Synthesis and biochemical evaluation of baclofen analogues locked in the baclofen solid-state conformation.

The synthesis of six close analogues of baclofen [3-(4-chlorophenyl)-4-aminobutyric acid] (BAC), a potent GABAB agonist, are reported. The compounds were designed starting from the structural informations contained in the solid state of BAC, regarded as a possible bioactive conformation, in which the p-chlorophenyl ring is perpendicular to the GABA backbone. A similar conformational situation was created by rigidifying the BAC structure by means of methylene (1), ethylene (2 and 6), or propylene (3) units, or by introducing chlorine atoms (4 and 5) into the ortho positions ("ortho effect"). Only compound 5 showed affinity for the GABAB receptor. Compound 6 [1-(aminomethyl)-5-chloro-2,3-dihydro-1H-indene-1-acetic acid], which was initially considered as representing the optimal mimic of the solid-state conformation of BAC, was surprisingly found inactive. An extensive conformational analysis was performed on compounds 1-6 in order to evaluate their flexibility and the overlap of their conformational population with respect to BAC. For this purpose a distance map was generated from three possible pharmacophoric groups: the amino and the carboxylic functions, and the phenyl ring. Finally, several explanations are proposed to account for the poor affinities of the prepared compounds such as steric hindrance or flexibility demand of the receptor.     

Syntheses and evaluation of 2,5-disubstituted 4-thiazolidinone analogues as antimicrobial agents

Two novel series of 4-thiazolidinone derivatives, bearing 2-nitrophenyl imino and 4-nitrophenyl imino groups at position-2 and substituted arylidene groups at position-5, have been synthesized and evaluated for antimicrobial activity against four bacterial and one fungal strain. The success of the synthesis of compounds was confirmed on the basis of spectral analysis. All the newly synthesized compounds were obtained in high yields and exhibited good antibacterial activity; however, the antifungal potential was limited to a few agents.     

Synthesis and pharmacological evaluation of propranolol-cyclic analogues

Three propranolol analogues, bearing the oxygen of the --OH group enclosed in a 1,4-dioxanic rigid system, were synthetized. The lack of beta-blocking activity found for these compounds demonstrates the important role played by a free--OH group in the drug-receptor interaction.     

Synthesis and antimicrobial evaluation of bicyclomycin analogues

The synthesis and antimicrobial evaluation of novel bicyclomycin analogues are described. The series of analogues were prepared from the basic 8,10-diaza-2-oxabicyclo[4.2.2]decane-7,9-dione, 7,9-diaza-2-oxabicyclo[3.2.2]nonane-6,8-dione 8,10-diaza-5-methylene-2-oxabicyclo[4.2.2]decane-7,9-dione and 7,9-diaza-4-methylene-2-oxabicyclo[3.2.2]nonane-6,8-dione nuclei. For compounds where R1 = p-methoxybenzyl, deprotection of the lipophilic amides with ceric ammonium nitrate affords the corresponding lipophobic free amides. The basic bicyclic nucleus of bicyclomycin (8h, R1 = R2 = R3 = R4 = H) has been synthesized for the first time as well as increasingly more complex congeners bearing the C-6 OH, 5-methylene; C-1'-C-3' trihydroxyisobutyl group. In general, it has been found that the bicyclic nucleus of bicyclomycin is devoid of antimicrobial activity, the entire structure of bicyclomycin being generally obligate for activity. In one instance, the racemic analogue 10c (R1 = CH2Ph, R2 = OH, R3 = H) showed interesting antimicrobial activity against several Gram-positive organisms; the minimum inhibitory concentrations were of the same order of magnitude as bicyclomycin displays toward Gram-negative organisms. Totally synthetic (+/-)-bicyclomycin was half as active as the natural antibiotic. The design, synthesis, and antimicrobial activity (and/or lack thereof) of bicyclomycin and the analogues are discussed in the context of a proposed chemical mechanism of action.     

Synthesis, physicochemical and anticonvulsant properties of some n-substituted amides of 3-spirocycloalkylpyrrolidine-2,5-dione

The synthesis and physicochemical properties of new derivatives of N-benzyl and N-phenyl amides of 2-(3-spirocyclohexanepyrrolidine-2,5-dione) acetic acid. 4-(3-spirocyclohexanepyrrolidine-2,5-dione) benzoic acid and 4-(3-spirocyclopentanepyrrolidine-2,5-dione) benzoic acid are described. N-substituted amides were prepared by condensing the obtained acids with the corresponding phenyl- or benzylamine derivatives in DMF, in the presence of the N,N-carbonyldiimidazol (CDIM) reagent at room temperature. The compounds were evaluated for anticonvulsant activity. The portion coefficients were calculated using the Prolog P module of the Pallas system. The structure of the new amides was confirmed by elemental and spectral analyses.     

Synthesis and evaluation of cytotoxicity of stilbene analogues

Resveratrol analogs were newly synthesized and evaluated for cytotoxicity in cultured human lung and colon cancer cells. 3,5,4-Trimethoxy-trans-stilbene and 3,5,2',4'-tetramethoxy-trans-stilbene were found to be more potent rather than resveratrol. 3,4,5-Trimethoxy-4'-bromo-cis-stilbene was the most active among the test compounds.     

Synthesis and antimicrobial evaluation of novel platensimycin analogues

Since the isolation of the natural products platensimycin and platencin as new antibiotic lead structures, several total syntheses as well as syntheses of derivatives have been developed. Most of these approaches are very laborious and the target molecules are often produced in only poor overall yields. The following approach describes the synthesis of rather simple platensimycin analogues focussing on some structure elements that have previously been identified as being essential for binding to the Fab F enzyme in fatty acid biosynthesis. Two of the new analogues show significant antimicrobial activities.     

Synthesis and biological evaluation of new niphathesine analogues

Niphathesine C and related pyridine alkaloids are well known natural products with interesting antimicrobial activities, characterized by a pyridine ring and a lipophilic side chain with a terminal nitrogen-containing functional group. This paper describes the synthesis of analogues of these alkylpyridine alkaloids with variation of the heterocyclic ring and the terminal functional group. Key steps of the syntheses are a Sonogashira reaction of appropriate aryl iodides with undec-10-ynol or undec-10-ynoic acid derivatives. The resulting compounds were tested in an agar diffusion assay against several bacteria and fungi.     

Synthesis and antifungal evaluation of PCA amide analogues

To improve the physical and chemical properties of phenazine-1-carboxylic acid (PCA) and find higher antifungal compounds, a series of PCA amide analogues were designed and synthesized and their structures were confirmed by ¹H NMR, HRMS, and X-ray. Most compounds showed some antifungal activities in vitro. Particularly, compound 3d exhibited inhibition effect against Pyriculariaoryzac Cavgra with EC₅₀ value of 28.7 μM and compound 3q exhibited effect against Rhizoctonia solani with EC₅₀ value of 24.5 μM, more potently active than that of the positive control PCA with its EC₅₀ values of 37.3 μM (Pyriculariaoryzac Cavgra) and 33.2 μM (Rhizoctonia solani), respectively.     

Synthesis and biological evaluation of bombesin constrained analogues

Analogues of bombesin which incorporate dipeptide or turn mimetics have been synthesized. One of them (compound 11) containing a seven-membered lactam ring revealed a good affinity for GRP/BN receptors on rat pancreatic acini (K(i) value of 1.7 +/- 0.4 nM) and on Swiss 3T3 cells (K(i) value of 1.0 +/- 0.2 nM). On the basis of this observation, antagonists containing the same dipeptide mimic were obtained by modification of the C-terminal part of the bombesin analogues. The most potent constrained compounds (15 and 17) were able to antagonize 1 nM bombesin-stimulated amylase secretion from rat pancreatic acini with high potency (K(i) = 21 +/- 3 and 3.3 +/- 1.0 nM, respectively) and 10(-7) M bombesin-stimulated ?(3)Hthymidine incorporation into Swiss 3T3 cells (K(i) = 7.8 +/- 2. 0 and 0.5 +/- 0.1 nM, respectively).     

Synthesis and biological evaluation of some stilbene-based analogues

The phytoalexin 3,5,4′-trihydroxy-trans-stilbene (resveratrol) has attracted considerable attention from biologists and chemists due to its diverse biological properties. Owing to the biological importance of this compound, we have synthesized new stilbene-based analogues by using substituted benzyl chlorides and substituted aldehydes in a two-step reaction and evaluated their in vitro antioxidant, antibacterial and antifungal potential. Most of the compounds displayed moderate to significant radical scavenging activity. (E)-1-(3,4-difluorophenyl)-2-(4-fluorophenyl)ethene (4c) showed nearer equipotent antibacterial activity against Staphylococcus aureus. (E)-1,2-bis(4-fluorophenyl)ethene (4a), (E)-1-(3-fluorophenyl)-2-(4-fluorophenyl)ethene (4b), (E)-1-(2,4-dichlorophenyl)-2-(3,4-dichlorophenyl)ethene (4f), (E)-1-(2,4-dichlorophenyl)-2-(3-chlorophenyl)ethene (4g), (E)-1-(2,4-dichlorophenyl)-2-(4-fluorophenyl)ethene (4j) (E)-1-(4-fluorophenyl)-2-(3-chlorophenyl)ethene (4l) and (E)-1-(4-chlorophenyl)-2-(4-fluorophenyl)ethene (4n) inhibited the growth of Penicillium chrysogenum.     

Synthesis and biological evaluation of acyclic neplanocin analogues

Acyclic neplanocin analogues were prepared by condensation of adenine or N2-acetylguanine with (E)-1,4-dichlorobut-2-ene and subsequent hydrolysis. The N-9-substituted product 9-[(E)-4-hydroxybut-2-enyl]adenine was obtained when adenine was employed as the starting purine, while N2-acetylguanine yielded both the N-7 and N-9 isomers. Cell-culture studies revealed that only the chloro-substituted intermediate 9-[(E)-4-chlorobut-2-enyl]adenine exhibited significant cytotoxicity against P-388 mouse lymphoid leukemia cells, while the N-9-substituted guanine analogue 9-[(E)-4-hydroxybut-2-enyl]guanine inhibited replication of herpes simplex viruses type 1 and type 2.     

3-(1H-咪唑-5-基亚甲基)哌嗪-2,5-二酮类化合物的合成

目的 通过化学方法合成3类含有咪唑的二酮基哌嗪生物碱（penilloid A、JBIR-74、JBIR75）。方法 以氨基酸衍生物为起始原料,经缩合、脱保护、环化、乙酰化、羟醛缩合和去乙酰化等反应合成目标化合物。结果 合成了6个含有咪唑基的二酮哌嗪类化合物,包括天然产物penilloid A、JBIR-74、JBIR-75。其中penilloid A和JBIR-74为首次合成,为二酮哌嗪类化合物的化学合成方法提供了新的思路和方法。     

Synthesis and anticonvulsant properties of new 1-phenyl and 1-phenylamino-3-phenylpyrrolidine-2,5-dione derivatives

A series of N-aryl and N-aminoaryl 3-phenyl pyrrolidine-2,5-diones were synthesized and tested for anticonvulsant activity in the maximum electroshock seizure (MES) and pentetrazol seizure threshold (sc Met) tests. Structures of the novel compounds were confirmed by elemental and spectral analyses.     

Synthesis and antiseizure evaluation of isoindoline-1,3-dione derivatives in mice

Epilepsy is the most common serious chronic noninfective neurological condition in the world. Despite the presence of various antiepileptic drugs in the market for epileptic patients, the necessity for development and discovery of novel antiepileptic drugs is felt. In fact, only 60–70 % of patients respond to the current drugs, and a high incidence of adverse effects is also observed. In the present study, a new series of phthalimide derivatives (compounds 3a–3m) were synthesized through the reaction of phthalic anhydride and various derivatives of aniline in toluene solvent (Reflux, 24 h). Antiepileptic activity of synthesized compounds (3a–3m) was investigated using two experimental models namely, maximal electroshock (MES) and pentylenetetrazole (PTZ), and the obtained results were compared with diazepam as reference drug. Neurotoxicity of compounds was also evaluated using rotarod model. Compound 3m with para methoxy substituent exhibited the anticonvulsant activity at 15.1 ± 1.53 (12.23–17.96) mg/kg dose in MES model compared to other derivatives. Unfortunately, none of the tested compounds rendered acceptable protection in subcutaneous PTZ model.     

Synthesis and structure-activity relationship study of antimicrotubule agents phenylahistin derivatives with a didehydropiperazine-2,5-dione structure

Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.     

Analogues of aminoglutethimide based on 1-phenyl-3-azabicyclo[3.1.0]hexane-2,4-dione: selective inhibition of aromatase activity

In exploring the structural features responsible for the inhibitory activity of aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] (1) toward the cholesterol side chain cleavage (CSCC) enzyme from bovine adrenals and the human placental aromatase enzyme, analogues have been synthesized in which the piperidine-2,6-dione ring is replaced by substituted or unsubstituted azabicyclo[3.1.0]hexane-2,4-dione rings. The unsubstituted analogue 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (9a) is a slightly more potent inhibitor of aromatase than 1 (Ki = 1.2 microM, cf. 1.8 microM for 1) but is noninhibitory toward the CSCC enzyme. The substituted analogues 1-(4-aminophenyl)-3-butyl-3-azabicyclo[3.1.0]hexane-2,4-dione (9e) and 1-(4-aminophenyl)-3-pentyl-3-azabicyclo[3.1.0]hexane-2,4-dione (9f) are approximately 100 times more potent than 1 (Ki values of 1, 9e, and 9f are 1.8, 0.015, and 0.02 microM, respectively) in inhibiting aromatase, with no significant activity toward the CSCC enzyme. Type II difference spectra were exhibited by 1, 9a, and 9f in their interaction with the aromatase enzyme (respective Ks values of 1, 9a, and 9f are 0.13, 0.08, and 0.01 microM). Modification of the para amino function by alkylation, its relocation, replacement by H, or replacement by a methyl, aldehyde, or secondary alcohol group produced analogues that were inactive toward both enzyme systems.     

Synthesis and antimalarial activity evaluation of some isoquine analogues

The worldwide diffusion of resistance in malaria parasite, especially the Plasmodium falciparum, towards currently available drugs has become a major health and development challenges to human society. Isoquine, an isomeric analogue of amodiaquine, has been reported recently as a second generation lead compound for development of cost-effective and potentially safer alternative to amodiaquine which cause adverse effects including agranulocytosis and liver damage. In this study, a series of seven analogues of isoquine have been synthesized and subjected to in vitro antimalarial activity screening against the chloroquine sensitive 3D7 strain of Plasmodium falciparum. A simple two-step Mannich reaction was used to synthesize the compounds. All the seven compounds possessed little to moderate antimalarial activity. However, the analogues with aliphatic alcoholic amino group side chain having promising activity than the compounds with substituted aromatic ring side chain and compounds substituted with urea while analogues with heterocyclic ring side chain exhibits moderate antimalarial activity.     

Synthesis and evaluation of curcumin analogues as cytotoxic agents

Seventeen curcumin analogues were prepared and evaluated for in vitro and in vivo cytotoxicity against an Ehrlich ascites carcinoma (EAC). In vitro results revealed that compounds 10, 7, and 12 were the most potent analogues against EAC respectively. However, in vivo evaluation of compound 10 proved its capability to normalize the blood picture compared with 5-fluorouracil, a well-known anticancer drug.