxicity [1.01?×?10^?7 (GI₅₀ M)] is 100-fold less. Other set of experiments showed that thuriferic acid, a derivative of podophyllotoxin a thousand times less citotoxic [1.21?×?10^?5 (GI₅₀ M)] than deoxypodophyllotoxin, caused significant inhibition of paw edema development in the carrageenan-induced inflammation test (63.4%?±?3.3%), effect comparable to those of deoxypodophyllotoxin (66.3%?±?4.4%), and the standard drug indomethacin (61.5%?±?2.5%).

Conclusion: We conclude that deoxypicropodophyllotoxin and thuriferic acid are effective in reducing edema formation. However, deoxypicropodophyllin is more related with analgesic activity than anti-inflammatory effect.     

Synthesis of O-allyl derivatives of 2,3-dihydroxypropyluracil and thymine and their antiviral activity

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 25, No. 12, pp. 35–37, December, 1991.     

Synthesis and biological activity of 7 beta-(2-amino-2-carboxy)-ethylthioacetamido-7 alpha-methoxycephalosporin derivatives

C-7 and C-3 substituents of a new antibiotic SF-1623 were chemically modified to improve the bioactivity, and substituent effect at C-7 and C-3 was examined on the basis of MIC and ED50 values against selected bacteria. Among a large number of derivatives, MT-141 possessing 2-D-2-amino-2-carboxyethylthioacetamido residue at C-7 and N-methyltetrazolyl-thiomethyl residue at C-3 showed a high order of antibacterial activity in vitro and especially in vivo.     

Analgesic activity of thioureido derivatives of arylsemicarbazones

The synthesis of a series of novel arylsemicarbazones derived from 4-aminoacetophenone and their evaluation for analgesic activity are described. The p-chloro-substituted derivatives (12-15) are extremely potent compounds as compared to standard drugs currently being used.     

New derivatives of 5-amino-3-methyl-4-isothiazolecarboxylic acid and their immunological activity

Several new compounds - 4 and 5-substituted derivatives of 3-methyl-4-isothiazolecarboxylic acid were synthesized. These compounds have aminoacylamino groups in position 5 of the isothiazole ring. In position 4, the carboxylic group was replaced by ethyl ester. The biological activites of the obtained compounds were analyzed in the humoral immune response and delayed type hypersensitivity reaction to sheep red blood cells (SRBC) in the mouse model, as well as in the proliferative response of splenocytes to T-cell and B-cell mitogens in vitro.     

Preparation of 7-oxaaporphine derivatives and evaluation of their dopaminergic activity

A series of 7-oxaaporphine derivatives was prepared. The compounds were evaluated as dopaminergic agents. None of them showed either affinity for dopamine receptors or activity in vivo in the climbing behavior (mice) and turning behavior (6-hydroxydopamine-lesioned rats) tests. The lack of activity is tentatively related to the effect of the oxygen atom on the pKa of these molecules.     

Analgesic activity of acylated 2-benzoxazolinone derivatives.

Ten new benzoxazolinone derivatives having a disubstituted benzoyl group at the six position of the ring were synthesized by reacting 2-benzoxazolinone with aromatic carboxylic acids in the presence of polyphosphoric acid. The structure of the compounds were elucidated by IR, 1H NMR, MS and elemental analysis. Analgesic activity was evaluated by a modified Koster test. Seven compounds showed analgesic activities higher than that of acetylsalicylic acid.     

Synthesis and metal ion binding activity of methyl 12-amino-13-nitro-7-oxo dehydrodeisopropylabietate derivatives

Starting from dehydrobaietic acid with the analogous structure of carnosic acid, the intermediate methyl 12-bromo-13-nitro-7-oxo dehydrodeisopropylabietate was synthesized through methylation, bromination, carbonylation, and nitration. Subsequently, the coupling of methyl 12-bromo-13-nitro-7-oxo dehydrodeisopropylabietate with aliphatic or aromatic primary amine by Ullmann condensation reaction produced a series of methyl 12-imino-13-nitro-7-oxo dehydrodeisopropylabietate derivatives. In order to probe their antioxidant effects through metal ion chelation mechanism, the metal ion binding abilities on Cu²⁺ and Fe²⁺ of these compounds were studied using fluorescence quenching method. The results indicated that each compound showed obvious chelation activity with the binding constants (K _A) of the 10² L?mol^?1 order of magnitude, which implied its potential pharmacology application as antioxidant by the inhibition of Feton reaction through chelation with Cu²⁺ and Fe²⁺.     

Synthesis and antiarrhythmic activity of epimeric 17-amino-5α-androstan-3-ols and their derivatives

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 22, No. 3, March, 1988.     

Synthesis of the 7,8-dihydro-7-deazapurine derivatives and their antibiotic activity

Thecis- andtrans-diastereomers of the 7,8-dihydro-7-deazapurine derivatives were synthesized from the corresponding diastereomers of 4-trans-cyano-2-methyl-3-phenyl-5-oxopyrrolidine (5), which were reduced from the 2-cis- and 2-trans-diastereomers of 4-trans-cyano-2-hydroxymethyl-3-phenyl-5-oxopyrrolidine (2)via tosylation, iodination and following elimination, respectively. The preparedcis- andtrans-diastereomers of 6-amino-2-mercapto-8-methyl-7-phenyl-7,8-dihydro-7(9H)-deazapurine (8) were transferred to the corresponding 2-methylthio-diastereomers9 and following desulfurization with Raney-nickel leaded to thecis-andtrans-diastereomers of 6-amino-8-methyl-7-phenyl-7,8-dihydro-7(9H)-deazapurine (10), respectively. The synthesized 7-deazapurine derivatives were tested for their antibiotic activity by the serial two-fold dilution method.     

Synthesis of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives and evaluation of their antidepressant and anxiolytic activity

Recently a series of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives bearing different substituents were synthesized and screened pharmacologically in order to evaluate their central nervous system activity. The purpose of this study was to evaluate the effects of the title compounds on CNS activity by varying the substituents in the thiadiazole moiety. It was found that some of these compounds possess marked antidepressant and anxiolytic properties comparable in efficiency to the reference drugs Imipramine and Diazepam. The most potent compound 3k was further investigated to complete its pharmacological profile with respect to undesired side effects. Behavioral results showed that 3k is a very promising compound, characterized by a mixed antidepressant-anxiolytic activity accompanied by a therapeutic dose range that is essentially 2 orders of magnitude less than that at which side effects such as sedation and amnesia are evident.