Synthesis and antimicrobial studies of novel 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one 4'-phenylthiosemicarbazones

New series of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one 4'-phenylthiosemicarbazones (compounds 9-16) was obtained from the corresponding 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones. The synthesized compounds have been characterized by their elemental, analytical, and spectral studies. Besides, these reported compounds were screened for their antibacterial and antifungal activities against a spectrum of microbial organisms. These studies proved that against bacteria, compounds 10 and 11 against Bacillus subtilis, compound 13 against Salmonella typhi, show maximum inhibition potency at low concentration (6.25 μg/mL), whereas against fungal, compounds 11, 13, and 16 against Candida albicans and compounds 12 and 13 against Cryptococcus neoformans, showed beneficial antifungal activity at minimum concentration (6.25 μg/mL).     

Design, synthesis, stereochemistry and antioxidant properties of various 7-alkylated 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones

We used the modified Mannich condensation to synthesize three closely-related series of 7-alkylated 3-ABNs 1-5 viz., 7-methylated 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (7-Me ABNs 1-5), 7-ethylated 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (7-Et ABNs 1-5) and 7-tert-pentylated 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (7-tert-pentyl ABNs 1-5). All compounds yielded good as single isomers by the use of PPA·SiO(2) as a heterogeneous Bronsted acidic catalyst. The 1D, 2D NMR, and single-crystal XRD interpretations unambiguously characterized the stereochemistry of the synthesized compounds. In solution as well as solid-state, all compounds exist in the twin-chair conformation with equatorial orientations of all substitutions, despite their nature and positions. The chemical methods viz., DPPH, reducing power, and phospho-molybdenum methods identified some of the target curcumin analogs as active compounds. Among them, 7-Me ABN 4 (7-methyl-2,4-bis(3-methoxy-4-hydroxyphenyl)-3-azabicyclo[3.3.1]nonan-9)-one exerted the best antioxidant profile that comparable to standard l-ascorbic acid, α-tocopherol and curcumin. Hence, we evaluated further for its intracellular ROS inhibition potency on RAW 264.7 macrophage cells, and found to be effective as well as non-toxic at 100μM.     

Design,synthesis and biological evaluation of novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-1,3-thiazolidin-4-ones as a new class of antimicrobial agents

New series of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one thiosemicarbazones (9–16) obtained from the corresponding 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (1–8) upon cyclization with ethylbromoacetate in the presence of sodium acetate–acetic acid buffer afforded novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-1,3-thiazolidin-4-ones (17–24). The synthesized compounds have been characterized by their elemental, analytical and spectral studies. Besides, the reported compounds were screened for their antibacterial and antifungal activities against a spectrum of microbial organisms. These studies proved that compounds 11/18/20/23 against Staphylococcus aureus, 19/20/24 against Salmonella typhi show maximum inhibition potency at low concentration (6.25 μg/ml) whereas 18/19 against Candida albicans and 19/20/21 against Rhizopus sp. showed beneficial antifungal activity at minimum concentration.     

Synthesis, stereochemistry and in vitro antimicrobial evaluation of novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-4-phenyl-2,3-dihydrothiazoles

2-[(2,4-Diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-4-phenyl-2,3-dihydrothiazoles (3a-3k) have been synthesized by the cyclization of 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one thiosemicarbazones with phenacyl bromide and characterized by analytical (melting point and elemental analysis) and spectral (IR, (1)H NMR, (13)C NMR, D(2)O exchange, NOESY and mass) techniques. The novel Hantzsch products (3a-3k) were screened for their in vitro antibacterial and antifungal activities against some selected microorganisms. Structure activity relationship (SAR) for the reported compounds was studied by comparing their MIC values with standard drugs (Streptomycin and Amphotericin B). The results show that 3e against Escherichia coli and Cryptococcus neoformans3i against Bacillus Subtilis, 3b against Aspergillus flavus, and 3k against Rhizopus sp. were found to show significant growth inhibition.     

Synthesis of N-substituted 9-azabicyclo[3.3.1]nonan-3alpha-yl carbamate analogs as sigma2 receptor ligands

A series of N-substituted 9-azabicyclo[3.3.1]nonan-3alpha-yl phenylcarbamate analogs was prepared and their affinities for sigma (sigma(1) and sigma(2)) receptors were measured in vitro. The results of their structure-activity relationship study identified two new compounds, N-(9-(4-aminobutyl)-9-azabicyclo[3.3.1]nonan-3alpha-yl)-N'-(2-methoxy-5-methylphenyl)carbamate and N-(9-(6-aminohexyl)-9-azabicyclo[3.3.1]nonan-3alpha-yl)-N'-(2-methoxy-5-methylphenyl)carbamate, having a high affinity and selectivity for sigma(2) versus sigma(1) receptors. These compounds were also used in the preparation of biotinylated and fluorescent probes of the sigma(2) receptor.     

Design and synthesis of spiro[indole-thiazolidine]spiro[indole-pyrans] as antimicrobial agents

A series of novel spiro[indole-thiazolidine]spiro[indole-pyran] derivatives were synthesized from N-(bromoalkyl)indol-2,3-diones via monospiro-bisindole intermediates; the two indole nuclei being connected via N-(CH(2))(n)-N linker. Synthesized compounds were evaluated for their antimicrobial activities in vitro against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Staphylococcus epidermis), four Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, and Klebsiella pneumonia) as well as four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and Candida albicans) using Cup plate method. Bis spiro-indoles exhibited stronger antibacterial and antifungal efficiency than their corresponding mono spiro-indoles. Compound 10e, the most active derivative was shown to inhibit the growth of all bacterial strains and two fungal strains (A. niger and C. albicans).     

Synthesis,spectral, crystal and antimicrobial studies of biologically potent oxime ethers of nitrogen,oxygen and sulfur heterocycles

Three series of oxime ethers viz, 2,6-diarylpiperidin-4-one O-benzyloximes 5a–o, 2,6-diaryltetrahydropyran-4-one O-benzyloximes 7a–e and 2,6-diaryltetrahydrothiopyran-4-one O-benzyloximes 11a–b and 12a–c were synthesized and stereochemistry is established by their spectral and single crystal analysis. A SAR study has been carried out for the above oxime ethers against a panel of antibacterial (Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi and Escherichia coli) and antifungal agents (Candida albicans, Candida-51, Rhizopus sp., Aspergillus niger, Aspergillus flavus and Cryptococcus neoformans), respectively, using Ciprofloxacin and Amphotericin B as standards. Most of the chloro/methyl/methoxy substituted compounds exerted moderate to good activity against all the tested organisms; moreover, some compounds (5i, 5l, 5n, 5o, 7c2, 7d1, 7d2, 7e, 11b and 12c) exhibited promising activity than standard drugs.     

A convenient 'one-pot' synthesis and in vitro microbiological evaluation of novel 2,7-diaryl-[1,4] -diazepan-5-ones

A convenient method for the 'one-pot' synthesis of novel target molecule 2,7-diaryl-[1,4]-diazepan-5-ones from the respective 2,6-diaryl-piperidin-4-ones was catalyzed by NaHSO4.Al2O3 heterogeneous catalyst in dry media under microwave irradiation in solvent-free conditions. Moreover, the catalyst could be recovered and re-used up to 4 times after washing with ethyl acetate. They were evaluated for potential antibacterial activity against Staphylococcus aureus, beta-Haemolytic streptococcus, Vibreo cholerae, Salmonella typhii, Escherichia coli, Klebsiella pneumonia, Pseudomonas and antifungal activity against Aspergillus flavus, Aspergillus fumigatus, Mucor, Candida albicans and Rhizopus. Structure-Activity Relationship (SAR) led to the conclusion that, of all the compounds 25-32 tested, compound 30 exerted strong in vitro antibacterial activity against S. aureus, S. typhii, and Pseudomonas and all the compounds 25-32 were less active against E. coli, whereas all the compounds 25-32 displayed potent in vitro antifungal activity against all the fungal strains used, except compound 30, which was more effectual against Mucor.     

Efficient microwave enhanced regioselective synthesis of a series of benzimidazolyl/triazolyl spiro [indole-thiazolidinones] as potent antifungal agents and crystal structure of spiro[3H-indole-3,2'-thiazolidine]-3'(1,2,4-triazol-3-yl)-2,4'(1H)-dione

A microwave-assisted three-component, regioselective one-pot cyclocondensation method has been developed for the synthesis of a series of novel spiro[indole-thiazolidinones] (6a-l) using an environmentally benign procedure at atmospheric pressure in open vessel. This rapid method produces pure products in high yields within few minutes in comparison to a conventional two-step procedure. The crystal structure of one representative compound has been determined by X-ray diffraction. The synthesized compounds have been screened 'in vitro' for antifungal activity against Rhizoctonia solani, Fusarium oxysporum and Collectotrichum capsici. All compounds have shown good activity against these pathogens.     

Efficient synthesis and biological evaluation of some 2,4-diamino-furo[2,3-d]pyrimidine derivatives

The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, reacted with ammonia to give ethyl 3,4-dihydro-6-methyl-4-oxo-2-arylamino-furo[2,3-d]pyrimidine-5-carboxylate 3. Further reaction of 3 with POCl₃ and various amines generated ethyl 4-alkylamino-2-arylamino-6-methyl-furo[2,3-d]pyrimidine-5-carboxylate 5 in good yields. Their structures were confirmed by ¹H NMR, EI-Ms, IR and elemental analysis. Compound 5b was further analyzed by single crystal X-ray diffraction. Compound 5 exhibited cytotoxicity against two lung cancer cell lines. For example, compound 5a showed the best inhibition activities against A459 with IC₅₀ 0.8 μM.     

Thiazolo[5,4-f]quinazolin-9-ones, inhibitors of glycogen synthase kinase-3

In an effort to identify new protein kinase inhibitors with increased potency and selectivity, we have developed the microwave-assisted synthesis of thiazolo[5,4-f]quinazolin-9-ones. The effects of eighteen derivatives on CDK1/cyclin B, CDK5/p25, and GSK-3 were investigated. Several turned out to inhibit GSK-3 in the micromolar range. Molecular modeling studies suggest that the most selective GSK-3 inhibitors 7a-d bind into the ATP-binding site through a key hydrogen bond interaction with Val135 and target the specific hydrophobic backpocket of the enzyme.     

Synthesis, spectral analysis, antibacterial and antifungal activities of some 4,6-diaryl-4,5-dihydro-3-hydroxy-2[H]-indazole-a novel fused indazole derivative

A novel class of 4,6-diaryl-4,5-dihydro-3-hydroxy-2[H]-indazoles 25-32 were synthesized and evaluated for their in vitro antibacterial and antifungal activities. Four Compounds, which all possessed electron withdrawing functional groups (-Cl, -NO(2), -Br) 27, 28, 30 and 32 were more potent against the tested bacterial/fungal strains than the standard bacterial and fungal drugs ciprofloxacin and fluconazole respectively.     

Design,synthesis and photoinduced DNA cleavage studies of [1,2,4]-triazolo[4,3-a]quinoxalin-4(5H)-ones

An expedient and eco-friendly synthesis of 1-aryl/heteroaryl-[1,2,4]-triazolo[4,3-a]quinoxalin-4(5H)-ones (4) has been accomplished via iodobenzene diacetate mediated oxidative intramolecular cyclization of 3-(2-(aryl/heteroarylidene)hydrazinyl)-quinoxalin-2(1H)-ones (3). Ten synthesized compounds 3 and 4 (10–40 μg) on irradiation with UV light at λ_max 312 nm could lead to cleavage of supercoiled pMaxGFP DNA (Form I) into the relaxed DNA (Form II) without any additive. Further, DNA cleaving ability of triazoles was quantitatively evaluated and was found to be dependent on its structure, concentration, and strictly on photoirradiation time. Mechanistic investigations using several additives as potential inhibitors/activator revealed that the DNA photocleavage reaction involves Type-I pathway leading to formation of superoxide anion radicals (O₂⁻) as the major reactive oxygen species responsible for photocleavage process.     

Synthesis and antihypertensive activity of novel 3-benzyl-2-substituted-3H-[1,2,4]triazolo[5,1-b]quinazolin-9-ones

A series of 3-benzyl-2-substituted-3H-[1,2,4]triazolo[5,1-b]quinazolin-9-ones have been synthesized by the cyclocondensation of 3-amino-2-benzylamino-3H-quinazolin-4-one with a variety of one-carbon donors. The starting material 3-amino-2-benzylamino-3H-quinazolin-4-one was synthesized from methyl anthranilate by a novel innovative route. The title compounds were evaluated for their in vivo antihypertensive activity using spontaneously hypertensive rats (SHR). While all the test compounds exhibited significant antihypertensive activity, 3-benzyl-2-methyl-3H-[1,2,4]triazolo[5,1-b] quinazolin-9-one exhibited antihypertensive activity more than the reference standard prazocin.     

Stereoselective synthesis of hexahydro-3-methyl-1-arylchromeno[3,4-b]pyrrole and its annulated heterocycles as potent antimicrobial agents for human pathogens

Synthesis of a series of novel hexahydrochromenopyrrole analogues has been accomplished through an intramolecular 1,3-dipolar cycloaddition (1,3-DC reaction) of azomethine ylides, generated by the aldehyde induced decarboxylation of secondary amino acids. These compounds were screened for antibacterial and antifungal activities against six human pathogenic bacteria and three human pathogenic fungi and found to have good antimicrobial properties against most of the microorganisms.     

Strongly acidic auxin indole-3-methanesulfonic Acid: synthesis of [C]indole-3-methanesulfonic Acid and studies of its chromatographic, spectral, and biological properties

A radiochemical synthesis is described for [¹⁴C]indole-3-methanesulfonic acid (IMS), a strongly acidic auxin analog. Techniques were developed for fractionation and purification of IMS using normal and reverse phase chromatography. In addition, the utility of both Fourier transform infrared spectrometry and fast atom bombardment mass spectrometry for analysis of IMS has been demonstrated. IMS was shown to be an active auxin, stimulating soybean hypocotyl elongation, bean first internode curvature, and ethylene production. IMS uptake by thin sections of soybean hypocotyl was essentially independent of solution pH and, when applied at a 100 micromolar concentration, IMS exhibited a basipetal polarity in its transport in both corn coleoptile and soybean hypocotyl sections. [¹⁴C]IMS should, therefore, be a useful compound to study fundamental processes related to the movement of auxins in plant tissues and organelles.     

2,4-Diamino-9H-pyrimido[4,5-b]indol-5-ols: synthesis, in vitro cytotoxic activity, and QSAR investigations

A series of novel 2,4-diaminopyrimido[4,5-b]indol-6-ols has been synthesized and the in vitro cytotoxic activities were evaluated against four human cancer cell lines originating from solid tumors. An increase in activity was observed when a heteroaromatic ring was annulated on side g of the pyrimido[4,5-b]indole system to give compounds with activities comparable to ellipticine and cisplatin. To understand the experimental cytotoxic activities, QSAR investigations were performed, which showed a very good linearity between the experimental and predicted IC(50).     

Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma

The Type 1 PI3Kinases comprise a family of enzymes, which primarily phosphorylate PIP2 to give the second messenger PIP3, a key player in many intracellular signaling processes [Science, 2002, 296, 1655; Trends Pharmacol. Sci.2003, 24, 366]. Of the four type 1 PI3Ks, the gamma-isoform, which is expressed almost exclusively in leukocytes [Curr. Biol., 1997, 7, R470], is of particular interest with respect to its role in inflammatory diseases such as rheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD) [Mol. Med. Today, 2000, 6, 347]. Investigation of a series of 4,6-disubstituted-4H-benzo[1,4]oxazin-3-ones has led to the identification of single-digit nanomolar inhibitors of PI3Kgamma, several of which had good cell based activity and were shown to be active in vivo in an aspectic peritonitis model of inflammatory cell migration.     

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.     

Synthesis of benzo[3,4]azepino[1,2-b]isoquinolin-9-ones from 3-arylisoquinolines via ring closing metathesis and evaluation of topoisomerase I inhibitory activity, cytotoxicity and docking study

Benzo[3,4]azepino[1,2-b]isoquinolinones were designed and developed as constraint forms of 3-arylisquinolines with an aim to inhibit topoisomerase I (topo I). Ring closing metathesis (RCM) of 3-arylisoquinolines with suitable diene moiety provided seven membered azepine rings of benzoazepinoisoquinolinones. Spectral analyses of these heterocyclic compounds demonstrated that the methylene protons of the azepine rings are nonequivalent. The shielding environment experienced by these geminal hydrogens differs unusually by 2.21ppm. As expected, benzoazepinoisoquinolinones displayed potent cytotoxicity. However, cytotoxic effects of the compounds were not related to topo I inhibition which is explained by non-planar conformation of the rigid compounds incapable of intercalating between DNA base pairs. In contrast, flexible 3-arylisoquinoline 8d attains active conformation at drug target site to exhibit topo I inhibition identical to cytotoxic alkaloid, camptothecin (CPT).