Synthesis and biological activity of substituted 4-aryl-2-methylenehydrazino-4-oxobut-2-enoic acids and their derivatives

Aseries of substituted 2-methylenehydrazino-4-aryl-4-oxobut-2-enoic acids and their anilides and esters were obtained using reactions of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids and their amides and esters with benzophenone hydrazone, benzyl monohydrazone, and triphenylphosphazines. The methyl ester of 2-(1,2-diphenyl-2-oxoethylidenehydrazino)-4-(4-chlorophenyl)-4-oxobut-2-enoic acid was also synthesized by decyclization of 3-(1,2-diphenyl-2-oxoethylidenehydrazino)-5-(4-chlorophenyl)-3H-furan-2-one using methanol. The synthesized compounds exhibit moderate anti-inflammatory, analgesic, and antimicrobial activity.     

Synthesis of 3-aryl-2-substituted-4(3H)-quinazolines as potential antimicrobial agents

Three new series of 4(3H)-quinazolinone derivatives were synthesized, namely: [3-Aryl-4(3H)-quinazolinon-2-yl]-methylenehydrazino-(N- substituted)-thiocarbamides, 3-Aryl-2-(3-substituted-4-phenyl-2,3-dihydrothiazol-2-ylidenehy drazonomethyl)-4 (3H)-quinazolinones and 3-Aryl-2-(3-substituted-4-oxothiazolidin-2-ylidenehydrazonometh yl)-4(3H)-quinazolinones. The antimicrobial activities of the synthesized compounds were also studied.     

Synthesis of 3-hydroxy-2- and -4-pyridone nucleosides as potential antitumor agents

The ribo- and arabinofuranosyl nucleosides of antitumor active 2- and 4-pyridones 1a and 2a were prepared by direct condensation of the silylated bases with either 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (4a) or 2,3,5-tri-O-benzyl-1-p-nitrobenzoyl-D-arabinofuranose (7) in the presence of trimethylsilyl triflate (Me3SiOTf). In the case of the arabinofuranosyl nucleosides, separation of the alpha and beta anomers was accomplished at the stage of O-benzyl-protected compounds (8b + 9b, and 10b + 11b) after chemical functionalization of the 3-hydroxy group of the pyridone aglycons with acetyl and benzyl groups, respectively. Deblocking of the protected ribo- and arabinofuranosyl nucleosides was performed by the standard methods. In vitro activity against P-388 cells in culture indicated that the 4-pyridone riboside 6d was the most active member of the series with a twofold lower ID50 than the parent pyridone 2a. However, this and all the other compounds tested in this series showed no activity against the in vivo model system of murine P-388 leukemia at doses ranging from 25 to 400 mg/kg qd 1-5.     

4-[1-(4-Fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid as a prototype to develop dual inhibitors of HIV-1 integration process

In recent years several potent HIV-1 integrase (IN) inhibitors have been identified and after the successful clinical use of raltegravir, they have gained a definitive place in the treatment of HIV-1 infection. Yet, there is a continuous effort to design newer inhibitors that target different steps in the integration process. Furthermore, the increased understanding of IN structural biology has opened novel approaches to inhibit IN, such as targeting its multimerization or interaction with cellular cofactors. On these bases, we have concentrated our research on the identification of small molecules able to inhibit two different stages of the integration process: the IN strand-transfer phase and the IN–LEDGF/p75 interaction. We found that the 4-[1-(4-fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid (CHI-1043) is an interesting anti-HIV agent exhibiting dual inhibitory effects. This work has suggested the possibility of also constructing an integration dual inhibitor using a design-in strategy.     

Synthesis of 2-amino-4-alkylmercapto-6-aryl-1,3,5-s-triazines and 4-amino-6-alkyl-mercapto-2-aryl-5-cyano-pyrimidine

Synthesis of 2-Amino-4-alkylmercapto-6-aryl-1, 3, 5-s-triazines and 4-Amino-6-alkyl-mercapto-2-aryl-5-cyano-pyrimidine The synthesis and the properties of 2-amino-4-alkylmercapto-6-aryl-1, 3, 5-triazines and 4-amino-6-alkylmercapto-2-aryl-5-cyanopyrimidine are described.     

1,5-Diarylpyrrole-3-acetic acids and esters as novel classes of potent and highly selective cyclooxygenase-2 inhibitors

A small set of substituted 1,5-diarylpyrrole-3-acetic and -glyoxylic acid derivatives have been synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity data have been rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site.     

Synthesis of 5-aryl-2H-tetrazoles, 5-aryl-2H-tetrazole-2-acetic acids, and [(4-phenyl-5-aryl-4H-1,2,4-triazol-3-yl)thio]acetic acids as possible superoxide scavengers and antiinflammatory agents

A series of 5-aryl-2H-tetrazoles, 5-aryl-2H-tetrazole-2-acetic acids, and [(4-phenyl-5-aryl-4H-1,2,4-triazol-3-yl)thio]acetic acids were synthesized and tested in vitro for superoxide scavenging activity, in vivo in the carrageenan-induced rat paw edema assay, and in the reverse passive Arthus reaction. The hydroxy-substituted compounds were effective as in vitro scavengers of superoxide but were not effective as in vivo antiinflammatory agents.     

Synthesis and antimicrobial activity of β-N-acylhydrazides of 4-aryl-2-hydroxy-4-oxo-2-butenoic (aroylpyruvic) acids

A series of β-N-acylhydrazides of 4-aryl-2-hydroxy-4-oxo-2-butenoic (aroylpyruvic) acids have been synthesized in 80–90% yield via decyclization reactions of 5-aryl-2,3-dihydrofuran-2,3-diones with hydrazides of aromatic acids in anhydrous dioxane. Physicochemical characteristics of the products were determined. Their antimicrobial properties were examined. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 9, pp. 32–33, September, 2008.     

Substituted 3-amino-1,1-diaryl-2-propanols as potential antidepressant agents

Following the discovery that 3-(dimethylamino)-1,1-diphenyl-2-propanol hydrobromide (1) possesses potent reserpine-prevention activity in mice, a series of analogues of 1 was synthesized and evaluated as potential antidepressant agents. Several routes to analogues of 1 were evaluated, the most generally applicable of which was the regiospecific ring opening of a suitably functionalized 1,1-diaryl-2,3-epoxypropane (obtained in three stages from the corresponding benzophenone) with the appropriate amine. The more interesting compounds of the series were evaluated for their propensity to cause undesirable peripheral anticholinergic effects, all compounds tested being markedly less active than imipramine on this parameter. On the basis of its good activity in biochemical and pharmacological animal models of depression, together with its relative lack of anticholinergic side effects, 1-(3-chlorophenyl)-3-(dimethylamino)-1-phenyl-2-propanol hydrochloride (20, BRL 14342) was chosen for further evaluation.     

Derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine as novel, potent, and selective A3 adenosine receptor antagonists

A number of derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine ( 5) were synthesized and biologically evaluated as A 3 adenosine receptor (A 3 AR) antagonists. The new compounds were designed as open chain analogues of a triazolopyrimidinone derivative displaying submicromolar affinity for the A 3 AR, which had been previously identified using a 3D database search. Substituents R, R', and R' attached to the parent compound 5 were chosen according to factorial design and stepwise lead optimization approaches, taking into account the essentially hydrophobic nature of the A 3 AR binding site. As a result, 5m (R = n-C 3H 7, R' = 4-ClC 6H 4CH 2, R' = CH 3) was identified among the pyrimidine derivatives as the ligand featuring the best combination of potency and selectivity for the target receptor. This compound binds to the A 3 AR with a K i of 3.5 nM and is devoid of appreciable affinity for the A 1, A 2A, and A 2B ARs.     

Synthesis and use of 3-amino-4-phenyl-2-piperidones and 4-amino-2-benzazepin-3-ones as conformationally restricted phenylalanine isosteres in renin inhibitors.

The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)- (cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleuci namide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)- [(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5- methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.     

Cytochrome p450 retinoic acid 4-hydroxylase inhibitors: potential agents for cancer therapy

Retinoids play a crucial role in cellular differentiation and proliferation of epithelial tissue and their utility in oncology and dermatology is well documented. This mini review focuses on the role of all-trans-retinoic acid (ATRA or RA), the principal endogenous retinoid and its metabolism in cancer therapy. ATRA has been used successfully in differentiating therapy of acute promyelecytic leukemia and other types of cancers. However, its usefulness is limited by the rapid emergence of ATRA resistance due (in part) to ATRA - induced acceleration of ATRA metabolism. A novel strategy to subjugate the limitation associated with exogenous ATRA therapy has been to modulate and/or increase the levels of endogenous ATRA by inhibiting the cytochrome P450-dependent ATRA-4-hydroxylase enzyme(s) responsible for ATRA metabolism. These inhibitors are also referred to as retinoic acid metabolism blocking agents (RAMBAs). This review highlights development in the design, synthesis and evaluation of RAMBAs since 1987. Major emphasis is given to liarozole, the most studied and only RAMBA to undergo clinical investigation and also the recently developed novel and highly potent 4-azoly retinoids. The potential role of a new family of cytochrome P450 enzymes, CYP26, with specificity towards ATRA is also discussed.