Showing papers in "Archiv Der Pharmazie in 2009"

Breast Cancer, Estrogen Receptor and Ligands

Abstract: This review emphasizes the relationship of breast cancer, estrogen receptor and ligands, especially the centrality of the estrogen receptor, which mediates on one hand the hormone-induced gene transcription and on the other hand the anti-estrogen action against breast cancer The characterization of the estrogen receptor ligand-binding domain co-crystallized with agonists or antagonists provided a molecular basis to gain an insight into the regulation of estrogen receptor and, thereby, to describe the mechanism of the hormone therapy in treating breast cancer

Synthesis and biological evaluation of 2-mercapto-1,3-benzothiazole derivatives with potential antimicrobial activity.

Abstract: The enhancement of bacterial resistance of pathogens to currently available antibiotics constitutes a serious public health threat So, intensive efforts are underway worldwide to develop new antimicrobial agents To identify compounds with a potent antimicrobial profile, we designed and synthesized low molecular weight 2-mercaptobenzothiazole derivatives 2a-2l and 3a-3l Both series were screened for in-vitro antibacterial activity against the representative panel of Gram-positive and Gram-negative bacteria strains The biological screening identified compounds 2e and 2l as the most active ones showing an interesting antibacterial activity with MIC values of 312 microg/mL against Staphylococcus aureus and 25 microg/mL against Escherichia coli, respectively The replacement of the S-H by the S-Bn moiety resulted in considerable loss of the antibacterial action of the 3a-3l series The antibiotic action of compounds 2e and 2l was also investigated by testing their activity against some clinical isolates with different antimicrobial resistance profile Moreover, the involvement of the NorA efflux pump in the antibacterial activity of our molecules was evaluated Finally, in this paper, we also describe the cytotoxic activity of the most interesting compounds by MTS assay against HeLa and MRC-5 cell lines

Synthesis of novel 2,5-disubstituted 1,3,4-thiadiazoles for their potential anticonvulsant activity: pharmacophoric model studies.

Abstract: A series of novel N(1)-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N(4)-(4-substituted benzaldehyde)-semicarbazone 1-12, N(1)-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N(4)-[1-(4-substituted phenyl)ethanone]-semicarbazone 13-16, and N(1)-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N(4)-[1-(4-substituted phenyl) (phenyl) methanone]-semicarbazone 17-20 were synthesized for their anticonvulsant activity. The chemical structures of the compounds were proved by elemental and spectral (IR, (1)H-NMR,( 13)C-NMR, and MS) analysis. The anticonvulsant potential of the compounds was investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models. Compound 19 was found to possess significant anticonvulsant activity in both the models employed for anticonvulsant evaluation. Compounds 8, 13, 15, and 16 also demonstrated a marked anticonvulsant property. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity. The efforts were also made to establish structure-activity relationships among the synthesized compounds.

Synthesis and Biological Evaluation of Some Novel Polysubstituted Pyrimidine Derivatives as Potential Antimicrobial and Anticancer Agents

Abstract: Synthesis and evaluation of the antimicrobial and cytotoxic activity of two series of polysubstituted pyrimidines comprising the thioether functionality and other pharmacophores, reported to contribute to various chemotherapeutic activities are described. All newly synthesized compounds were subjected to in-vitro antibacterial and antifungal screening. Out of the compounds tested, 18 derivatives displayed an obvious inhibitory effect on the growth of the tested Gram-positive and Gram-negative bacterial strains, with special effectiveness against the Gram-positive strains. Compounds 1, 2, 6, 7, 9, 10, 11, 21, and 24 revealed remarkable broad antibacterial spectrum profiles. Among those, compounds 1, 2, 6, 7, 9, and 24 exhibited an appreciable antifungal activity against C. albicans. Compound 2 proved to be the most active antimicrobial member identified here as it showed twice the activity of ampicillin against B. subtilis and the same activity of ampicillin against M. Luteus and P. aeruginosa together with a moderate antifungal activity. Further, eleven analogs were evaluated for their in-vitro cytotoxic potential utilizing the standard MTT assay against a panel of three human cell lines: breast adenocarcinoma MCF7, hepatocellular carcinoma HePG2, and colon carcinoma HT29. The obtained data revealed that six of the tested compounds 1, 3, 7, 12, 13, and 15 showed a variable degree of cytotoxic activity against the tested cell lines at both the LC(50) and LC(90) levels. Compound 7 proved to be the most active cytotoxic member in this study with special effectiveness against the colon carcinoma HT29 and breast cancer MCF7 human cell lines for LC(50 )and LC(90). Thus, compounds 1 and 7 could be considered as possible dual antimicrobial-anticancer agents.

Synthesis and Biological Evaluation of Some Polymethoxylated Fused Pyridine Ring Systems as Antitumor Agents

Abstract: A series of 3,5-bis(arylidene)-4-piperidones like chalcone analogues carrying variety of methoxylated aryl groups, pyrazolo[4,3-c]pyridines, pyrido[4,3-d]pyrimidines, and pyrido[3,2-c]pyridines, carrying an arylidene moiety, and some pyrano[3,2-c]pyridines, like flavone and coumarin isosteres, were synthesized and screened for their in-vitro antitumor activity at the National Cancer Institute (NCI, USA). The tested compounds 7, 9, 10, 12, 13, 15, 17, and 19 exhibited a broad spectrum of antitumor activity. Compounds belonging to the pyrazolo[4,3-c]pyridine series proved to be more active than those of the pyrido[3,2-c]pyridine and pyrano[3,2-c]pyridine analogues, in which the monomethoxylated derivatives showed better antitumor activity when compared with their corresponding dimethoxylated congeners. Compound 7 is considered to be the most active member identified in this study with a broad spectrum of activity against 22 different tumor cell lines belonging to the nine subpanels employed, and a particular effectiveness against the breast cancer T-47D cell line (GI 54.7%). The pyrano[3,2-c]pyridine heterocyclic system 19 proved to be the most active antitumor agent among the six-membered fused pyridines, with variable activity against 18 different tumor cell lines, and special activity against the non-small cell lung cancer Hop-92 and ovarian cancer OVCAR-4 cell lines (GI values 63.9 and 48.5%, respectively).

Synthesis and Studies of New 2-(Coumarin-4-yloxy)-4,6-(substituted)-s-Triazine Derivatives as Potential Anti-HIV Agents

Abstract: Novel 2-(coumarin-4-yloxy)-4,6-(substituted)-s-triazine derivatives i e, diaryltriazine (DATA) are reported as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus HIV-1 (III-B), HIV-2 (ROD), and the double RT mutant HIV-1 (K103N and Y181C) were assessed Modifications at positions 4 and 6 of the coumarinyl-triazine scaffold generated interesting derivatives displaying good to moderate anti-HIV activity against selected HIV strains as compared to nevirapine and efavirenz The synthesized compounds were characterized by FTIR, (1)H-NMR, and mass spectral data together with elemental analysis

Pyrazolo[3,4-d]pyrimidine Derivatives as COX-2 Selective Inhibitors: Synthesis and Molecular Modelling Studies

Abstract: The pyrazolo[3,4-d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti-inflammatory activity of 5-benzamido-pyrazolo[3,4-d]pyrimidin-4-one derivatives and considering the easy synthesis of this class of compounds, a set of new 5-benzamido-1H-pyrazolo[3,4-d]pyrimidin-4-ones has been prepared in 42-80% yields by reacting 5-aminopyrazole-4(N-benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a, b, 10a-d, and 11a, b revealed a superior inhibitory profile against COX-2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results.

Synthesis, antibacterial and antifungal activities of novel 1,2,4-triazolium derivatives.

Abstract: A series of novel 1,2,4-triazolium derivatives was synthesized starting from commercially available 1H-1,2,4-triazole, 2,4-dichlorobenzyl chloride, or 2,4-difluorobenzyl bromide. Their antibacterial and antifungal activities were evaluated against Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922, Bacillus proteus, Bacillus subtilis, Pseudomonas aeruginosa, Candida albicans ATCC 76615, and Aspergillus fumigatus. All structures of the new compounds were confirmed by NMR, IR, and MS spectra, and elemental analyses. The antimicrobial tests showed that most of synthesized triazolium derivatives exhibit significant antibacterial and antifungal activities in vitro. 1-(2,4-Difluorobenzyl)-4-dodecyl-1H-1,2,4-triazol-4-ium bromide and 1-(2,4-Dichlorobenzyl)-4-dodecyl-1H-1,2,4- triazol-4-ium bromide were the most potent compounds against all tested strains with the MIC values ranging from 1.05 to 8.38 μM. They exhibited much stronger activities than the standard drugs chloramphenicol and fluconazole which are in clinical use. The results also showed that the antimicrobial activities of triazolium derivatives depend upon the type of substituent, the length of the alkyl chain, and the number of triazolium rings.

Facile Synthesis and In‐Vitro Antitumor Activity of Some Pyrazolo[3,4‐b]pyridines and Pyrazolo[1,5‐a]pyrimidines Linked to a Thiazolo[3,2‐a]benzimidazole Moiety

Abstract: The key precursor E-3-(N,N-dimethylamino)-1-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)prop-2-en-1-one 4 was synthesized in good yield using Gold's reagent. The reaction of enaminone 4 with 5-amino-3-aryl-1-phenylpyrazoles 5a, b in refluxing acetic acid in the presence of sulphuric acid, yielded pyrazolo[3,4-b]pyridines 7a, b. Similarly, pyrazolo[1,5-a]pyrimidines 10a, b and 14a-f were prepared by reaction of enaminone 4 with 5-amino-1H-pyrazoles 8a, b and 12a-f, respectively. The structure of pyrazolo[1,5-a]pyrimidine 10b was determined by X-ray diffraction. The synthesized compounds were tested for their in-vitro antitumor activity against the colon cancer cell line CaCo-2; their cytotoxicity against the normal fibroblast cell line BHK was explored as well. Some of the tested compounds exhibited cell growth inhibitory activity. The significant antitumor activity of compound 14f against the CaCo-2 cell line (IC(50 )= 0.5 microg/mL) was coupled with a lower toxicity against BHK (IC(50 )= 2.3 microg/mL).

Synthesis and evaluation on anticonvulsant and antidepressant activities of 5-Alkoxy-tetrazolo[1,5-a]quinazolines.

Abstract: Several 5-alkoxy-tetrazolo[1,5-a]quinazoline derivatives have been synthesized by reacting 2,4-dichloroquinazoline with various phenols or aliphatic alcohol and then with sodium azide. The structures of these compounds have been confirmed by IR, MS,( 1)H-NMR, and elementary analysis. Anticonvulsant activities were evaluated using the maximal electroshock (MES) test. Most of the synthesized compounds displayed weak anticonvulsant activity at a dose of 300 mg/kg. Antidepressant activities were investigated by forced swimming test. Two compounds, namely 5-(hexyloxy)tetrazolo[1,5-a]quinazoline and 5-(4-methoxyphenoxy)tetrazolo[1,5-a]quinazoline, showed significant antidepressant activity, which decreased the immobility time by 62.2 and 51.7% at 100 mg/kg dose level.

Immunomodulatory and anticancer activities of some novel 2-substituted-6-bromo-3-methylthiazolo[3,2-a]benzimidazole derivatives.

Abstract: Ethyl 6-bromo-3-methyl-1,3-thiazolo[3,2-a]benzimidazole-2-carboxylate 2 was prepared by the ambient temperature bromination of ethyl 3-methyl-1,3-thiazolo[3,2-a]benzimidazole-2-carboxylate 1. The acid hydrazide 4 was obtained by the reaction of ester 2 with hydrazine hydrate. Treatment of compound 4 with benzaldehyde or 2-thiophenaldehyde yielded the corresponding hydrazones 6a and 6b, respectively, while the reaction of acid hydrazide 4 with ethoxymethylene malononitrile (7a) or with ethyl ethoxymethylene cyanoacetate (7b) in refluxing ethanol afforded pyrazole derivatives 9a and 9b, respectively. Taken together, from the biological investigations compounds 9a and 9b were the most significant inhibitors of LPS-stimulated NO generation from Raw murine macrophage 264.7, and, as another result, compounds 2 and 4 had a weak radical scavenging activity against DPPH radicals. Moreover, 2, 4, and 9a had a concomitant strong cytotoxicity against both colon carcinoma cells (HCT-116) and hepatocellular carcinoma cells (Hep-G2) while 9b showed specific cytotoxicity only against colon carcinoma cells.

Fluorinated 1,2,4-Triazolo[1,5-a]pyrimidine-6-carboxylic acid derivatives as antimycobacterial agents.

Abstract: A series of fluorinated 1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylic acid derivatives was designed and synthesized as fluoroquinolone analogues. The synthesized compounds were screened against Mycobacterium tuberculosis H(37)R(v) strain at 6.25 microg/mL concentration. Compound 4, the 7-oxo-2-(trifluoromethyl)-4,7-dihydro-1,2,4-triazolo[5,1-a]pyrimidine-6-carboxylic acid was found to be a very potent inhibitor, being able to inhibit 92% growth of M. tuberculosis H(37)R(v )at 6.25 microg/mL concentration. At the same time, it proofed to be nontoxic to mammalian cells (IC(50) > 62.5 microg/mL in VERO cells).

6‐Substituted Indolo[1,2‐c]quinazolines as New Antimicrobial Agents

Abstract: A series of 2-o-arylidineaminophenylindoles and their cyclic derivatives (indolo[1,2-c]quinazolines) were synthesized. The reactions occurred under relatively mild conditions and afforded the desired product in good yields. Molecular structures of the synthesized compounds were confirmed by IR, (1)H-NMR,( 13)C-NMR, MS spectra, and elemental analyses. Furthermore, all the final products were screened for in-vitro antibacterial activity against three Gram-positive and three Gram-negative bacteria and also tested for their inhibitory action against three strains of fungi. Compound IIc showed potent activity against all the bacterial (except S. typhimurium) and fungal strains. Especially, compounds IIi and IIj which have isoquinolyl and pyridyl substituents displayed potent antibacterial as well as antifungal activities compared to those of the respective standard drugs Ampicillin and Ketoconazole.

Design and synthesis of a gossypol derivative with improved antitumor activities.

Abstract: A novel chemical process has been devised for the synthesis of a new derivative of gossypol, 6,7,6',7'-tetrahydroxy-5,5'-diisopropyl-3,3'-dimethyl-[2,2']binaphthalenyl-1,4,1',4'-tetraone (Apogossypolone). This new process has only four steps, with a shorter synthesis span, a simple purification process, and improved yield and quality. The structure of apogossypolone was characterized by( 1)H-nuclear magnetic resonance, (13)C-nuclear magnetic resonance, mass spectroscopy, infrared spectroscopy, and elemental analysis. Cell-cytotoxicity assay demonstrates that apogossypolone is three- to six-fold more potent than the parent compound, (-)-gossypol, in inhibiting the human prostate tumor cell lines PC-3 and DU-145 as well as the human breast cancer cell line MDA-MB-231. The colony-formation assay with DU-145 cells showed that apogossypolone inhibited more than 70% of colony formation at 1 muM, whereas (-)-gossypol at 10 muM only inhibited less than 50% of colony formation. The results indicate that apogossypolone exerts strong antitumor activities in human prostate and breast cancer cells, and thus represents a promising cancer therapeutic.

Design, synthesis, and in-vivo pharmacological screening of N,3-(substituted diphenyl)-5-phenyl-1H-pyrazoline-1-carbothioamide derivatives.

Abstract: Various 3,5-(substituted diphenyl)-4,5-dihydro-pyrazole-1-carbothioic acid phenylamides were synthesized starting from substituted acetophenones. Structures of the compounds were confirmed on the basis of spectral data. The compounds were evaluated for their anticonvulsant and antidepressant activity. Interestingly, out of 26 compounds, four (3f, 3g, 3t, and 3u) were found to protect 100% of the animals in the MES screen at a dose of 25 mg/kg. They were also found to have appreciable anticonvulsant activity in scPTZ screen. Two compounds, 3j and 3o, significantly reduced the duration of the immobility time at 25 mg/kg dose, when compared to control.

Synthesis and Antimycobacterial Activity of a Novel Series of Isonicotinylhydrazide Derivatives

Abstract: A novel series of 14 new isonicotinyl hydrazide derivatives 2a-g, 3a-g containing a 4-thiazolidinone / 2-azetidinone nucleus were synthesized by reacting N'-substituted arylidene / heteroarylidene isonicotinyl hydrazide 1a-g with thioglycollic acid in the presence of dry benzene and with chloroacetyl chloride in the presence of triethylamine, respectively. Structures of all newly synthesized compounds were characterized on the basis of elemental analyses and spectral data (IR and (1)H-NMR). All the title compounds were tested for their in-vitro antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv using Alamar-Blue susceptibility test, and the activity is expressed as the minimum inhibitory concentration (MIC) in microg/mL. Among the series, compounds 2b, 2g, 3b, and 3g displayed an encouraging antimycobacterial activity profile as compared to that of the reference drugs isoniazid / rifampicin.

Design, synthesis, and antifungal activity of novel conformationally restricted triazole derivatives.

Abstract: A series of new triazole derivatives were designed and synthesized on the basis of the active site of lanosterol 14alpha-demethylase from Candida albicans (CACYP51). 2-(2,4-Difluorophenyl)-3-(methyl-(3-phenoxyalkyl)amino)-1-(1H-1,2,4-triazol-1-yl)propan-2-ols show excellent in-vitro activity against most of the tested pathogenic fungi. The MIC(80) value of compound 8a against Candida albicans is 0.01 microM, which provides a good starting template for further structural optimization. The binding modes of the designed compounds were investigated by flexible molecular docking. The compounds interacted with CACYP51 through hydrophobic, van-der-Waals, and hydrogen-bonding interactions.

Design, synthesis, and biological evaluation of prenylated chalcones as vasorelaxant agents.

Abstract: Five prenylated chalcones and one allylated chalcone were prepared according to the analysis based on support vector machine (SVM) classification model. Most of the synthesized chalcones showed potent vasorelaxant activities through evaluation in aortic rings with the endothelium pre-contracted by phenylephrine (PE), indicating that the experimental activities were in good agreement with the theoretical ones. Structure-activity relationship of these compounds showed that the substituent pattern and number of hydroxyl groups were crucial for their vasorelaxant activities and that the replacement of prenyl group with allyl group retained the potent activity.

Synthesis of Monomeric and Dimeric Acridine Compounds as Potential Therapeutics in Alzheimer and Prion Diseases

Abstract: Starting from substituted 9-chloroacridines, a series of quinacrine and spacered dimeric acridine compounds was prepared Their ability to interrupt the protein association of prion- and Alzheimer-specific proteins and Ab peptides was explored using a fast screening system based on FACS analysis The bis-acridines displayed a higher activity than the corresponding monomers Among these derivatives, best results were obtained with the 2,4-dimethoxy-6-nitro compound 7h for Abeta-peptides and the 2-methoxy-6-nitro compound 7f for PrP

Studies on synthesis and pharmacological activities of 1,2,4-triazolo[3,4-b]1,3,4-thiadiazoles and their dihydro analogues.

Abstract: 4-Amino-5-substituted aryl-3-mercapto-1,2,4-triazoles are versatile synthons for constructing various biologically active heterocycles. Starting from 4-amino-5-substituted aryl-3-mercapto-1,2,4-triazole 3a-c, a series of new 3,5-disubstituted-1,2,4-triazolo-[3,4-b]1,3,4-thiadiazoles and their 5,6-dihydrotriazolothiadiazoles were prepared. The structures of all the newly synthesized compounds have been confirmed by elemental analysis, IR,( 1)H-NMR, (13)C-NMR, and mass spectra. The antimicrobial effects of the synthesized compounds were investigated using the paper disc method. Anti-inflammatory and analgesic activities of the synthesized compounds were assessed by carrageenan-induced rat paw oedema method and by Eddy's hot plate method, respectively. Some of the compounds exhibited promising antimicrobial activities as well as moderate to good anti-inflammatory activity and analgesic activity.

Protein Kinase C Activators as Synaptogenic and Memory Therapeutics

Abstract: The last decade has witnessed a rapid progress in understanding of the molecular cascades that may underlie memory and memory disorders Among the critical players, activity of protein kinase C (PKC) isoforms is essential for many types of learning and memory and their dysfunction, and is critical in memory disorders PKC inhibition and functional deficits lead to an impairment of various types of learning and memory, consistent with the observations that neurotoxic amyloid inhibits PKC activity and that transgenic animal models with PKCβ deficit exhibit impaired capacity in cognition In addition, PKC isozymes play a regulatory role in amyloid production and accumulation Restoration of the impaired PKC signal pathway pharmacologically results in an enhanced memory capacity and synaptic remodeling / repair and synaptogenesis, and, therefore, represents a potentially important strategy for the treatment of memory disorders, including Alzheimer's dementia The PKC activators, especially those that are isozyme-specific, are a new class of drug candidates that may be developed as future memory therapeutics

Antifungal and antibacterial activity of the newly synthesized 2-xanthone derivatives.

Abstract: A series of 2-substituted xanthone derivatives 8-20 containing selected allyl, cinnamyl, morpholine, and imidazole moieties were synthesized and tested for their antifungal and antibacterial in-vitro properties. Of the newly synthesized derivatives, ten revealed antifungal activity especially against Trichophyton mentagrophytes (the biggest inhibition zones ranged 35 mm for 11 and 13). 2-(3-(Allylamino)propoxy)-9H-xanthen-9-one hydrochloride 9 inhibited growth of all of the examined fungal species. Significant efficacy against evaluated yeasts and dermatophytes was also observed for 6-chloro-2-methyl-9H-xanthen-9-one derivatives 11-13 containing encyclic amine moieties. Additionally, compounds 9, 11, and 12 hindered development of bacteria species but in a lesser degree. They were efficacious against Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis.

Synthesis and In‐Vitro Antitumor Activities of Some Mannich Bases of 9‐Alkyl‐1,2,3,4‐tetrahydrocarbazole‐1‐ones

Abstract: A novel series of 2-substituted aminomethyl-9-alkyl-1,2,3,4-tetrahydrocarbazole-1-ones 5a-q was synthesized via aminomethylation of 9-alkyl-1,2,3,4-tetrahydrocarbazole-1-ones 4a-e with hydrochlorides of the respective amines 6a-m. The structures of these newly synthesized compounds were characterized by (1)H-NMR, MS, and elemental analysis. All the compounds were tested for their cytotoxic activity in vitro against four human tumor cell lines including human non-small lung cancer cells (A549), human gastric adenocarcinoma (SGC), human colon cancer cell (HCT116), human myeoloid leukemia cells (K562), and one multi-drug resistant subline (KB-VCR). Most compounds showed moderate to potent cytotoxic activity against the tested cell lines. Preliminary mechanism research indicated that the most promising compound, 2-diethylaminomethyl-9-methyl-1,2,3,4-tetrahydrocarbazole-1-one 5c, exhibited a potential inhibitory effect against microtubule.

Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro antimycobacterial activity.

Abstract: An efficient and simple three-component domino synthesis of some new dihydropyrimidines (DHPMs) from aromatic aldehydes, 1,3-dicarbonyl compounds and N-(3-chloro-4-fluorophenyl)urea using molecular iodine as catalyst is described. The 1-substituted dihydropyrimidines were isolated in good to excellent yields (78-90%) within a short reaction time (4-6 h) at ambient temperature. The biological evaluation revealed that the newly synthesized compounds (4a-i and 5a-i) exhibited moderate antimycobacterial activity against Mycobacterium tuberculosis H37 RV.

Synthesis of 2-fluoro N(10)-substituted acridones and their cytotoxicity studies in sensitive and resistant cancer cell lines and their DNA intercalation studies.

Abstract: A series of 2-fluoro N(10)-substituted acridone derivatives with varying alkyl side chain length with propyl, butyl substitution, and a tertiary amine group at the terminal end of the alkyl side chain were synthesized and screened against cancer cell lines SW 1573, SW 1573 2R 160 (P-gp substrate) which are non-small lung cancer cell lines, MCF-7, MCF-7/MR (BCRP substrate) are breast cancer cell lines, 2008 WT, 2008MRP1, 2008MRP2, 2008MRP3 are ovarian cancer cell lines, and human embryo kidney cell lines like HEK293, HEK293 MRP4, and HEK293 MRP5i The propyl-series compounds showed lipophilicity in the range of 193 to 440 and the butyl series in the range of 237 to 478 The compounds 4, 7, and 8 showed good cytotoxicity against the 60 human cancer cell line panel of the National Cancer Institute, USA The compounds 14 and 15 showed a better cytotoxicity in most of the cancer cell lines compared to other compounds tested The DNA-binding properties of the compounds were evaluated based on their affinity or intercalation with CT-DNA measured with absorption titration The compound 11 bearing planar tricyclic ring linked with a butyl methylpiperazino side chain showed the highest binding affinity with a binding constant (K(i)) of 1038 x 10 M(-1) Evaluation of the compounds in cell lines with an overexpression of various multidrug resistance-related protein (MRP), P-glycoprotein (P-gp), or Breast Cancer Resistance Protein (BCRP) showed that all compounds are not substrates for any of these transporters

Synthesis and Anticonvulsant Activity of N‐(2‐Hydroxy‐ethyl)amide Derivatives

Abstract: A series novel of N-(2-hydroxyethyl)amide derivatives was synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test (Tox). The maximal electroshock test showed that N-(2-hydroxyethyl)decanamide 1g, N-(2-hydroxyethyl)palmitamide 1l, and N-(2-hydroxyeth-yl)stearamide 1n were found to show a better anticonvulsant activity and also had lower toxicity than the marked anti-epileptic drug valproate. In the anti-MES potency test, these compounds exhibited median effective doses (ED50) of 22.0, 23.3, 20.5 mg/kg, respectively, and median toxicity doses (TD50) of 599.8, >1000, >1000 mg/kg, respectively, resulting in a protective index (PI) of 27.5, >42.9, >48.8, respectively. This is a much better protective index than that of the marked anti-epileptic drug valproate (PI = 1.6). To further investigate the effects of the anticonvulsant activity in several different models, compounds 1g, 1l, and 1n were tested having evoked convulsions with chemical substances, including pentylenetetrazloe, isoniazide, 3-mercaptopropionic acid, bicuculline, thiosemicarbazide, and strychnine.

Synthesis of novel uracil non-nucleoside derivatives as potential reverse transcriptase inhibitors of HIV-1.

Abstract: Novel emivirine and TNK-651 analogues 5a–d were synthesized by reaction of chloromethyl ethyl ether and / or benzyl chloromethyl ether, respectively, with uracils having 5-ethyl and 6-(4-methylbenzyl) or 6-(3,4-dimethoxybenzyl) substituents. A series of new uracil non-nucleosides substituted at N-1 with cyclopropylmethyloxymethyl 9a–d, 2-phenylethyloxymethyl 9e–h, and 3-phenylprop-1-yloxymethyl 9i–l were prepared on treatment of the corresponding uracils with the appropriate acetals 8a–c. Some of the tested compounds showed good activity against HIV-1 wild type. Among them, 1-cyclopropylmethyloxymethyl-5-ethyl-6-(3,5-dimethylbenzyl)uracil 9c and 5-ethyl-6-(3,5-dimethylbenzyl)-1-(2-phenylethyloxymethyl)uracil 9g showed inhibitory potency equally to emivirine against HIV-1 wild type. Furthermore, compounds 9c and 9g showed marginal better activity against NNRTI resistant mutants than emivirine.

Synthesis and Antimicrobial Activity of Some Novel 2‐[4‐(Substituted Piperazin‐/Piperidin‐1‐ylcarbonyl)phenyl]‐1H‐benzimidazole Derivatives

Abstract: In this study, we report the synthesis and antimicrobial evaluation of several new 4-(1H-benzimidazol-2-yl)benzamides (11-30) and 5-chloro-1-(p-fluorobenzyl)-2-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-1H-benzimidazole (33). Compound 20 exhibited the best antibacterial activity with MIC value of 6.25 microg/mL against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). Significant antifungal activities were obtained with the compounds 13, 14, 18, 19, and 33 with MIC values of 3.12 microg/mL which are close to fluconazole.

Synthesis and antibacterial activity of a new series of 3-[3-(substituted phenyl)-1-isonicotinoyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives.

Abstract: A novel series of 3-[3-(substituted phenyl)-1-isonicotinoyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives 4a-k have been synthesized by the reaction of 3-[2,3-dibromo-3-(substituted phenyl) propanoyl]-2H-chromen-2-one 3a-k and isonicotinic acid hydrazide in the presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in-vitro antibacterial activity against Gram-positive and Gram-negative bacteria. Among the series, compounds 4e, 4i, and 4k displayed an encouraging antibacterial activity profile as compared to the reference drug ampicillin against tested bacterial strains.

Synthesis and Biological Evaluation of Novel Pyrazoles and Pyrazolo[3,4‐d]pyrimidines Incorporating a Benzenesulfonamide Moiety

Abstract: Synthesis and biological evaluation of novel pyrazoles and pyrazolo[3,4-d]pyrimidines are reported. Fourteen compounds were selected by the NCI and tested for their preliminary in-vitro anticancer activity, whereas all the synthesized compounds were evaluated for their in-vitro antimicrobial activity. Compound 12a was proven to possess the highest anticancer activity with a broad spectrum profile. It showed particular effectiveness towards leukemia HL-60 (TB), K-562, non-small cell lung cancer NCI-H23, and colon cancer HT 29, KM 12 cell lines (GI(50) = 6.59, 4.44, 1.37, 3.33, and 9.63 muM, respectively). Out of the synthesized compounds, thirteen derivatives were found to display pronounced antimicrobial activity especially against P. aeruginosa. Compounds 2c, 5b, 10, 11b, 17b, 18b, and 19 were proven to be the most active with a broad spectrum of activity. Compound 19 was found to be equipotent to ampicillin against B. subtilis, whereas compounds 11b and 19 were four times superior to ampicillin against P. aeruginosa, while compounds 5b and 18b were equipotent to ampicillin against the same organism. Moreover, compounds 2c, 10, and 11b were nearly equipotent to ampicillin against E. coli. On the other hand, compounds 2c, 5b, 10, 11a, 17b, and 18b exerted nearly half the activity of clotrimazole against C. albicans.