Synthesis and anti-HIV evaluation of the novel 2-(m-chlorobenzyl)-4-substituted-7-methyl-1, 1, 3-trioxo-pyrazolo[4, 5-e] [1, 2, 4]thiadiazines

A novel series of 2-(m-Chlorobenzyl)-4-substituted-1, 1, 3-trioxo-2H,4H-pyrazolo[4, 5-e][1, 2, 4] thiadiazines (7a-k) were synthesized, and evaluated for their anti-HIV replication in MT-4 cell cultures. Compound (7a) showed activity against HIV-1-induced cytopathicity, with an EC₅₀ value of 45.6 μM, but none of the compounds exhibited inhibitory activity against HIV-2.     

Synthesis and evaluation of anti-inflammatory and analgesic activity of 3-[(5-substituted-1,3,4-oxadiazol-2-yl-thio)acetyl]-2H-chromen-2-ones

A novel series of 3-[(5-substituted-1,3,4-oxadiazol-2-yl-thio)acetyl]-2H-chromen-2-one (7a–i) were synthesized by the condensation between the appropriately substituted 5-substituted-1,3,4-oxadiazolyl-2-thione (4a–i) derived from various existing NSAIDs and 3-(2-bromoacetyl)-2H-chromen-2-one (6) under reflux in the presence of sodium ethoxide. Structure of the synthesized compounds was established on the basis of physicochemical, elemental analysis, and spectral data. The title compounds were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 200 mg/kg bw. Among the series, four compounds 7c, 7e, 7f, and 7h were found to possess a significant anti-inflammatory and analgesic activity profile. In addition, these compounds were also found to possess a less degree of ulcerogenic potential as compared to standard NSAIDs.     

Triphenyltin(IV) 2-[(<Emphasis Type="Italic">E</Emphasis>)-2-(aryl)-1-diazenyl]benzoates as anticancer drugs: synthesis,structural characterization,in vitro cytotoxicity and study of its influence towards the mechanistic role of some key enzymes

Triphenyltin(IV) complexes of composition [Ph₃SnL¹H]_n (1) and [Ph₃SnL²H]_n (2) (where L¹H = 2-[(E)-2-(3-formyl-4-hydroxyphenyl)-1-diazenyl]benzoate and L²H = 2-[(E)-2-(4-Hydroxy-5-methylphenyl)-1-diazenyl]benzoate) were synthesized and characterized by spectroscopic (¹H, ¹³C and ¹¹⁹Sn NMR, IR, ¹¹⁹Sn M?ssbauer) techniques in combination with elemental analysis. The molecular structures and geometries of the complexes (1 and 2) were fully optimized using the quantum mechanical method (PM3). Complexes (1 and 2) were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumour cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The test compounds 1 and 2 exhibit comparable results and both the compounds are found to be far superior to CCDP (cisplatin), 5-FU (5-fluorouracil) and ETO (etoposide) across a panel of cell lines and the activity is more pronounced for the A498 (22 fold) and H226 (33 fold) cell lines compared to CCDP, and A498 (13 fold), H226 (39 fold) and MCF-7 (33 fold) cell lines compared to ETO. The test compounds are even 23 fold more active in magnitude in terms of the ID₅₀ value at least against the H226 cell lines when compared with MTX (methotrexate). Further, the mechanistic role of cytotoxic activity of test compounds (1 and 2), are discussed in relations to the theoretical results of docking studies with some of the key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II.     

Synthesis and antimicrobial study of fluoroquinolone-based 4-thiazolidinones

The title compounds 2-substituted phenyl-3-{1-cyclopropyl-6-fluoro-7-[4-(4-methoxyphenylpiperazin-1-yl]-4-oxo-1,4-dihydroquinoline} carboxamido-1,3-thiazolidin-4-ones 6a–j have been synthesized from lead molecule 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1; this reacted with thionyl chloride to give acid chloride 2 and with hydrazine hydrate to afford hydrazide 3. The hydrazide 3 on condensation with substituted aromatic aldehydes a–j gave Schiff base; these on reaction with N-(4-methoxyphenyl) piperazine and thioglycolic acid furnished title compounds 6a–j. All of the synthesized compounds have been established by elemental analysis. IR and NMR spectral data and have been screened for antifungal and antibacterial activities.     

Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

Design,synthesis and cytotoxic activity of novel 1-aroyl-4-(2-chloroethyl)semicarbazides

A series of aroyl derivatives of 4-(2-chloroethyl)semicarbazide were designed and synthesized to explore their antiproliferative activity against human brain carcinoma (U251) and human liver carcinoma (Hepg2) cell lines. The synthesized compounds were characterized by elemental analyses and spectroscopic data. It was established that compounds in which semicarbazide fragments are substituted with a (2-indolyl)carbonyl moiety showed a higher cytotoxic activity than the corresponding benzoyl derivatives. 1-[(5-Benzyloxy-1H-indol-2-yl)carbonyl]-4-(2-chloroethyl)semicarbazide (24) showed the highest cytotoxic activity against Hepg2 (IC₅₀= 21 μg/ml), while 4-(2-chloroethyl)-1-[(5-methoxy-1H-indol-2-yl)carbonyl]semicarbazide (23) was the most active compound against U251 (IC₅₀ = 8 μg/ml). __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 4, pp. 12–15, May, 2007.     

Synthesis and structure-activity relationships of 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolonecarboxylic acid antibacterials having fluorinated 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] substituents

A series of novel 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolones bearing fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituents at the C-7 position (2-4) was synthesized to obtain potent drugs for infections caused by Gram-positive pathogens, which include resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE). These fluorinated compounds 2-4 exhibited potent antibacterial activity comparable with that of a compound bearing a non-fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidine moiety at the C-7 position (1) and had at least 4 times more potent activity against representative Gram-positive bacteria than ciprofloxacin (CPFX), gatifloxacin (GFLX), or moxifloxacin (MFLX). Among them, the 7-[(3S,4R)-4-(1-aminocyclopropan-1-yl)-3-fluoropyrrolidin-1-yl] derivative 3 (=DQ-113), which showed favorable profiles in preliminary toxicological and nonclinical pharmcokinetic studies, exhibited potent antibacterial activity against clinically isolated resistant Gram-positive pathogens.     

Dibutyltin(IV) complexes containing arylazobenzoate ligands: chemistry,in vitro cytotoxic effects on human tumor cell lines and mode of interaction with some enzymes

Dibutyltin(IV) complexes of composition Bu₂Sn(LH)₂, where LH is a carboxylate residue derived from 2-[(E)-(5-tert-butyl-2-hydroxyphenyl)diazenyl]benzoate (L¹H) with water molecule (1), 4-[(E)-(5-tert-butyl-2-hydroxyphenyl)diazenyl]benzoate (L²H) (2) and 4-[(E)-(4-hydroxy-5-methylphenyl)diazenyl]benzoate (L³H) (3), were synthesized and characterized by spectroscopic (¹H, ¹³C and ¹¹⁹Sn NMR, IR, ¹¹⁹Sn M?ssbauer) techniques. A full characterization was accomplished from the crystal structure of complex 1. The molecular structures and geometries of the complexes (1a i.e. 1 without water molecule and 3) were fully optimized using the quantum mechanical method (PM6). Complexes 1 and 3 were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumor cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. Compound 3 is found to be four times superior for the A498, EVSA-T and MCF-7 cell lines than CCDP (cisplatin), and four, eight and sixteen times superior for the A498, H226 and MCF-7 cell lines, respectively, compared to ETO (etoposide). The mechanistic role of cytotoxic activity of test compounds is discussed in relation to the theoretical results of docking studies with some key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II associated with the propagation of cancer.     

Synthesis and antitumor activity of (4-hydroxyphenyl)[5-substituted alkyl/aryl)-2-thioxo-1,3,4-thiadiazol-3-yl]methanone and [(3,4-disubstituted)-1,3-thiazol-2ylidene]-4-hydroxybenzohydrazide

To examine new drug leads with potential anticancer activity, some (4-hydroxyphenyl)[5-substituted alkyl/aryl)-2-thioxo-1,3,4-thiadiazol-3-yl]methanone (4.a–4.c) and [-(3,4-disubstituted)-1,3-thiazol-2ylidene)]-4-hydroxybenzohydrazide (6.a–6.d) were synthesized using appropriate synthetic route. The newly prepared compounds 4.a–4.c and 6.a–6.d demonstrated inhibitory effects on the growth of a wide range of cancer cell lines especially on leukemia (HL-60), non-small lung cancer (HOP-92), renal cancer (ACHN) at the range of GI₅₀ −4.23 to −7.23.     

Synthesis and antimycobacterial activity of substituted 2-nitro-1-(4-tolylsulfonyl)-2-(3-methylphenyl-1,2,4-oxadiazol-5-yl)ethanes

A series of substituted 2-nitro-1-(4-tolylsulfonyl)-2-(3-methylphenyl-1,2,4-oxadiazol-5-yl)ethanes were synthesized and their antimycobacterial activity with respect to Mycobacterium Lufu and Mycobacterium tuberculosis species was studied. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 7, pp. 30–31, July, 2006.     

Synthesis,characterization, and antimicrobial activity of some new coumarin derivatives

A number of new [(4-methyl-2-oxo-2H-chromen-7-yl)amino]methylcoumarins (5a–c), benzofuran (6), and benzoxazol (7) were synthesized through the reaction of 7-amino-4-methylcoumarin (1) with a number of organic halides. In addition, series of N-substituted 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (11a–h) and (12a–d) were prepared from the reaction of 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (8) with corresponding heteroaryl/alkyl halides (2–4, 9, and 10). The synthesized compounds were characterized by elemental analysis and by spectroscopic techniques such as ¹H-NMR, ¹³C-NMR, and mass spectrometry and were tested for their in vitro antimicrobial activity. The newly synthesized compounds exerted significant inhibitory activity against the growth of tested bacterial strains and a few of them are found to be potent antimicrobial agents.     

Synthesis and anticonvulsant evaluation of 3-substituted-4-(4-hexyloxyphenyl)-4H-1,2,4-triazoles

A series of 3-substituted-4-(4-hexyloxyphenyl)-4H-1,2,4-triazole derivatives (3a-s) were synthesized as open-chain analogues of 7-hexyloxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines (1c) using 4-hexyloxyaniline, acyl hydrazines, and dimethoxy-N,N-dimethylmethanamine as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES test) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). MES test showed that all open-chain compounds exhibited strong anticonvulsant activity and lower neurotoxicity, and that some possessed obviously stronger activity than compound 1c. Compound 3d, 3-propyl-4-(4-hexyloxyphenyl)-4H-1,2,4-triazole was found to be the most potent with an ED₅₀ value of 5.7 mg/kg and protective index (PI = TD₅₀/ED₅₀) value of 11.5, which was much greater than that of the prototype drug phenytoin (PI = 6.9).     

Design, synthesis, and QSAR study of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives as cytotoxic agents

This study deals with the synthesis of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives (6a–j) from isatin (3) and 5,7-dibromoisatin (4). All newly synthesized compounds were characterized using IR, ¹H NMR, MS, and elemental analysis followed by evaluation of their cytotoxic activity by XTT assay on breast cancer cell line MCF-7 and non-cancer African green monkey cell line VERO. Correlation study for QSAR and in vitro assay was performed. The outcomes indicated that electron withdrawing substitutions at para position of phenyl ring and 5, 7 positions of isatin ring and increasing lipophilicity of the compound increased the cytotoxic activity. The 2-(5,7-dibromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-(4-nitrophenyl)acetamide (6b) was found to be the most active compound in the series and demonstrated higher selectivity toward MCF-7 cell line. The IC₅₀ values were 1.96 and 1.90 μM for test compound (6b) and vinblastin (reference drug), respectively. This indicates compound (6b) may possess equipotent cytotoxic activity to vinblastine. The compound (6b) is particularly promising, since it could kill cancer cells 19–20 times more effectively than the non-cancer cells. This property of (6b) may enable us to effectively control tumors with low side effects. Hence, we propose that 2-(5,7-dibromo-2,3-dioxo-2,3-dihydro-1H- indol-1-yl)-N-(4-nitrophenyl)acetamide may be used as lead for further development.     

New cycloartanes and new iridoids from Dolichandrone spathacea collected in the mangrove forest of Soc Trang province,Vietnam

Abstract

Two new cycloartanes, named dolichandrone A (1) and dolichandrone B (2), as well as two new iridoids, named [6-O-[(E)-4-methoxycinnamoyl]-1β-hydroxy-dihydrocatalpolgenin (3) and 6-O-[(E)-4-methoxycinnamoyl]-1α-hydroxy-dihydrocatalpolgenin (4), together with four known iridoids (5–8), were isolated from the leaves and barks of Dolichandrone spathacea. Their structures were elucidated by means of extensive analysis of their HRESIMS, 1D and 2D NMR spectroscopic data. All of these compounds have been isolated for the first time from this plant. Compounds 1, 2, 5, and 7 were evaluated for their cytotoxic activity in vitro against four human cancer cell lines KB, Lu, HepG2, and MCF7. The results showed that only compound 2 exhibited a good cytotoxicity against KB cell line with IC₅₀ of 18.77 μM.     

Synthesis and characterization of (Z)-N-(1-[2-{3-[(dimethylamino)methyl)]-2-methoxyphenyl}-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl]ethylidene) benzenamine derivatives as potent antifungal agents

In the present study, a series of (Z)-N-(1-[2-{3-[(dimethylamino)methyl)]-2-methoxyphenyl}-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl]ethylidene)benzenamine derivatives have been synthesized and characterized by IR, 1H NMR and 13C NMR spectra. All the synthesized compounds were evaluated for their antifungal activity and were compared with the standard drug, clotrimazole. The compounds demonstrated excellent to weak antifungal activity. Among the synthesized derivatives, 4f and 4h showed significant activity and 4c exhibited moderate activity against Candida albicans, Candida tropicalis and Aspergillus niger as compared with the standard antifungal agent - clotrimazole. The minimum inhibitory concentration of the compounds was in the range of 1.62-25 microg/mL against fungi. Furthermore, the substitution of chloro, nitro and methoxy groups at para position of benzene moiety play an important role in enhancing the antifungal activity of this class of compounds.     

1-(7-Chloroquinolin-4-yl)-2-[(1H-pyrrol-2-yl)methylene]hydrazine: a potent compound against cancer

Heteroaromatic derivatives (3a–f) have been synthesized and evaluated for their activity against four cancer cell lines. Among the studied compounds, 1-(7-Chloroquinolin-4-yl)-2-[(1H-pyrrol-2-yl)methylene]hydrazine (3e) exhibited an excellent cytotoxic activity against the referred lines, and especially on melanoma cells (MDAMB-435). In this case, compound 3e is four times more active than the standard substance Doxorubicin. Together with other results from our group, 7-chloro-4-quinolinylhydrazones derived from chloroquine could be considered a relevant finding toward the rational design of new leads for antitumor compounds.     

A new cytotoxic coumarin, 7-[(<Emphasis Type="Italic">E</Emphasis>)-3′,7′-dimethyl-6′-oxo-2′,7′-octadienyl] oxy Coumarin,from the leaves of <Emphasis Type="Italic">Zanthoxylum schinifolium</Emphasis>

A new coumarin, 7-[(E)-3′,7′-Dimethyl-6′-oxo-2′,7′-octadienyl]oxy coumarin (1), together with three known compounds, schinilenol (2), schinindiol (3) and 7-[(E)-7′-hydroxy-3′,7′-dimethylocta-2′,5′-dienyloxy]-coumarin (4) were isolated from the methylene chloride fraction of Z. schinifolium by normal and reverse phase column chromatographies. Their structures were determined on the basis of physical and spectroscopic evidences. Compound 1 (IC₅₀ 8.10 μM) showed potent cytotoxicity compared to auraptene (IC₅₀ 55.36 μM) against Jurkat T cells. The other isolated compounds 2 and 4 exhibited weak cytotoxicities.     

Synthesis of 2-(3-Substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]octanes and 2α-(3-Substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-enes as Potential Muscarinic Agonists

Radioligand binding affinities of seven muscarinic receptor ligands which possess an oxadiazole ring side chain have been determined in rat heart, rat brain, and m₁- or m₃-transfected CHO cell membrane preparations to determine the selectivity for subtypes of muscarinic receptor. The ratios of binding constants in brain membranes were measured as an indicator of potential agonist activity against [³H]QNB and [³H]Oxo-M. These muscarinic ligands did not discriminate the subtypes of muscarinic receptors. Six muscarinic ligands which have a 3-amino- or 3-methyl-1,2,4-oxadiazol-5-yl groups attached to the 8-methyl-8-azabicyclo[3.2.1]oct-2-ene or 8-methyl-8-azabicyclo[3.2.1]octane head group show binding constants between 2.04 x 10^–6 and 1.79 x 10^–5 M in rat heart, rat brain, and m₁- or m₃-transfected CHO cell membrane preparations. 1-Methyl-2-[3-amino-1,2,4-oxadiazol-5-yl]piperidine shows low binding constants of approximately 10^–4 M in rat heart and rat brain. (1R,5S)-2-[3-Amino-1,2,4-oxadiazol-5-yl]-8-methyl-8-azabicyclo-[3.2.1]oct-2-ene [(1R,5S)-17] was the most active compound.     

Synthesis and antimicrobial activity of 2-phenyl-3-{1-cyclopropyl-6-fluoro-7-[4-methylpiperazin-1-yl]-4-quinolone}carboxamido-3-thiazolidin-4-ones

The title compounds VIa – j have been prepared from the lead molecule 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid I. The lead molecule was converted to hydrazide III via acid chloride II, which on reaction with different substituted aromatic aldehydes a – j afforded Schiff base, and on further structural variation of the Schiff base furnished the final compoundsVIa – j (Scheme I). The synthesized compounds were tested for their antibacterial and antifungal activity (MIC) in vitro against two Gram-positive bacteria, S. aureus and S. pyogenes, and two Gram-negative bacteria E. coli and P. aeruginosa, and fungi C. albicans, A. niger, and A. clavatus, taking gentamycin, ampicillin, chloramphenicol, ciprofloxacin, norfloxacin, nystatin, and griseofulvin as standard drugs. All the synthesized compounds have been established by elemental analysis amd IR and NMR spectral data.