Synthesis of new derivatives of 2,3-dihydro-7-benzo[b]furanol with potential pharmacological activity

A series of 13 new ether-linked derivatives of 2,2-dimethyl-2.3-dihydro-7-benzofuranol have been designed and synthesized. Seven of them were evaluated for anti-HIV potency. They showed a relatively high cytotoxicity and a low anti-HIV- I activity.     

Synthesis of new derivatives of 2,2-dimethyl-2,3-dihydro-7-benzo[b]furanol with potential antimicrobial activity

A series of 13 new ether-linked derivatives of 2,2-dimethyl-2,3-dihydro-7-benzo[b]furanol have been designed and synthesized. Ten of them were evaluated for their potential antimicrobial activity against some Gram-positive and Gram-Negative bacteria and fungi of the Candida species.     

Synthesis of 3-(3-pyridyl)- and 3-(3-benzo[b]thienyl)-D-alanine

The DL-arylamino acid ethyl ester derivatives of β-(3-pyridyl)-DL-alanine, and β-(3-benzo[b]thienyl)-DL-alanine were synthesized by diethyl acetamidomalonate condensation with the respective arylmethyl halides followed by partial hydrolysis to the monoethyl ester and decarboxylation. Each derivative was enzymatically resolved to a separable mixture of the corresponding N-acetyl-L-amino acid and the unchanged D amino acid derivative. Acidic hydrolysis of the latter gave the corresponding D-amino acid, the optical purity of which was established by HPLC analysis of the 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate (GITC) derivative. The free D amino acids were converted to D-BOC derivatives by reaction with di-tert-butyldicarbonate in tert-butyl alcohol, water and sodium hydroxide.     

Synthesis and cytotoxic activity of carboxamide derivatives of benzo[b][1,6]naphthyridines

The reaction of 4-dimethylaminomethylene-6-methyl-4H-pyrano[4,3-b]quinoline-1,3-dione with a range of primary amines gave rise to a series of 2-substituted 6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acids. The derived 4-N-[2-(dimethylamino)ethyl]carboxamides were tested for growth inhibitory properties against murine P388 leukemia, Lewis lung carcinoma (LLTC), and human Jurkat leukemia cell lines. Most compounds were potent cytotoxins, with some having IC(50) values less than 10 nM. Five were tested in vivo against subcutaneous colon 38 tumors in mice, and a single dose (3.9 mg/kg) proved to be curative for the 2-methyl and 2-(3,4-dimethoxyphenyl) derivatives in this refractory model.     

beta-Adrenoceptor blocking activity of 3-alkylamino-1-(3-benzo[ b ]thienyloxy)-2-propanols and closely related bicyclic compounds

A preliminary pharmacological study of a thiophenic isoster of propranolol and related compounds with a tert. butylamino or homoveratrylamino group instead of the isopropylamino group is described. The synthesis and some pharmacological properties of derivatives in which the benzene ring is replaced by a cyclopentene or cyclohexene ring are also reported. Compounds carrying the tert. butylamino moiety turned out to be similar to propranolol in their pharmacological properties.     

5-Chloro-2-phenyl-1-benzo[b]thiophene-3-alkanimines, potential antipsychotic agents.

The title compounds (most notably 2a) were synthesized on the basis of the N-methylation hypothesis of schizophrenia. They were evaluated in dopamine and haloperidol receptor assays. The binding characteristics were comparable in some cases to known neuroleptics.     

Synthesis and pharmacological activity of benzo[b]thiophene-3-carboxylic acid derivatives

Several dialkylaminoethyl benzo[b]thiophene-3-carboxylates, N-(2-dialkylaminoethyl)benzo[b]thiophene-3-carboxamides, 2-dialkylaminoethyl benzo[b]thiophene-3-carbamates, and substituted ureas with benzo[b]thiophene moiety, were prepared and tested for local anesthetic, anticholinergic, and antihistaminic activities. Several of the compounds showed significant activity.     

Selective thromboxane synthetase inhibitors. 4. 2-(1H-imidazol-1-ylmethyl) carboxylic acids of benzo[b]furan, benzo[b]thiophene, indole, and naphthalene

The preparation of a series of 2-(1H-imidazol-1-ylmethyl)-substituted carboxylic acids of benzo[b]furan, benzo-[b]thiophene, indole, and naphthalene is described. All compounds showed a similar level of activity as TxA2 synthetase inhibitors in vitro, having IC50 values between 1 and 7 X 10(-8) M. In the cases examined, compounds had, at most, only negligible activity against PGI2 synthetase, cyclooxygenase, and steroid 11 beta-hydroxylase. The benzo[b]thiophenes generally showed the greatest potency in vivo, and compounds 72, 73, and 75 caused almost complete inhibition of thromboxane production for 6 h after oral administration of 0.5 mg/kg to conscious dogs. In the case of 73 and 75, thromboxane production was still inhibited by 80% after 24 h.     

Synthesis and biological activity of [L-hydroxyproline]3-tuftsin analogue and its α- or β-O-D-glucosylated derivatives

Syntheses are described of the Hyp³-tuftsin analogue and of its derivatives α- or β-O-glycosylated at the side chain function of the hydroxyproline residue. The carbohydrate-free tetrapeptide was prepared by reacting Z-Thr-Lys(Z)-OH with H-Hyp-Arg(NO₂)-OBzl by the mixed anhydride procedure. In the synthesis of the α-glycosylated analogue the O-glycosyl amino acid was incorporated by reacting Boc-(Glcα+β)Hyp-OH with H-Arg(NO₂)-OBzl through the same procedure. The α-glucosylated dipeptide was isolated from the diastereomeric mixture, selectively deblocked, and acylated with Z-Thr-Lys(Z)-OH by the mixed anhydride procedure. In the preparation of the β-glucosylated analogue the BOP procedure was used for reacting Boc-[Glc(Ac)₄β]Hyp-OH with H-Arg(NO)₂-OBzl was well as for the final coupling to tetrapeptide. Removal of protecting groups from crude tetrapeptides was achieved by catalytic hydrogenation. Deacetylation of the sugar moiety of the β-glucosylated tetrapeptide was achieved by treatment with sodium methoxide in methanol. The synthetic compounds were isolated by ion exchange chromatography, and characterized by elemental analysis, amino acid analysis, optical rotation and proton NMR. Their capacity to evoke the release of interleukin 1 from mouse peritoneal macrophages and to modulate immunogenic activity of antigen-fed cells was evaluated, in comparison with tuftsin and rigin. All of the analogues were found to possess tuftsin-like activity.     

Synthesis and cytotoxic and antitumor activity of benzo[b]pyrano[3, 2-h]acridin-7-one analogues of acronycine

Benzo?b?cronycine (6-methoxy-3,3,14-trimethyl-3, 14-dihydro-7H-benzo?bpyrano?3,2-h?cridin-7-one, 4), an acronycine analogue with an additional aromatic ring linearly fused on the natural alkaloid basic skeleton, was synthesized in three steps, starting from 3-amino-2-naphthalenecarboxylic acid (5). Eight 1, 2-dihydroxy-1,2-dihydrobenzo?b?cronycine esters and diesters (17-24) were obtained by catalytic osmic oxidation, followed by acylation. All these compounds were significantly more cytotoxic than acronycine, when tested against L1210 leukemia cells in vitro. The potency of the cyclic carbonate 24 was in the range of the most active drugs currently used in cancer chemotherapy. Two selected diesters (17 and 24) were evaluated in vivo against P388 leukemia and colon 38 adenocarcinoma implanted in mice. Both compounds were markedly active at doses 16-fold lower than the dose of acronycine itself. Against colon 38 adenocarcinoma, compounds 17 and 24 were highly efficient, inhibiting tumor growth by more than 80%. Diacetate 17 was the most active, inhibiting tumor growth by 96% at 6.25 mg/kg, with two of seven mice being tumor-free on day 43.     

Synthesis, antiretroviral and antioxidant evaluation of a series of new benzo[b]furan derivatives

The antiretroviral and anti-oxidant profile of a series of new C-2 and C-7 substituted benzo[b]furans was explored by employing well established antiviral and antioxidant protocols. The most potent antioxidant compound tested was analog 7, which bears an OH at C-7 and a benzoyl group at C-2. In the influenza A type H3N2 virus screens analog 8a was almost five-fold more active than its counterparts and equipotent to rimantadine and amantadine. In the influenza B screening all of the new compounds tested were at least ten-fold more active than the control drug amantadine. The anti-HIV screening, using acutely infected MT-4 cells, showed that compound 8f (n = 4), was fifteen-fold more active than its monomer congeners, 8a and 8c, d and almost five-fold more potent than monomer 8b and dimer 8f (n = 3).     

Synthesis of aminomethyl derivatives of naphtho[1,2-b]furan

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 24, No. 11, pp. 29–31, November, 1990.     

Synthesis and biological activity of derivatives of cycloalkyl[b]pyrrolidine alcohols

Translated from Khimiko-farmatsevticheskii Zhurnal,Vol. 23, No. 7, pp. 836–840, July, 1989.     

Synthesis and fungistatic activity of 3-(2-dialkylaminoethylthio)thieno [2,3-c] and [3,2-d] isothiazole derivatives

A series of 5-acyl-4-amino-3-(2-dialkylaminoethyl)thieno-[2,3-c] and [3,2-d]isothiazole derivatives was synthesized. The compounds were evaluated for antifungal activity.