Synthesis and evaluation of novel pseudomycin side-chain analogues. Part 3.

To increase the therapeutic utility of C-18 side-chain bearing pseudomycin analogue 2, we prepared additional analogues and prodrugs of 2 containing further modifications at various positions within its core structure. Each of the newly synthesized derivatives (10-15) exhibited reduced tail vein toxicity relative to the parent compound. Some of the new pseudomycin derivatives (e.g., 14) also showed improved in vivo antifungal activity relative to its corresponding parent compound.     

Synthesis and antimicrobial activity of some novel phenyl and benzimidazole substituted benzyl ethers

In this study, a series of novel phenyl- and benzimidazole-substituted benzyl ethers were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Methicillin-resistant S. aureus (MRSA), Escherichia coli, Candida albicans, and Candida krusei. Compound 6g exhibited the most potent antibacterial activity with lowest MIC values of 3.12 and 6.25 microg/mL against S. aureus and MRSA, respectively.     

Synthesis and testing of novel classical cannabinoids: exploring the side chain ligand binding pocket of the CB1 and CB2 receptors

A series of C3 cyclic side-chain analogues of classical cannabinoids were synthesized to probe the ligand binding pocket of the CB1 and CB2 receptors. The analogues were evaluated for CB1 and CB2 receptor binding affinities relative to delta(8)-THC. The C3 side-chain geometries of the analogues were studied using high field NMR spectroscopy and quantum mechanical calculations. The results of these studies provide insights into the geometry of the ligand binding pocket of the CB1 and CB2 receptors.     

Synthesis of novel hydroxymethyl substituted analogues related to carbovir and neplanocin A

Two enantiomerically pure hydroxymethyl substituted cyclopentene nucleoside analogues (42 and 53) related to carbovir and neplanocin A, respectively, were prepared from the chiral pool of iridoid glucosides. In addition two saturated hydroxymethylated analogues (44 and 45) were obtained from a protected intermediate.     

Synthesis and phosphodiesterase 5 inhibitory activity of novel phenyl ring modified sildenafil analogues.

New sildenafil analogues containing an ether ring fused into the phenyl moiety, 6a--d and 7a--d, were efficiently synthesized from the readily available starting materials, 1a--d and 2, in five steps. Ab initio calculations indicated that introduction of a cyclic ether to the phenyl group might enhance the co-planarity of the molecule. The torsional angles were calculated to be 2--3 degrees for the 5-membered cyclic ether derivatives, 6a, 6c, 7a, and 7c, and 12--16 degrees for the 6-membered ones, 6b, 6d, 7b, and 7d. On the other hand, sildenafil showed the least co-planarity with the torsional angle of 23 degrees compared with the target compounds, 6a--d and 7a--d. In the enzyme assay, however, the in vitro PDE 5 inhibitory activity was found out to be inversely related to the degree of co-planarity. In other words, the least planar sildenafil showed the highest activity, and the most planar 5-membered cyclic ether derivatives were least active by 100--200-fold compared with sildenafil. Our study clearly demonstrated that the open chain 2'-alkoxy group of the phenyl ring, although less effective for inducing the co-planarity, seemed to act as a much better lipophilic requirement than the cyclic alkoxy moiety.     

Synthesis and biological evaluation of a novel phenyl substituted sydnone series as potential antitumor agents

A series of compounds containing an N-(4'-substituted-3'-nitrophenyl)sydnone moiety with potential antitumor activity was prepared based on active analogues. The rationale behind the design of these compounds is presented along with the 4-step synthetic route to the derivatives in the 4'-position of the phenyl sydnone framework. Out of the six novel compounds, the 4'-fluoro derivative has an improved activity against all three cell lines as compared to the earlier leads.     

Synthesis and in-vivo hypolipidemic activity of some novel substituted phenyl isoxazol phenoxy acetic acid derivatives

The present study was undertaken to evaluate in-vivo hypolipidemic activity of a novel series of 2-methyl-2-(substituted phenyl isoxazol)phenoxyacetic acid derivatives by triton induced hyperlipidemia in rats. The newly synthesized compounds 5a, 5d and 5g showed significant decrease in the serum TCH, TG, LDL and VLDL along with an increase in serum HDL levels as compared to standard drug Fenofibrate. The treated groups also showed significant decrease in the atherogenic index and increase in % protective activity compared to control group.     

Synthesis and biological evaluation of novel C6-amino substituted 4-azasteroidal purine nucleoside analogues

Novel C6-amino substituted purine nucleoside analogues (2–12) bearing a modified pyranose-like D ring of the 4-azasteroid moiety were efficiently synthesized through nucleophilic substitution at C6 position of the steroidal nucleoside precursors (1a, b) with versatile amines. All the synthesized new compounds were evaluated for their anticancer activity in vitro against Hela, PC-3 and MCF-7 cell lines. Among them, compounds 4b, 7b and 9b exhibited significant cytotoxicity with the IC₅₀ values of 2.99 μM (PC-3), 2.84 μM, (PC-3) and 2.69 μM (Hela), respectively.     

Syntheses and biological evaluation of novel pseudomycin side-chain analogues. Part 2

A series of aliphatic side-chain analogues of pseudomycin was synthesized and evaluated during the course of our side-chain SAR effort. We found that several of the pseudomycin side-chain analogues (e.g., 10) exhibited good in vitro activity against all three major fungi responsible for systemic fungal infections.     

Synthesis and biological evaluation of DNA targeting flexible side-chain substituted beta-carboline derivatives

A series of 3-substituted-beta-carboline derivatives was synthesized from L-tryptophan. The intercalating binding mode of these compounds with DNA, the effects of the flexible alkylamine side chain on the intercalating ability and their antitumor activity were studied, which agreed well with the molecular modeling results.     

N-甲基取代苯基氨基甲酸酯的系列合成及其对家蝇的生物活性

利用酰氯水相简易工艺合成了52个N-甲基取代苯基氨基甲酸酯类化合物, 并测定了它们对家蝇Musca domestica的室内毒力。结果表明：烷基单取代化合物中,间位取代物的活性大于邻、对位;单卤素取代物中,邻位取代活性大于间位和对位,邻溴代物大于邻氯代物;对位硫甲基和邻位硫乙基取代物的活性均较高。对于烷基间位苯环取代化合物,在一定限度内随烷基分子量增大,化合物对家蝇的毒力增高,其次序为异丙基>乙基>甲基>未取代基。     

Synthesis and evaluation of amide side-chain modified Agomelatine analogues as potential antidepressant-like agents

In this work, nineteen analogues of Agomelatine were readily synthesized through structural modification of the acetamide side-chain starting from the key common intermediate 2-(7-methoxynaphthalen-1-yl) ethanamine (3), which was prepared from commercially available compound 2-(7-methoxynaphthalen-1-yl) acetonitrile (2) in two steps. Corticosterone-induced PC12 pheochromocytoma cells phenotypic in vitro model was utilized to evaluate their potential antidepression activities. Imide compound 4a and acylamino carboxylic acid analogue 5b showed good protective effects on traumatic PC12 cells with protection rates of 34.2% and 23.2%, respectively. Further in vivo assessments in C57 mice FST (forced swim test) model demonstrated that compound 4a significantly reduced the immobility time of the tested subjects, indicating antidepressant-like activity. Preliminary toxicity assays conducted on human normal liver L02 cells and embryonic kidney 293 cells suggested a relatively low safety risk for compound 4a compared with the marketed drugs Agomelatine and Fluoxetine. The promising antidepressant-like efficacy of compound 4a, together with the relatively low toxicity to the normal tested cells and high liability of diffusion through the blood–brain barrier (BBB), presents us insights of exploration of me-better drug candidates of Agomelatine.     

Synthesis and in vitro antiprotozoal evaluation of substituted phenalenone analogues

A set of derivatives encompassing structural modifications on the privileged phenalenone scaffold were assessed for their antiparasitic activities against the most clinically relevant forms of trypanosomiasis and leishmaniasis. Several compounds exhibited leishmanicidal effects at levels comparable or better than the reference drug pentamidine, while the parent phenalenone was shown to have a level of activity against Trypanosoma cruzi comparable to the marketed drug benznidazole.     

Synthesis of a novel side-chain to side-chain cyclized enkephalin analogue containing a carbonyl bridge

A novel type of cyclic opiod peptide analogue, cyclo(N^ϵ,N^ϵ′-carbonyl- D -Lys²,Lys⁵)enkephalinamide, was prepared from a linear precursor peptide. The peptide was synthesized on the Merrifield resin and also by a combination of the solid-phase technique and the classical method in solution. In both cases the cyclization was performed by reaction of bis(4-nitrophenyl)carbonate with the free side-chain amino groups of the two lysine residues. The described method permits the convenient preparation of novel peptide analogues cyclized via a ureido group incorporating the side-chain amino groups of two α,ω-diamino acid residues. The cyclic enkephalin analogue containing a 21-membered ring structure showed preference for μ over δ opioid receptors in opioid bioassays in vitro. © 1997 European Peptide Society and John Wiley & Sons, Ltd.     

Synthesis and biological testing of non-fluorinated analogues of levofloxacin

Quinolones without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non-fluorinated analogues of the antibacterial quinolone Levofloxacin were synthesized and tested.     

Synthesis and antimicrobial activity of novel globomycin analogues

Globomycin, a signal peptidase II inhibitor, and its derivatives show potent antibacterial activity against Gram-negative bacteria. The synthesis and antimicrobial activity of novel globomycin analogues are reported. One of the analogues showed a more potent activity against Gram-negative bacteria than globomycin and also exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).     

Synthesis and antihistamine evaluations of novel loratadine analogues

A series of loratadine analogues containing hydroxyl group and chiral center were synthesized. The effect of the synthesized compounds on the histamine-induced contractions of guinea-pig ileum muscles was studied. In addition, the in vivo asthma-relieving effect of the analogues in the histamine induced asthmatic reaction in guinea-pigs was determined. Most of the compounds exhibited definite H₁ antihistamine activity. The S-enantiomers, compounds 2, 4 and 8, are more potent than the R-enantiomers, compounds 1, 3 and 7. Compound 6 was the most active one among the eight synthesized compounds.