Studies on fused heterocyclic 3,6-disubstituted-1,2,4-triazolo-1,3,4-thiadiazoles: synthesis and biological evaluation

In this study, a series of 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles (5a–t) were synthesized by condensing 4-amino-3-mercapto-(4H)-1,2,4-triazoles (4a–c) with different aromatic or aroyl acids through one-pot reaction. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation actions. Some of the newly synthesized compounds showed very good anti-inflammatory activity with low GI toxicity and reduced lipid peroxidation. These compounds also showed interesting profile of analgesic activity in acetic acid-induced writhing test. The findings of the study indicate that the synthesized compounds have superior GI safety profile along with reduction in lipid peroxidation as compared to that of the standard.     

Synthesis of novel isatin-thiazoline and isatin-benzimidazole conjugates as anti-breast cancer agents

A series of new isatin-thiazoline 3a–h and isatin-benzimidazole 4a–h derivatives were synthesized via condensation of isatin Mannich bases 2a–h with either 2-aminothiazoline or 2-aminobenzimidazole. The structures of the newly synthesized compounds were characterized by spectral data. The anti-breast cancer activity of some of the synthesized compounds was assessed in the MCF-7 human breast cancer cell line. The results showed that compounds 4b, 4d and 4g possess significant antiproliferative activity against MCF-7 cells.     

Triazenoindazoles and triazenopyrazolopyridines: Design,synthesis, and cytotoxic activity

Several triazenoindazoles 3a–e and triazinopyrazolopyridines 6a–i were prepared through the reaction of the corresponding 3-amino-4-chloroindazole and 3-aminopyrazolopyridine diazonium salts 2 and 5 with a number of secondary amines. All compounds were evaluated for their in vitro cytotoxic activity on three cell lines, HepG2, MCF7, and HeLa. Most compounds inhibited cell growth with IC₅₀ less than 0.1 μM. Compound 6d was the most potent, with an IC₅₀ of 0.03 μM against HepG2 and 0.05 μM against MCF7 and HeLa cells.     

Simple and efficient synthetic routes to bioactive s-triazinyl dithiocarbamate derivatives

Series of 2,4-diarylamino-6-[N-(3′-methylphenyl)dithiocarbamoyl]-s-triazines (4a–l) and 2,4-bis[N-(3′-methylphenyl)dithiocarbamoyl]-6-arylamino-s-triazines (7a–l) were synthesized by two different synthetic routes. In the first route (A), 2,4,6-tricholoro-s-triazine (1) was condensed with N-(3-methylphenyl)ammoniumdithiocarbamate to afford compounds 3 or 6, which on reaction with different aryl amines afforded compounds 4a–l or 7a–l. In the second route (B), condensation of 1 with different aryl amines yielded compounds 2a–l or 5a–l. On further treatment with N-(3-methylphenyl)ammoniumdithiocarbamate these afforded compounds 4a–l or 7a–l. The newly synthesized compounds 4a–l and 7a–l were characterized by elemental analyses, infrared (IR), and ¹H nuclear magnetic resonance (NMR) spectroscopic investigation. All the products were evaluated for their antibacterial and antifungal activity.     

Synthesis of new pyrazole,triazole, and thiazolidine-pyrimido [4, 5-b] quinoline derivatives with potential antitumor activity

2-Hydrazinyltetrahydropyrimido [4, 5-b] quinolin-4(3H)-one (3) was prepared by desulfurization reaction of S- and N-dimethyl derivatives 2 with hydrazine hydrate. Reactions of (3) with malonitrile, carbondisulfide, potassium thiocyanate, phthalic anhydride and aromatic aldehydes afforded 3, 5-di aminopyrazolopyrimido [4, 5-b] quinoline (4), triazolotetrahydropyrimido [4, 5-b] quinoline (5), aminotriazolopyrimido [4, 5-b] quinoline (6), aminophthalimidopyrimido [4, 5-b] quinoline (7) and N-arylidene hydrazinepyrimido [4, 5-b] quinoline 8a–d, respectively. Furthermore, 8a–d reacted with mercaptoacetic acid gave the thiazolidinonepyrimido [4, 5-b] quinoline 9a–d, which afforded the thiazolotriazolopyrimido [4, 5-b] quinolinone 10a–d upon treatment with ethanolic potassium hydroxide. The newly synthesized compounds were characterized by elemental analyses, IR, 1H-NMR, 13C-NMR and mass spectrometer. The investigated compounds were screened for their cytotoxicity. Compounds 4, 6 and 5 exhibited potent antitumor activity.     

Synthesis and antimicrobial and anticancer activity of new of imidazo[2,1-<Emphasis Type="Italic">b</Emphasis>][1,3,4]thiadiazoles

A series of new 3-aryl-4-(6′-aryl-imidazo[2,1-b][1,3,4]thiadiazol-2′-yl-phenylsydnones (16 – 27) were synthesized. The structures of the synthesized compounds were confirmed by the IR, ¹H NMR, and mass spectroscopy techniques and elemental analysis. All the newly synthesized compounds were evaluated for their anticancer activity against cervical cancer cell line (Hela) and antimicrobial activity, in particular, antitubercular activity against Mycobacterium tuberculosis (H₃₇Rv).     

Potential anti-inflammatory activity and ulcerogenicity study of some novel pyrimido[4′,5′:4,5]pyrimido[1,6-<Emphasis Type="Italic">a</Emphasis>]azepine derivatives

A series of novel tricyclic pyrimido[4′,5′:4,5]pyrimido[1,6-a]azepine derivatives were synthesized using the starting compound 3-amino-1-oxo-2-phenyl-5-(pyrrolidin-1-yl)-1,2,4a,5,6,7,8,9-octahydropyrimido[1,6-a]azepine-4-carbonitrile 4. This series includes the 3-aryl derivatives 6a, b, the 3-cycloaminoalkyl derivatives 8a–f, the 3-mercaptomethyl derivatives 10 and 11a, b, the 2-cycloaminomethyl derivatives 13a–c, the 1-cycloamino derivatives 15a–c and the 1-amino derivative 16. The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw oedema test in rats using diclofenac sodium as the reference drug. Ulcer indices for the most active compounds were calculated. The 3-mercaptomethylacetic acid derivative 10 was the most active compound, showing activity comparable to diclofenac sodium with minimal ulcerogenic effect while the rest of the tested compound exhibited moderate anti-inflammatory activity.     

Synthesis,antiproliferative activity,acute toxicity and assessment of the antiandrogenic activities of new androstane derivatives

A number of 17-oxo-5-androsten-3β-yl esters (9a–9f) and 3β-alkoxy-5-androsten-17-ones (11a–11e) were synthesized from commercially available (25R)-5-spirosten-3β-ol (Diosgenin) (4) as starting material. The synthesized compounds were evaluated for their antiproliferative activity against the prostate-specific cancer cell line DU-145, acute toxicity and effect on serum androgen levels, and compared with finasteride as positive control. Some of the compounds exhibited better cytotoxicity and antiandrogenic activity than the reference control. The detailed synthesis, spectroscopic data and biological activity of the synthesized compounds are reported.     

Synthesis of new 1,2,4-triazoles as anti-inflammatory and anti-nociceptive agents

A series of fifteen new substituted 1,2,4-triazoles (6a – 6o) have been synthesized in order to obtain new agents with potential anti-inflammatory and anti-nociceptive activity. The title compounds were synthesized using 4-methylbenzoic acid as a starting reactant. The synthesized compounds were characterized by spectroscopic methods (IR, ¹H NMR, ¹³ C NMR, FAB⁺ − MS) and elemental analysis (nitrogen analysis). The title compounds were evaluated for anti-inflammatory activity by the carrageenan induced paw edema method, and some compounds were evaluated for anti-nociceptive activity by the hot plate method and tail immersion method. Compounds N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-piperidin-1-ylacetamide (6f), 2-(4-benzylpiperazin-1-yl)-N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]acetamide (6i) and N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-morpholin-4-ylacetamide (6 k) showed significant anti-inflammatory activity compared to other synthesized compounds, and N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-morpholin-4-ylacetamide (6 k) exhibited superior anti-nociceptive activity.     

Synthesis and antimicrobial activities of 2-azetidinyl-4-quinazolinone derivatives of diclofenac analogue

A new class of 2-azetidinyl-4-quinazolinones 6a–k was synthesized by multi-step process, starting from 2-[2-(2,6-dichlorophenyl)amino]phenyl acetic acid 1. Acid 1 was easily converted to acid chloride 2, which on cyclization reaction with 5-bromo anthranilic acid yielded benzoxazinone 3. The condensation reaction of 3 with benzene-1,4-diamine afforded 4-quinazolinone 4. Finally the title compound 6a–k was synthesized from 4-quinazolinone 4 by Schiff base formation 5a–k with aromatic aldehyde and then cyclization reaction with chloroacetylchloride. The in vitro antimicrobial activity of compounds 5a–k and 6a–k were tested. These compounds showed pronounced antimicrobial activity when 4-Cl and 4-OCH ₃ groups were present.     

Synthesis and antiproliferative activity of 1-[(sub)]-6-fluoro-3-[(sub)]-1, 3,4-oxadiazol-2-yl-7-piperazino-1, 4-dihydro-4-quinolinone derivatives

A series of 1-[(sub)]-6-fluoro-3- [(sub)]-1, 3, 4-oxadiazol-2-yl-7-piperazino-1, 4-dihydro 4-quinolinones were synthesized by the reaction between ciprofloxacin and norfloxacin with an appropriate acid hydrazide in phosphorous oxychloride. All newly synthesized compounds were evaluated for their antiproliferative activities against human lung tumor cell lines (A 549). Fluoroquinolone with oxadiazole (Q ₂ ) 1-cyclopropyl-6-fluoro-3- [5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]-7-piperazino-1, 4-dihydro-4-quinolinone was found to be the most active compound in vitro with a half-maximal inhibitory concentration (IC₅₀) of 9.0 μg/mL.     

Synthesis,in vitro cytotoxicity,and anti-microbial studies of 1,4-bis(4-substituted-5-mercapto-1,2,4-triazol-3-yl)butanes

Synthesis and evaluation of cytotoxicity and anti-microbial activity of a series of 1,4-bis(4-substituted-5-mercapto-1,2,4-triazol-3-yl)butane derivatives comprising thioether functionality and other pharmacophore modifications are described. All the newly synthesized compounds were characterized by IR, NMR, elemental analyses, and mass spectral studies. The compounds 4a–f, 5a–f, and 6a–f were evaluated for in vitro cytotoxicity potential using the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against a panel of three human cancer cell lines: Lung carcinoma A-549, Colon carcinoma HT-29, and Breast Cancer MDA MB-231. All the compounds were subjected to in vitro anti-bacterial activity against Bacillus subtilus (ATCC 6633), Staphylococcus aureus (ATCC-25923), Escherichia coli (ATCC-25922), and Pseudomonas aeruginosa (ATCC-27853) and their minimal inhibitory concentrations were determined.     

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 evaluation of 2,6-piperidinedione derivatives as potentially novel compounds with analgesic and other CNS activities

New 2,6-piperidinediones 2_a–g and 4_a–d were prepared by initial condensation of aromatic aldehydes or cycloalkanones with cyanoacetamide to give α-cyanocinnamides l_a–g or cycloalkylidenes 3_a,b which underwent Michae1 addition with ethyl cyanoacetate or diethylmalonate. Compounds 4_a–d were alkylated by various alkyl halides to produce the N-alkylated 2,6-piperidinedione derivatives 5_a–m. Some new selected compounds 2_a–c,f, 4_a–d & 5_e,h,j were pharmacologically evaluated for potential anticonvulsant, sedative and analgesic activities. These compounds exhibited significant anticonvulsant and analgesic effects after a single I.P. administration 100 mg/kg b.wt. . On the other hand all the investigated compounds induced hypnotic activity and prolonged the phenobarbital sodium- induced sleep as compared with the control group and the most potent compound was found to be 2_f.     

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.     

EGFR tyrosine kinase targeted compounds: synthesis, docking study, and in vitro antitumor activity of some new quinazoline and benzo[d]isothiazole derivatives

The preparation of new quinazoline and benzo[d]isothiazole-based antitumor agents is described. The target compounds fall into three groups including the N-substituted derivatives 2a–d, the substituted amino derivatives 4–6a–d, and the dimeric compounds 7–9a,b. Docking study of the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) tyrosine kinase was performed to compare the binding mode of these compounds to the known EGFR inhibitor, lapatinib. All compounds were tested, in vitro, for their activity against human mammary carcinoma cell line (MCF7) in which EGFR is highly expressed. All compounds showed significant growth inhibitory activity. The remarkable activity of the bis quinazoline derivative 8a (IC₅₀ = 0.06 μg/ml; 1.64 nmol/ml) is to be noted.     

Synthesis and in vivo anticancer and antiangiogenic effects of novel thioxothiazolidin-4-one derivatives against transplantable mouse tumor

A series of novel thioxothiazolidin-4-one derivatives 5(a–g) were synthesized by the coupling of different amines containing aliphatic, substituted aromatic, and heterocyclic moieties, such as oxadiazol, pyrazole, isoxazole, and piperazine with 2-(5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid. All compounds were characterized by ¹H NMR, LCMS, FTIR and elemental analysis. In this study, we investigated the possibility that these novel thioxothiazolidin-4-one derivatives 5(a–g) inhibits tumor growth and tumor induced angiogenesis using mouse Ehrlich Ascites Tumor (EAT) as a model system. Our results demonstrated that the compounds significantly reduced ascites tumor volume, cell number, and increased the life span of EAT-bearing mice. In addition, the compounds manifested strong antiangiogenic effects and suppressed tumor induced endothelial proliferation in the mice peritoneum. From our findings, it is noted that the derivatives 5(a–e) may be possible candidates for anticancer therapy with the ability to inhibit tumor angiogenesis and tumor cell proliferation.     

Synthesis and antimicrobial activity of new pyridine derivatives-I

2-Amino substituted benzothiazoles 2a–l and 2-chloropyridine-3-carboxylic acid 3 were used to prepare 2-[N-(substitutedbenzothiazolyl)amino]pyridine-3-carboxylic acids (4a–l) in 2-ethoxy ethanol. Acid chlorides (5a–l) were condensed with 2-hydroxyethyl piperazine (6) and 2,3-dichloropiperazine (7) to prepare amide derivatives 2-[N-(substituted benzothiazolyl)amino]pyridin-3-yl(4-(2-hydroxyethyl)piperazin-1-yl)methanones (8a–l) and 2-[N-(substituted benzothiazolyl) amino]pyridin-3-yl(2,3-dichloropiperazine-1-yl)methanones (9a–l), respectively. The structures of new compounds have been established on the basis of elemental analysis and spectral (IR, ¹H NMR, and Mass spectra) studies. The in vitro antimicrobial activity was screened for all the synthesized compounds. Variable and modest activity were observed against the investigated strains of bacteria and fungi.     

Synthesis of 6-aziridlnylbenzimidazole derivatives and theirin vitro antitumor activities

In search for new antitumor agents, twelve 6-aziridinylbenzimidazole derivatives were synthesized and their cytotoxicities were tested against three cancer cell lines (mouse lymphocytic leukemia P388 and B16, and human gastric carcinoma SNU-16). From 4-amino-3-nitrotoluene as the starting material, 2-(acetoxymethyl)benzimidazoles (5a–d) were obtained by Phillips reaction. These benzimidazoles were then reacted with Fremy's salt to give a mixture of three 2-(acetoxymethyl) (8a–c) and four 2-(hydroxymethyl)benzimidazole-4,7-diones (9a–d). Addition of these quinones with aziridine afforded 6-aziridinyl-2-(acetoxymethyl) (10a–c) and 6-aziridinyl-2-(hydroxymethyl)benzimidazole-4,7-diones (11a–d). Utilizing 2-(hydroxymethyl)benzimidazole-4,7-diones (9b,d), esters10d and13e–h were prepared by the sequential reactions of esterification and addition. The synthesized compounds show potent cytotoxicity against all of three cell lines tested. The cytotoxicities of10a–d or11a–d against SNU-16 were superior to those of13e–h, and were equal to or slightly higher than that of mitomycin C. Compounds11a–d were slightly more cytotoxic than10a–d in all cell lines tested.     

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.