Depigmenting activities of kojic acid derivatives without tyrosinase inhibitory activities

We synthesized benzoate ester derivatives of kojic acid with and without adamantane moiety. Benzoate derivatives 2a-e that did not contain an adamantane moiety showed potent tyrosinase inhibitory activities. However, depigmenting activity was not noted in a cell-based assay. Contrasting results were obtained for benzoate derivatives (3a-e) containing an adamantane moiety. Compounds 3a-e showed potent depigmenting activities without tyrosinase inhibitory activities. To the best of our knowledge, this is the first study showing the depigmenting activities of kojic acid derivatives without tyrosinase inhibitory activities.     

Synthesis, QSAR and anti-HIV activity of new 5-benzylthio-1,3,4-oxadiazoles derived from α-amino acids

2-(1-[(4-Chloro/methylphenylsulfonylamino)alkyl]-5-thioxo-4,5-dihydro-1,3,4-oxadiazoles (4a-e) were synthesized, in four steps, via the sulfonyl derivatives of l-amino acids (l-alanine, l-methionine and l-phenylalanine) 1a-e, the esters 2a-e, the hydrazides 3a-e and finally the cyclization to 4a-e. Alkylation of 4a-e with 1.0 mole eq. of substituted benzyl halides furnished S-benzyl derivatives 5a-t, while 1.1 mole eq. yielded major 5a-t and minor amount of 6a-d. Alternatively, treatment of 4a-e with 2.0 mole eq. of substituted benzyl halides furnished 6a-d only. The structures of 5b and 5l were further confirmed by single crystal X-ray analysis. Compounds 5a-t and 6a-d showed no selective inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 5f and 5j-5q exhibited some inhibitory activity against both types with EC(50) values (>11.50 - >13.00 μg/mL). These results suggest that the structural modifications of these compounds might lead to the development of new antiviral agents. The quantum structure-activity relationship of these novel structural congeners is discussed.     

Pterocarpanquinones, aza-pterocarpanquinone and derivatives: synthesis, antineoplasic activity on human malignant cell lines and antileishmanial activity on Leishmania amazonensis

Pterocarpanquinones (1a-e) and the aza-pterocarpanquinone (2) were synthesized through palladium catalyzed oxyarylation and azaarylation of conjugate olefins, and showed antineoplasic effect on leukemic cell lines (K562 and HL-60) as well as colon cancer (HCT-8), gliobastoma (SF-295) and melanoma (MDA-MB435) cell lines. Some derivatives were prepared (3-8) and evaluated, allowing establishing the structural requirements for the antineoplasic activity in each series. Compound 1a showed the best selectivity index in special for leukemic cells while 2 showed to be more bioselective for HCT-8, SF-295 and MDA-MB435 cells. Pterocarpanquinones 1a and 1c-e, as well as 8 were the most active on amastigote form of Leishmania amazonensis in culture. Compounds 1a, 1c and 8 showed the best selectivity index.     

Design and synthesis of novel Cdc25A-inhibitors having phosphate group as a hydrophilic residue

Compounds (6a-e) were synthesized by phosphorylation of hydrophobic perhydroindan derivatives derived from vitamin D(3), and were found to show strong inhibitory activity towards dual-specificity phosphatase Cdc25A (IC(50)=0.7-24.5 microM).     

Synthesis and anti-inflammatory activity of phthalimide derivatives,designed as new thalidomide analogues

This paper describes the synthesis and anti-inflammatory activity of new N-phenyl-phthalimide sulfonamides (3a-e) and the isosters N-phenyl-phthalimide amides (4a-e), designed as hybrids of thalidomide (1) and aryl sulfonamide phosphodiesterase inhibitor (2). In these series, compound 3e (LASSBio 468), having a sulfonyl-thiomorpholine moiety, showed potent inhibitory activity on LPS-induced neutrophil recruitment with ED(50)=2.5mg kg(-1), which was correlated with its inhibitory effect on TNF-alpha level.     

Novel series of 17β-pyrazolylandrosta-5,16-diene derivatives and their inhibitory effect on 17α-hydroxylase/C(17,20)-lyase

The Claisen condensation of 3β-acetoxypregna-5,16-dien-20-one (1) with ethyl formate in the presence of sodium methylate in pyridine is known to lead to 3β-hydroxy-21-hydroxymethylidenepregna-5,16-dien-20-one (2) in good yield. With the methods described for the preparation of the saturated D-ring pyrazolyl series, the reactions of 2 with phenylhydrazine and its p-substituted derivatives in acetic acid resulted in mixtures of two steroidal regioisomers, the 1'-aryl-3'-pyrazolyl-(4a-e) and 1'-aryl-5'-pyrazolyl (5a-e) steroids. Compounds 4a-e are unknown in the literature. The arylpyrazoles produced were tested against 17α-hydroxylase/C(17,20)-lyase (P450(17α)) in vitro and neither of the regioisomers exerted efficient inhibition.     

2-Deoxy-2,3-didehydro-N-acetylneuraminic acid analogues structurally modified at the C-4 position: synthesis and biological evaluation as inhibitors of human parainfluenza virus type 1

To explore the influence of binding to human parainfluenza virus type 1 (hPIV-1), a series of 4-O-substituted Neu5Ac2en derivatives 6a-e was synthesized and tested for their ability to inhibit hPIV-1 sialidase. Among compounds 6a-e, the 4-O-ethyl-Neu5Ac2en derivative 6b showed the most potent inhibitory activity (IC50 6.3 microM) against hPIV-1 sialidase.     

Design,synthesis, neuroprotective,antibacterial activities and docking studies of novel thieno[2,3-d]pyrimidine-alkyne Mannich base and oxadiazole hybrids

A series of thieno[2,3-d]pyrimidine alkyne Mannich base derivatives (7a-e, 8a-e) and thieno[2,3-d]pyrimidine 1,3,4-oxadiazole derivatives (9a-e, 10a-e) have been synthesized and evaluated for their neuroprotective and neurotoxicity activities where 9a, 10d displayed good neuroprotection 10.6 and 11.88?µg/mL respectively against the H₂O₂ induced cell death at the EC₅₀ values and 9b, 9d showed respective toxic effects on PC12 cells at CC₅₀ 86.12 and 94.16?µg/mL. Compounds 9a, 9e, 10a and 10b showed strong antibacterial activity against two gram positive (S. aureus, B. subtilis) and two gram-negative strains (E. coli, P. aeruginosa) and showed good binding affinities with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC. This is the first report for the demonstration of thieno[2,3-d] pyrimidine derivatives as promising neuroprotective agents against H₂O₂ induced neurotoxicity on PC12 cells.     

Anti-tumor and proapoptotic effect of novel synthetic benzophenone analogues in Ehrlich ascites tumor cells

A series of substituted benzophenone analogues, (2-aroyl-4-methylphenoxy)acetamides 4a-e, have been synthesized via three-step synthesis sequence beginning with the 2-hydroxybenzophenones 1a-e in excellent yield. 1a-e on reaction with ethyl chloroacetate afford ethyl (2-aroyl-4-methylphenoxy)acetates 2a-e which on alkaline hydrolysis afforded (2-aroyl-4-methylphenoxy)ethanoic acid 3a-e. Compounds 3a-e on condensation with p-chloroaniline furnished benzophenone analogues 4a-e. In the present report, we investigated the anti-tumor and proapoptotic effect of benzophenones in Ehrlich ascites tumor (EAT) cells. Treatment of benzophenones in vivo resulted in inhibition of proliferation of EAT cells and ascites formation. Further, we demonstrate that the induction of apoptosis in EAT cells is mediated through activation of caspase-3. These results suggest a further possible clinical application of these synthetic compounds as potent anti-tumor and proapoptotic compounds.     

Synthesis and anti-histaminic evaluation of N-phenyl-(alkyl)-5-(dialkylamino)methyl-2-amino-2-oxazolines

New N-phenyl(alkyl)-5-(dialkylamino)methyl-2-amino-2-oxazolines, 5a-e, have been synthesized from the corresponding 3-phenyl(alkyl)carbamoyl-2-iminooxazolidines 2. A two-stage hydrolysis reaction led finally to the corresponding ring-opened N-phenyl(alkyl)-N'-[1-(3-(dialkylamino)-propan-2-ol)]ureas 4. The oxazoline ring was regenerated through an intramolecular nucleophilic substitution involving an halogen atom introduced by the reaction of thionyl chloride on 4. Pharmacological properties of 5a-e were evaluated on histaminic and adrenergic receptors in guinea-pig trachea and rat aorta. Compounds 5b and 5e showed a selective anti-histaminic effect on guinea-pig airways, but a significant response was obtained for a concentration >10(-6) M. No pharmacological activity was obtained with oxazoline 5c whereas oxazolines 5a and 5d seemed to present a non-selective effect on the contractile mechanism of the smooth muscle cell.     

Synthesis and in vitro antiviral activity evaluation of 9-(2-azido-2,3-dideoxy-beta-D-threo-pentofuranosyl)adenine derivatives

9-(2-Azido-2,3-dideoxy-beta-D-threo-pentofuranosyl)adenine derivatives (1a-e) containing a lipophilic function at the N-6 position in the purine ring were prepared and evaluated for their antiviral activity. The compounds 1a-e turned out to be inactive as antiviral agents.     

Molecular modeling study and synthesis of novel pyrrolo[2,3-d]pyrimidines and pyrrolotriazolopyrimidines of expected antitumor and radioprotective activities

Novel pyrrolo[2,3-d]pyrimidine derivatives 4a-e, 10, 14, 15, pyrazolopyrrolopyrimidine 13, pyrrolotriazolopyrimidine 5-9, 17 and pyrrolopyrimidotriazine 18 are reported herein. The design of these compounds was based upon the molecular modeling simulation of the fitting values and conformational energy values of the best-fitted conformers to VEGFRTK inhibitor hypothesis. This hypothesis was generated from its corresponding lead compounds using CATALYST software. The structures of these compounds were confirmed by microanalyses, IR, (1)H NMR, and mass spectral data. Compounds 6 and 15 showed interesting in vitro antitumor activity compared to doxorubicin as positive control. These results are nearly consistent with the molecular modeling studies. Docking studies were made on compound 15 to predict its binding mode. Moreover, compound 10 exhibited a significant radioprotective activity.     

Synthesis, cannabinoid receptor activity, and enzymatic stability of reversed amide derivatives of arachidonoyl ethanolamide

Retroanandamide (2f) and its 10 analogues (1a-e, 2a-e) were synthesized and evaluated for the cannabinoid receptor activation by a [35S]GTPgammaS binding assay using rat cerebellar membranes, and Chinese hamster ovary cell membranes expressing human CB2 receptors. The primary goal of the study was to develop cannabinoid receptor agonists having improved enzymatic stability compared to endogenous N-arachidonoyl ethanolamide (AEA). Furthermore, by reversing the amide bond of AEA, the formation of arachidonic acid would be prevented. Finally, an effect of the carbonyl carbon position on the cannabinoid receptor activity was explored by synthesizing retroanandamide analogues having different chain lengths (1a-e, C19; 2a-f, C20). All the synthesized compounds, except 2c, behaved as partial agonists for the both cannabinoid receptors. In rat brain homogenate, the reversed amides possessed significantly higher stability against FAAH induced degradation than AEA. Therefore, the reversed amide analogues of AEA may serve as enzymatically stable structural basis for the drug design based on the endogenous cannabinoids.     

Non-sequential vasopressin peptides. Stereochemistry and biological activity.

Two cyclic disulfides of structure Cys-Tyr-Arg-Arg-Tyr-Cys-NH2 (1) and Cys-Tyr(Me)-Arg-Arg-Tyr(Me)-Cys-NH2 (2), two nonapeptide derivatives of 1 extended at the C-terminal with Pro-Arg-Gly-NH2 (3) or Pro-D-Arg-Gly-NH2 (4) and derivatives of 3 and 4 having Mpr in position 1, i.e. analogs (5) and (6), respectively, were synthesized, and their stereochemistry and biological activity were studied. All the peptides displayed low dose-dependent uterotonic activity in vitro and antidiuretic activity in vivo. None of the peptides increased the blood pressure of the experimental animals. Compounds 2, 4 and 6 showed a low inhibitory effect on AVP pressor activity; compound 6, in addition, displays a significant and long-lasting vasodepressor effect. NMR measurements indicated the existence of hydrogen bond between the amino acid residues in positions 2,5 and 3,4 of peptides 1 and 2, and side-chain interactions between amino acid residues in positions 2,3 and 4,5 of peptide 1. No such side-chain interactions were detected in peptide 2.     

Synthesis, anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activity evaluation of benzimidazole/benzoxazole derivatives and some Schiff's bases

A series of N-(acridin-9-yl)-4-(benzo[d]imidazol/oxazol-2-yl) benzamides has been synthesized by the condensation of 9-aminoacridine derivatives with benzimidazole or benzoxazole derivatives. Condensation of 2-hydroxy naphthaldehyde with functionalized diamines leads to the formation of Schiff's bases and not imidazole derivatives. All these compounds were characterized by correct FT-IR, (1)H NMR, MS and elemental analyses. These compounds were screened for anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activities. Compounds 11 and 7e(f) showed good anti-inflammatory (35.8% at 50 mg/kg po) activity and good analgesic activity (60% at 50 mg/kg po), respectively. Compound 3b showed significant in vitro activity against CDK-5 (IC(50)=4.6 microM) and CDK-1(IC(50)=7.4 microM) and compound 3a showed moderate CDK-5 inhibitory activity (IC(50)=7.5 microM). The other compounds showed moderate anti-inflammatory and analgesic activities.     

Naphthalene Derivatives and Quinones from Ventilago denticulata and Their Nitric Oxide Radical Scavenging,Antioxidant, Cytotoxic,Antibacterial, and Phosphodiesterase Inhibitory Activities

New naphthalene derivatives ( 1 and 2 ) and a new isomer ( 3 ) of ventilagolin, together with known anthraquinones, chrysophanol ( 4 ), physcion or emodin 3‐methyl ether ( 5 ), and emodin ( 6 ), were isolated from vines of Ventilago denticulata. The isolated compounds exhibited cytotoxic activity with IC₅₀ values of 1.15 – 40.54 μg/ml. Compounds 1 – 3 selectively exhibited weak antibacterial activity (MIC values of 200.0 – 400.0 μg/ml), while emodin ( 6 ) displayed moderate antibacterial activity with MIC value of 25.0 μg/ml. The isolated compounds showed nitric oxide and DPPH radical scavenging activities. Compounds 1 – 3 and 6 exhibited weak xanthine oxidase inhibitory activity, while emodin ( 6 ) acted as an aromatase inhibitor with the IC₅₀ value of 10.1 μm . Compounds 1 and 2 exhibited phosphodiesterase 5 inhibitory activity with IC₅₀ values of 8.28 μm and 6.48 μm , respectively.     

Detection of 1270 nm emission from singlet oxygen and photocytotoxic property of sugar-pendant 60 fullerenes

Sugar-pendant [60] fullerene derivatives have been prepared from carbohydrate-linked azides 1a-e. Both monosugar (4a-e) and bissugar derivatives (5a-e) produce singlet oxygen ((1)O(2)) under laser irradiation (355 nm) proved by the direct observation of (1)O(2) emission at 1270 nm. Monosugar derivatives exhibit photocytotoxicity varying by the attached sugar molecule.     

Synthesis and biological evaluation of 2,7-Dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione derivatives,a novel group of anticancer agents active on a multidrug resistant cell line

A series of anthrapyridazone derivatives with one or two basic side chains at various positions in the tetracyclic chromophore have been synthesized. The key intermediates in the synthesis are 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones 1, 12 and 15 monosubstituted at position 2 (4d, 16a-e), or 6 (2a-f) or disubstituted at positions 2 and 6 (4a-c) or 2 and 8 (17a-e) with appropriate alkylaminoalkylamines. All analogues showed in vitro cytotoxic activity against murine leukemia (L1210) and human leukemia (K562) cell lines. The compounds were also active against human leukemia multidrug resistant (K562/DX) cell line with resistance index (RI) in the range 1-3 depending on the compound's structure. Two of the most active in vitro compounds 4a and 11 were tested in vivo against murine P388 leukemia and displayed antileukemic activity comparable with that of Mitoxantrone. DNA-binding assays were performed and DNA affinity data were correlated with the structures of the compounds. The cytoplasmatic membrane affinity values (log k'(IAM)) have also been determined and the correlation with the resistance indexes discussed. The anthrapyridazones constitute a novel group of antitumor compounds that can overcome multidrug resistance.     

Synthesis, analgesic, anti-inflammatory, and antimicrobial activity of some novel pyrimido[4,5-b]quinolin-4-ones

Novel series of pyrimido[4,5-b]quinolines (3a-c), triazolo[4',3':1,2]pyrimido[4,5-b]-quinolines (7a-e, 9, and 14), tetrazolo[4',3':1,2]pyrimido[4,5-b]quinolin-5-one (13), [1,3]-pyrazolo[3',2':1,2]pyrimido[4,5-b]quinolines (12a and 12b), and 2-pyrazolyl-pyrimido[4,5-b]-quinolines (15, 16a, 16b, and 19) have been synthesized. Some of the new compounds were tested against various bacteria and fungi species. In addition, the analgesic and anti-inflammatory activities are reported. Compounds 8 and 9a possess high activity toward the fungi as compared with the reference drug Nystatin. The tested compounds 5 and 8 have moderate anti-inflammatory activities. Moreover compounds 5, 8, 10, and 16a, have activities higher than the reference drug in peripheral analgesic activity testing, Compounds 5, 7a, 11a, and 16a have potencies as the reference drug in central analgesic activity testing.