Regioselective synthesis of polycyclic aza-oxa and aza-oxa-thia heteroarenes as Colo-205 and HepG2 carcinoma cells growth inhibitors.

An efficient regioselective synthesis of polycyclic diheteroaryl[b,d]pyrans and diheteroaryl[c,e][1,2]diazepines has been reported through ring transformation reactions of 2-oxo-2,5-dihydrothiochromeno[4,3-b]pyrans (3,4), 2-oxo-5,6-dihydro-2H-benzo[b]pyrano[2,3-d]oxepine/thiepine (8, 9) and 6-oxo-3,6-dihydro-2H-naphtho[1,2-b]pyrano[2,3-d]oxepine (15) by hydrazine, at ambient and reflux temperature. Nine compounds viz 5a,b; 10a,c,d; 12b; 13b; 16 and 1-methylthio-5,6-dihydrobenzo[f]quinoline (0.1-100 µM) were screened for their cytotoxicity in normal (IEC-6), carcinoma (Colo-205) and HepG2 cell lines. None of the compounds showed cytotoxicity in normal IEC-6 cells while 10a,d and 16 resulted in killing of Colo-205 cells with IC50 ranging 20-60 µM while 10c and 13b caused killing of HepG2 cells with IC50 values ranging 60-80 µM concentration. Further, 10a,d and 16 caused apoptosis through a cascade of mitochondrial pathway in Colo-205 cells indicating anticancerous potential against intestinal cancer. Interestingly, compounds 10c and 13b exhibited apoptosis through mitochondrial pathway in HepG2 cells suggesting anticancer activity against hepatic cancer.

Direct alkenylation of indolin-2-ones by 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles: a novel approach.

A direct one-pot base-induced alkenylation of indolin-2-ones has been developed by using 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles. Different bases such as MeONa, NaH and t-BuONa have been used to optimize the reaction conditions to obtain the desired product. NaH in THF was found to be the most suitable for the alkenylation of indolin-2-ones. Reaction in the presence of other bases led to the formation of 1-aryl-3-methoxy/methylthio-5H-dibenzo[d,f][1,3]diazepin-6(7H)-ones. Quantum chemical calculations have been performed to explain the nature of the weak noncovalent interactions operating in the supramolecular architectures of alkenylated indoline-2-ones and to explain the relative stability of one of the tautomers with respect to the others.

Micelles catalyzed chemo- and regio-selective one pot and one step synthesis of 2,3,5,6-tetrakis(alkyl and arylsulfanyl)-1,4-benzoquinones and 2,5-diaminosubstituted-1,4-benzoquinones "In-Water" and their biological evaluation as antibacterial and antifungal agents.

Chemo- and regio-selective one pot and one step synthesis of novel 2,3,5,6-tetrakis (substituted thio)cyclohexa-2,5-diene-1,4-diones (4d-14), 2,5-dichloro-3,6-diaminocyclohexa-2,5-diene-1,4-diones and 2,5-diaminocyclohexa-2,5-diene-1,4-diones (16) by economical green methodology approach using LD (Laundry detergent) as a catalyst "In-Water" by nucleophilic addition and substitution reactions of 1,4-benzoquinone and chloranil with sulfur and nitrogen nucleophiles in high yields has been demonstrated. The antifungal profile of 4 and 16 indicates that compounds 4d and 16f had better antifungal activity compared to clinically prevalent antifungal drugs Fluconazole, 5-Fluorocytosine and Clotrimazole against Sporothrix schenckii and Trichophyton mentagraphytes. 16f had also been found to possess better antibacterial activity compared to Ampicillin in vitro against Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae. Compound 16f did not exhibit any toxicity towards mammalian cells L929.

Sequential approach to the synthesis of 'U and Z' shaped polycyclic heteroarenes.

The synthesis of three new classes of heteroarenes, built through the sequential fusion of naphthalene, benzo/naphtho[b]oxepine and thiochromene rings with pyran and pyrimidine ring systems to give 'U and Z' shaped structural frameworks is reported. The methodology is based on the synthesis of pyran fused intermediates, 1-methylthio-3-oxo-5,6-dihydro-3H-benzo[f]chromene-2-carbonitrile (3), 4-methylthio-2-oxo-5,6-dihydro-2H-benzo/naphtho[b]pyrano[2,3-d]oxepine-3-carbonitriles (10, 20) and 4-methylthio-2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-carbonitriles (15) from the reaction of 2-tetralone, benzo/naphtho[b]oxepin-5-ones and thiochromen-4-ones with methyl 2-cyano-3,3-dimethylthioacrylate respectively. Further condensation of intermediates 3, 10, 20 and 15 with amidines led to the formation of tetracyclic 'U' shaped 4-amino-2-aryl-7,8-dihydro-5-oxo-5H-naphtho[2,1-b]pyrimido[4,5-d]pyrans (8) and 'Z' shaped 4-amino-2-aryl-5-oxo-12,13-dihydro-5H-benzo/naphtho[b]oxepino[5,4-b]pyrimido[4,5-d]pyrans (12, 22) and 4-amino-2-aryl-5-oxo-5,12-dihydrothiochromeno[4,3-b]pyrimido[4,5-d]pyrans (17). Compound 12f forms a chain of dimers through N-HO interactions as indicated by the X-ray structure analysis, and the quantum chemical calculations performed at the MP2 level indicate that this interaction energy is 10 kJ mol(-1).

Non-catalytic approach to the synthesis of partially reduced 'S' shaped dioxathia- and oxadithiahelicenes through base induced inter- and intramolecular C-C bond formation.

An efficient and convenient route for the construction of helical 'S' shaped dioxathia- and oxadithiahelicenes with oxygen and sulfur atoms located in the middle of the outer helix has been developed through base induced inter- and intramolecular C-C bond formation from the reaction of 4-sec-amino-2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-carbonitriles with 3,4-dihydro-2H-benzo[b]oxepin-5(2H)-ones, 3,4-dihydrobenzo[b]thiepin-5(2H)-one and thiochroman-4-ones separately. Quantum chemical calculations have also been carried out to explore the geometries and electronic structures of newly synthesized compounds to envisage the pathway for interconversion of both atropisomers. The determination of helicity parameters and configurational stability demonstrate that the energy barrier is strongly dependent on the nature of hetero-atoms present.

Micelles catalyzed chemoselective synthesis 'in water' and biological evaluation of oxygen containing hetero-1,4-naphthoquinones as potential antifungal agents.

Various oxygen containing 1,4-naphthoquinone derivatives have been synthesized chemoselectively by an economical, viable green methodology approach using water as solvent with or without surfactants such as Triton X-100, SDS, LD (laundry detergent), and TBAB, a phase transfer catalyst and evaluated for their in vitro antifungal and antibacterial activity. The antifungal profile of 3, 4a, 4b, and 6 indicated that compounds 3a, 3b, 4b, 6a, and 6c have potent antifungal activity compared to clinically prevalent antifungal drugs Fluconazole and Amphotericin-B against Sporothrix schenckii, Trichophyton mentagraphytes, and Candida parapsilosis and compound 3b has been found to be a lead antifungal agent for further study.

'On water' assisted synthesis and biological evaluation of nitrogen and sulfur containing hetero-1,4-naphthoquinones as potent antifungal and antibacterial agents.

2-chloro-3-(4-methylpiperazin-1-yl)naphthalene-1,4-dione (3a), 2-chloro-3-(pyrrolidin-1-yl)naphthalene-1,4-dione (3b), 2-chloro-3-(piperidin-1-yl)naphthalene-1,4-dione (3c), 2-chloro-3-morpholinonaphthalene-1,4-dione (3d), 2-chloro-3-(2-phenylhydrazinyl)naphthalene-1,4-dione (3e), 2-(allylamino)-3-chloronaphthalene-1,4-dione (3f), 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)acetic acid (3g), 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)succinic acid (3h), methyl 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)acetate (3i), 2-chloro-3-(2-mercaptoethylthio)naphthalene-1,4-dione (3j), 3-hydroxy-4-methyl-4H-naphtho[2,3-b][1,4]thiazine-5,10-dione (3k) and compounds 3l-q have been synthesized by a green methodology approach using water as solvent and evaluated for their antifungal and antibacterial activity. The antifungal profile of 3a-n indicated that compounds 3a-d, 3j, 3e and 3k have potent antifungal activity. Amongst the most promising antifungal compounds, 3a-g, 3j, 3k showed better antifungal activity than clinically prevalent antifungal drugs Fluconazole and Amphotericin-B against Trichophyton mentagraphytes and compounds 3j and 3k have been found to be lead antifungal bicyclic and tricyclic 1,4-naphthoquinones. Compound 3k also exhibited pronounced antibacterial activity.

Design, synthesis and biological evaluation of novel nitrogen and sulfur containing hetero-1,4-naphthoquinones as potent antifungal and antibacterial agents.

A series of 2-Arylamino-3-chloro-1,4-naphthoquinones (3), 2-Amino-3-arylsulfanyl-1,4-naphthoquinones (5), 2-Arylamino-3-arylsulfanyl-1,4-naphthoquinones (6), Dihydrobenzo[f]naphtho[2,3-b][1,4]thiazepine-6,11-diones (9) (via Pictet-Spengler cyclization), Isoindoline-1,3-dione derivatives of 1,4-naphthoquinone (13), 2,2'-(1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis(methylene)dibenzonitrile (14), 13-Amino-12-substituted-6H-benzo[e]naphtho [2,3-b][1,4]diazepine-6,11(12H)-diones (15-16), 2-Chloro-3-arylsulfanyl-1,4-naphthoquinones (17-18) and 3-Methyl-6H-benzo[b]phenothiazine-6,11(12H)-dione (19) were synthesized and studied for their antifungal and antibacterial activities. The results indicate that compounds 3b, 5a and 5b have potent antifungal activity. Amongst the most promising antifungal compounds, 3b showed better antifungal activity than clinically prevalent antifungal drug Fluconazole (MIC(50)=2.0 microg/mL) against Sporothrix schenckii (MIC(50)=1.56 microg/mL), significant profile against Candida albicans (MIC(50)=1.56 microg/mL), Cryptococcus neoformans (MIC(50)=0.78 microg/mL) and Trichophyton mentagraphytes (MIC(50)=1.56 microg/mL) and same antifungal activity when compared with Amphotericin-B against C. neoformans (MIC(50)=0.78 microg/mL). Compounds 3b, 5a and 5b also showed promising antibacterial activity.

2,3-Disubstituted-1,4-naphthoquinones, 12H-benzo[b]phenothiazine-6,11-diones and related compounds: synthesis and biological evaluation as potential antiproliferative and antifungal agents.

A series of 2-chloro-3-arylsulfanyl-[1,4]naphthoquinones (2), 2,3-bis-arylsulfanyl-[1,4]naphthoquinones (3) and 12H-benzo[b]phenothiazine-6,11-diones and their analogs 6-8 were synthesized and evaluated for their antiproliferative activity against human cervical cancer (HeLa) cells. Compounds 3a and 3b were found to possess most potent antiproliferative and cell killing ability. Compounds 1-8 were also evaluated for antifungal activities. The structure-activity relationship of these compounds was studied and the results show that compound 2a (MIC(50)=1.56 microg/mL) exhibited in vitro potent antifungal activity compared to the clinically useful antifungal drug Fluconazole (MIC(50)=2.0 microg/mL) against Sporothrix. schenckii. Compound 2a (MIC(50)=1.56 microg/mL) also exhibited same antifungal activity compared to clinically useful drug Amphotericin-B (MIC(50)=1.56 microg/mL) against Trichophyton. mentagraphytes.

Naphtho[2,3-b][1,4]-thiazine-5,10-diones and 3-substituted-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thioalkanoate derivatives: synthesis and biological evaluation as potential antibacterial and antifungal agents.

A series of 3-substituted-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thio-alkanoate derivatives 3-21 and naphtho[2,3-b][1,4]-thiazine-5,10-diones 24 were synthesized and evaluated for their antibacterial and antifungal activities. The structure-activity relationships of these compounds were studied and the results show that the compound 24a exhibited better antibacterial activity than Gentamycin in vitro against Staphylococcus aureus. In addition 24a also imparted marked antifungal activity in vitro against Cryptococcus neoformans, Sporothrix schenckii, and Trichophyton mentagraphytes when compared with Fluconazole. Compounds 15, 18, 19, and 21 also exhibited significant antibacterial activity in vitro against S. aureus.

Design, synthesis, and biological evaluation of 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones and related compounds as antifungal and antibacterial agents.

A series of (S)-N-(3-chloro-1,4-naphthoquinon-2-yl)-alpha-amino acid ethyl esters 3 and 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones 6-23 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationship of these compounds was studied and the results show that the compounds 3a and 3b exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii whereas compounds 12 and 22 showed in vitro antibacterial activity against Klebsiella pneumoniae and Escherichia coli.

Synthesis and biological evaluation of novel (L)-alpha-amino acid methyl ester, heteroalkyl, and aryl substituted 1,4-naphthoquinone derivatives as antifungal and antibacterial agents.

A series of (S)-N-(1,4-naphthoquinon-2-yl)-alpha-amino acid methyl esters 3-9, 2-N,N-dialkylamino-1,4-naphthoquinones 10-11 and 2-hydroxy-3-(2'-mercaptoimidazolyl)-1,4-naphthoquinones and their cyclic analogs 12-15 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationships of these compounds were studied and the results show that the compounds 9b and 13c exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii, whereas compound 6a showed in vitro antibacterial activity against Streptococcus faecalis, K. pneumoniae, Escherichia coli, and Staphylococcus aureus.

Synthesis and biological evaluation of novel 1,4-naphthoquinone derivatives as antibacterial and antiviral agents.

A series of 1,4-naphthoquinone derivatives were synthesized and evaluated for antibacterial and antiviral activities. The structure-activity relationships of these compounds were also studied. The results suggest that compounds 9-22 showed in vitro marked antibacterial activity. Compounds 4c and 7a showed inhibitory effect against RNA dependent RNA polymerase induced poliovirus type 2 infected HeLa cells.

Synthesis of (1,4)-naphthoquinono-[3,2-c]-1H-pyrazoles and their (1,4)-naphthohydroquinone derivatives as antifungal, antibacterial, and anticancer agents.

A series of (1,4)-naphthoquinono [3,2-c]-1H-pyrazoles and their (1,4)-naphthohydroquinone derivatives 2-7 were synthesized and evaluated for antifungal, antibacterial, and anticancer activities. The structure-activity relationship of these compounds was studied and the results show that the compound 2b exhibited in vitro antifungal activity against Candida albicans and Cryptococcus neoformans, and also possessed antibacterial profile against Klebsiella pneumoniae and Escherichia coli whereas 1c showed anticancer activity against Walker 256 Carcinosarcoma in rats.

Synthesis and anti-implantation activity of new stilbene derivatives.

New stilbene (CAS 56-53-1) derivatives have been synthesized by reductive elimination of desoxybenzoin analogs which were obtained by Fries rearrangement of the corresponding phenolic esters. The chemical structures of the compounds obtained were confirmed by 1H-NMR, IR and elemental analysis. Anti-implantation activity of the compounds was determined by performing experiments with adult male and female Spargue-Dawley rats of proven fertility. A 67% inhibition of implantation was observed separately with compounds 3f and 3i.

Potential hypotensive agents: synthesis and hypotensive activity of oxime ethers derived from 1-naphthoxepines and related compounds.

The synthesis and pharmacological evaluation of substituted oximino-ethers 1 and 2 of naphth[1,2-b]- and naphth[2,1-b]-oxepin-5-ones (4 and 8) were carried out. The hypotensive activity of oximino-ethers 1 and 2 was evaluated on anaesthetized cats. The results indicated that 1c caused a fall of 80 mm/Hg for >100' at a dose of 5mg/kg iv in anaesthetized cats.

1- and 2-substituted naphthalenes: a new class of potential hypotensive agents.

A series of 2-substituted aminomethyloxy naphthalenes 1 and 4-(1-naphthoxy-2-substituted aminomethyl)-butanoic acids 2 were synthesized by Mannich reaction of 4-(2-naphthoxy)-butanoic acid 3 and 4-(1-naphthoxy)-butanoic acid 4 with appropriate secondary amines and para-formaldehyde. The newly synthesized compounds were tested for their hypotensive activity at 5 mg/kg i.v. dose in cats. The results indicated that the analogue 2-(N4-phenyl-N1-piperazino)-methyloxy naphthalene 1d (> N = N4-phenyl-N1-piperazino) was the most active analogue when its hypotensive activity was compared to the reference compound propranolol.

Chemo- and stereoselective synthesis of benzocycloheptene and 1-benzoxepin derivatives as alpha-sympathomimetic and anorexigenic agents.

The synthesis and pharmacological evaluation of cis- and trans-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ols 4a-c and 5a-c and cis- and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ols 4d-f and 5d-f were carried out. Chemo- and stereoselective synthesis of 5a-f was achieved by reduction of corresponding alpha-amino ketones 3a-f with LiAl(t-BuO)3H. cis-4-Amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 4d and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 5d exhibited marked anorexigenic activity in mice at a dose of LD50 800 and 500 mg/kg and ED50 75 and 55 mg/kg, respectively, while the analog cis-2,3-dihydroxy-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol 8 showed typical alpha-sympathomimetic activity.

Synthesis and evaluation of novel 1,4-naphthoquinone derivatives as antiviral, antifungal and anticancer agents.

The synthesis and evaluation of some 2-substituted-1,4-naphthoquinones 2, S-(1,4-naphthoquinon-2-yl)-mercaptoalkanoic acid amides 4, related benzoquinone and naphthoquinone derivatives 6-9 and 2,3-disubstituted 1,4-naphthoquinones 10-11 were carried out. The antifungal, antibacterial, antiviral and anticancer activities were determined by using the standard assay. The results show that compounds 2b and 10a showed in vitro antiviral activity against Influenza-A Virus and Herpes Simplex Virus and possess pronounced antifungal profile whereas 4a showed anticancer activities against Lymphoid Leukaemia P 388.

Design, synthesis and evaluation of novel 1,4-naphthoquinone derivatives as antifungal and anticancer agents.

A series of 1,4-naphthoquinone derivatives were synthesized and tested for antifungal and antitumor activity against a number of fungal disease causative species and Walker 256 carcinoma cell lines. The results show that the compounds 8a,e and 11b possess pronounced antifungal profile where as 7b and f were found to be active against Walker 256 carcinoma cell lines. Moreover 7c and 11a showed inhibitory effect against reverse transcriptase enzyme from Rauscher Murine Leukemia Virus.