Synthesis,Anti-Inflammatory,and Ulcerogenicity Studies of Novel Substituted and Fused Pyrazolo[3,4-d]pyrimidin-4-ones

In the present investigation, some new pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives (7–12) as well as fused pyrazolo[3′,4′:4,5]pyrimido[1,2-b]pyridazin-4(1H)-one (14–16) and 7,8,9,10-tetrahydropyrazolo[3′,4′:4,5]pyrimido[1,2-b]-cinnolin-4(1H)-one (17) ring systems were synthesized using the starting compound 5-amino-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5). The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. The theoretical calculation of their lipophilicity as C log P was performed. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw edema test in rats using indomethacin as the reference drug. Ulcer indices for the most active compounds were calculated. Seven compounds (10b, 11a–f) showed consistently good anti-inflammatory activity. In particular, 5-{[4-(4-bromophenyl)-3-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]amino}-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (11e) and its 3,4-bis(4-chlorophenyl) analog (11f) were found to be the most effective among the other derivatives, showing activity comparable to that of indomethacin with minimal ulcerogenic effects. Correlation of the biological data of the active compounds with their theoretically calculated C log P values revealed that lipophilicity influences the biological response.     

Synthesis and Biological Evaluation of a Series of Substituted Pyrazolo[3,4-d]-1,2,3-triazoles and Pyrazolo[3,4-d]oxazoles

In view of the biological relevance of triazole-based heterocyclic structures as antifungal, antiviral, and antitumor agents, we have synthesized a series of substituted pyrazolo[3,4-d]-1,2,3-triazoles ( 2e–h, 2j, 4b ) which we evaluated for their cytostatic and antiviral (HIV-1 included) activity and for their capability to inhibit the multiplication of various human pathogenic fungi and bacteria. Moreover, the biological activities of a few compounds, namely pyrazolo[3,4-d]oxazoles ( 3a–e ) and pyrazolo[3,4-d]-1,2,3-triazoles ( 2a–d, 4a, 5 ), previously obtained by us but not investigated for their biological activity, were also studied. Only compounds 3a–e were endowed with a significative antiproliferative activity on the human lymphoblastoid cell line MT-4 cells. All pyrazole derivatives proved ineffective in protecting cell cultures against the HIV-1-induced cytopathogenicity, and none of the compounds was active against the bacteria and fungi tested.     

A novel and eco-friendly procedure for the synthesis of some pyrazolo-thiadiazolo-pyrimidinones and its in vitro anti-bacterial activity

A novel series of 2-substituted-aminomethyl-8-phenyl-pyrazolo[3,4-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-4(1H)-ones have been synthesized by treating 2-chloromethyl-8-phenyl-pyrazolo[3,4-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-4(1H)-one with various nucleophiles. The chloromethyl derivative was prepared by treating 2-amino-3-mercapto pyrazolo[3,4-d]pyrimidine with one carbon donor, chloroacetic acid. The intermediate 2-amino-3-mercapto pyrazolo[3,4-d]pyrimidine was prepared by a novel, eco-friendly route starting from 2-amino-3-carbethoxy-1-phenyl-pyrazole. The target compounds exhibited broad-spectrum antibacterial activity (Kirby Bauer’s Method).     

Synthesis, anti-microbial evaluation, and molecular modeling of new pyrazolo[3,4-d]pyrimidine derivatives

Synthesis of some new pyrazolo[3,4-d]pyrimidine derivatives using readily available starting materials are described. A one-pot multi component cyclocondensation reaction was used to prepare the novel 3-methyl-4-aryl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-thiol which served as a new starting material for all new compounds in this research. The anti-microbial activities of the selective synthesized compounds have been evaluated. Some of the newly prepared compounds were found to have moderate to strong anti-microbial activity, e.g., compound 4a, 6a, and 8, in comparison to the reference drugs. Molecular modeling of the most three biologically active new compounds 4a, 6a, and 8 compared to the reference drugs tobramycin and fluconazole was carried out using Fieldalign 2.0 software.     

Synthesis and in vitro antitumor activity of new quinoline, pyrimido[4,5-b]quinoline, [1,2,3]triazino[4,5-b]quinoline, and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinoline analogs

New series of quinoline, pyrimido[4,5-b]quinoline, [1,2,3]triazino[4,5-b]quinoline, and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinoline analogs have been synthesized and characterized by analytical and spectrometrical methods (IR, ¹H NMR, ¹³C NMR, MS). Fifteen of the newly synthesized compounds; namely, 3a, b, 4b, 6a, b, 10a–f, and 14a–d were evaluated for their in vitro antitumor activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 4b and 10f are the most active members in this study, demonstrating significant broad spectrum antitumor activity against most of the tested sub-panel tumor cell lines. The detailed synthesis, spectroscopic, and biological data are described.     

Synthesis and antitumor activity of new pyrido[2,3-d]pyrimidine derivatives

New series of pyrido[2,3-d]pyrimidines such as; 5-(4-aryl-5-sulfanyl-4H-[1,2,4]triazol-3-yl) 1H,3H,8H-pyrido[2,3-d]pyrimidine-2,4,7-triones 6, 7; S-[3-(2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)-4-(4-substituted phenyl)-4H-[1,2,4]triazol-5-yl]-2-(4-phenylpiperazin-1-yl)ethanethioates 10, 11; 2,4,7-trioxo-N′-[(4-substituted piperazin-1-yl)acetyl]-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carbohydrazides 13–16 and N′-arylidene-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carbohydrazides 17–19 was synthesized through the reaction of the key intermediate 2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carbohydrazide 3 with different reagents. The structures of the newly synthesized compounds were elucidated through microanalysis, IR, ¹H NMR, ¹³C NMR, and mass spectroscopy. These compounds have been subjected to in vitro antitumor evaluation by bleomycin-dependant DNA damage assay. The most active antitumor compound 6 was selected for further in vivo evaluation of antineoplastic activity against Ehrlich ascites carcinoma in mice. It was observed that our target compound has a potent antitumor activity.     

Design,synthesis and antitumor activity of C3/C3 bis-fluoroquonolones cross-linked with [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazole

To contribute to the development of an efficient method for the conversion of antibacterial fluoroquinolones to antitumor fluoroquinolones, a series of C3/C3 bis-fluoroquinolone fused heterocycles cross-linked with a [1,2,4]-triazolo[3,4-b] [1,3,4]-thiadiazole core as a common bioisostere of two carboxylic acid groups was designed and synthesized as their hydrochloride salts. Structures were characterized by elemental analysis and spectral data and their in vitro antitumor activity against L1210, CHO and HL60 cell lines was screened by determination of their IC₅₀ values in the methylthiazole trazolium (MTT) assay. Two compounds were highly potent against the HL60 cell line and represent promising lead compounds for future development.     

Synthesis of novel building blocks of 1H-pyrrolo[3,4-b]quinolin-3(2H)-one and evaluation of their antitumor activity

A series of new building blocks consisting of 1H-pyrrolo[3,4-b]quinolin-3(2H)-one with potential as selective antitumor agents is described. Compounds were synthesized by using Heck reaction of N-allyl-1H-pyrrolo[3,4-b]quinolin-3(2H)-one with p-bromophenyl acetic acid followed by formation of amide (1a–h, 2a–d) by reaction with several secondary amines in good yields. The cytotoxicity of these compounds was evaluated against human cancer cell lines in vitro (SK–N–NH, A549). Studies suggest that most of these compounds were effective in inhibiting neuroblastoma cell growth, compound 1d was the most potent one (% IC₅₀ = 8.62 μM).     

Synthesis and cytotoxic evaluation of some new[1,3]dioxolo[4,5-g]chromen-8-one derivatives

Background

Homoisoflavonoids are naturally occurring compounds belong to flavonoid classes possessing various biological properties such as cytotoxicity. In this work, an efficient strategy for the synthesis of novel homoisoflavonoids, [1,3]dioxolo[4,5-g]chromen-8-ones, was developed and all compounds were evaluated for their cytotoxic activities on three breast cancer cell lines.

Methods

Our synthetic route started from benzo[d][1,3]dioxol-5-ol which was reacted with 3-bromopropanoic acid followed by the reaction of oxalyl chloride to afford 6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one. The aldol condensation of the later compound with aromatic aldehydes led to the formation of the title compounds. Five novel derivatives 4a-e were tested for their cytotoxic activity against three human breast cancer cell lines including MCF-7, T47D, and MDA-MB-231 using the MTT assay.

Results

Among the synthesized compounds, 7-benzylidene-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4a) exhibited the highest activity against three cell lines. Also the analysis of acridine orange/ethidium bromide staining results revealed that 7-benzylidene-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4a) and 7-(2-methoxybenzylidene)-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4b) induced apoptosis in T47D cell line.

Conclusion

Finally, the effect of methoxy group on the cytotoxicity of compounds 4b-4d was investigated in and it was revealed that it did not improve the activity of [1,3]dioxolo[4,5-g]chromen-8-ones against MCF-7, T47D, and MDA-MB-231.     

Synthesis and structure-activity relationship studies of substituted isoquinoline analogs as antitumor agent

A number of substituted isoquinolin-1-ones, possible bioisosteres of the 5-aryl substituted 2,3-dihydroimidaz[2,1-a]isoquinolines, were synthesized and tested for their antitumor activity against five different human tumor cell lines.O-(3-hydroxypropyl) substituted compound (15) exhibited the best antitumor activity which is 3–5 times better than 5-[4′-(piperidinomethyl) phenyl]-2,3-dihydroimidazo[2,1-a]isoquinoline (1).     

Studies on the synthesis,in vitro antitumor activity of 4H-benzo[h]chromene, 7H-benzo[h]chromene[2,3-d]pyrimidine derivatives and structure–activity relationships of the 2-,3- and 2,3-positions

Some 4H-benzo[h]chromene and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives were prepared as potential cytotoxic agents. The in vitro cytotoxic activity of the synthesized compounds was investigated in comparison with the well-known anticancer standard drugs Vinblastine, Colchicine, and Doxorubicin using MTT colorimetric assay. It was found that compounds 23, 15, 20, and 21 showed the highest anticancer activity against the three tumor cell lines MCF-7, HCT, and HepG-2, compared with Vinblastine and Colchicine, while compound 23 was the most active against HepG-2 as compared with Doxorubicin. We explored the SAR of 4H-benzo[h]chromenes with modification at the 2-,3- positions and 7H-benzo[h]chromeno[2,3-d]pyrimidine at 2,3-positions. The structure–activity relationship (SAR) study revealed that the antitumor activity on 4H-benzo[h]chromene and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives were significantly affected by the lipophilicity (hydrophobic or hydrophilic), of the substituent at 2-,3- and 2,3-positions. Structures of these compounds were established on the basis of spectral data, IR, ¹H NMR, ¹³C NMR, ¹³C NMR-DEPT, and MS data.     

Synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones as potential antimicrobial agents

Synthesis of new derivatives of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one via reaction of 7-(4-bromophenyl)-1,2-dihydro-5-(4-fluorophenyl)-2-thioxopyrido[2,3-d] pyrimidin-4(3H)-one with hydrazonoyl chlorides or reaction of 2-hydrazino-pyrido[2,3-d]pyrimidin-4(3H)-one with different aldehydes followed by cyclization of the products. All the newly synthesized compounds were evaluated for their antimicrobial activities and also their minimum inhibitory concentration against most of test organisms was performed. Amongst the tested compounds displayed excellent activity against all the tested microorganisms except SR and PA.     

Synthesis,characterization, and anticancer studies of S and N alkyl piperazine-substituted positional isomers of 1,2,4-triazole derivatives

A series of 3-[3-[4-(substituted)-1-cyclicamine]propyl]thio-5-substituted[1,2,4]triazoles (8a–m) and 2-[3-[4-(substituted)-1-cyclicamine]propyl]-5-(substituted)-2,4-dihydro-3H[1,2,4]triazole-3-thiones (9a–h) were synthesized with good yields starting from corresponding carboxylic acids using two different methods. The cytotoxicity studies of these derivatives were studied against five different human cancer cell lines. Six compounds had shown good anticancer activity. The triazole derivatives, 9d, 8j, and 8i were most potent particularly against U937 and HL-60 cells. The cytotoxic potency of the compounds varied between the cell lines suggesting that a structural property of these compounds as possible determinant of their biological activity.     

Design and Evaluation of Novel Antimicrobial and Anticancer Agents Among Tetrazolo[1,5-c]quinazoline-5-thione S-Derivatives

The novel heterocyclization of 5-(2-aminophenyl)-1H-tetrazole with potassium ethylxanthogenate or carbon disulfide was proposed. The potassium salt of the tetrazolo[1,5-c]quinazoline-5-thione was subsequently modified by alkylation with proper halogen derivatives to (tetrazolo[1,5-c]quinazolin-5-ylthio)alkyls, N,N-dialkylethylamines, 1-aryl-2-ethanones, 1-(alkyl)aryl-2-ethanols, carboxylic acids, and esters. The structures of all newly synthesized compounds were confirmed by FT-IR, UV-vis, LC-MS, ¹H, ¹³C NMR, and elemental analysis data. The substances were screened for antibacterial and antifungal activities (100 μg) against Escherichia coli, Staphylococcus aureus, Enterobacter aerogenes, Entrococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans. Preliminary bioluminescence inhibition tests against Photobacterium leiognathi Sh1 showed that substances 5.2–5.4, 6.1, 7.1 with ethanone or carboxylic acid substituents showed toxicity against bacteria cells. The substances chosen by the US National Cancer Institute (NCI) were screened for their ability to inhibit 60 different human tumor cell lines, where 2-(tetrazolo[1,5-c]quinazolin-5-ylthio)-1-(4-tolyl)ethanone (5.2), 3-(tetrazolo[1,5-c]quinazolin-5-ylthio)propanoic and related 3-metyl-butanoic acids (6.2, 6.3), and ethyl tetrazolo[1,5-c]quinazolin-5-ylthio)acetate (7.2) showed lethal antitumor activity (1.0 μM) against the acute lymphoblastic leukemia cell line (CCRF-CEM), and substances 5.2 and 6.3 exhibited moderate anticancer properties inhibiting growth of the leukemia MOLT-4 and HL06-(TB) cell lines. The moderate antitumor activity was demonstrated in 1-(2,5-dimethoxyphenyl)-2-(tetrazolo[1,5-c]quinazolin-5-ylthio)ethanone (5.4) against the CNS cancer cell line SNB-75. Comparing the docking mode of the Gefitinib and synthesised substances on the ATP binding site of EGFR, it could be assumed that these compounds might act in the same way. The results of the investigation could be considered as a useful base for future development of potent antimicrobials and antitumor agents among tetrazolo[1,5-c]quinazoline-5-thione S-derivatives.     

Steroidal saponins from the leaves of Yucca de-smetiana and their in vitro antitumor activity: structure activity relationships through a molecular modeling approach

Four steroidal saponins were isolated from the leaves of Yucca de-smetiana Baker. Their structures were established using one- and two- dimensional NMR spectroscopy and mass spectrometry. The structure of the new steroidal saponin was identified as: (25R)-3β-hydroxy-5α-spirostan-3-O-β-d-xylopyranosyl-(1 → 2)-β-d-galactopyranosyl-(1 → 2)-O-[β-d-glucopyranosyl-(1 → 3)]-β-d-glucopyranosyl-(1 → 4)-β-d-galactopyranoside (desmettianoside C) along with three known spirostanol and furostanol saponins. The isolated saponins were evaluated for their antitumor activity against HCT116, MCF7, HepG2, and A549 cell lines. Saponins 3 and 4 showed potent activity against HCT116, MCF7, and HepG2 cell lines in comparison with the positive control doxorubicin. A molecular modeling approach was performed to establish conformational criteria that could affect the biological activity of the isolated saponins.     

Synthesis and structure-activity relationship studies of 2,3-dihydroimidazo[2,1-a]isoquinoline analogs as antitumor agents

5-Aryl-2,3-dihydroimidazo[2,1-a]isoquinolines were reported to have strong antitumor activity and one of the derivatives such as 5-[4′-(piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1-a] isoquinoline (1, SDZ 62–434) was found to be more effective than the clinical cytostatic agent edelfosine (2) inin vitro andin vivo assays. Currently SDZ 62–434 is in clinical trials in Europe. The structure-activity relationship studies of SDZ 62–434 showed that compounds with substitution on ring A were less active than the lead compound. Ring B in SDZ 62–434 was essential for the activity because compounds without B ring had no antitumor activity. Among the 3-arylisoquinolin-1-one derivatives, 3-[4′-(piperidonomethyl)phenyl] substituted analog had no antitumor activity but simple phenyl substituted compound, such as4, showed the most potent antitumor activity in various human tumor cell lines.     

Synthesis and anticancer evaluation of novel 3,5-diaryl-thiazolo[4,5-d]pyrimidin-2-one derivatives

The 2-oxo analogs of thiazolo[4,5-d]pyrimidine-2-thiones were prepared to study their cytotoxic activity. Five of the newly synthesized compounds were selected by the National Cancer Institute (Bethesda, MD, USA) for a primary in vitro antitumor assay. 7-Chloro-3,5-diphenyl-thiazolo[4,5-d]pyrimidin-2-one (5a) proved to be the most active one among the screened derivatives and was further evaluated in the full panel of 60 cell lines at five different concentrations. The structures of compounds were determined by IR, ¹H-NMR, ¹³C-NMR, X-ray, and elemental analysis.     

Fused Thiopyrano[2,3-d]thiazole Derivatives as Potential Anticancer Agents

rel-(5aR,11bR)-3,5a,6,11b-tetrahydro-2H,5H-chromeno[4′,3′:4,5]thiopyrano[2,3-d][1,3]thiazol-2-ones formed by the stereoselective Knoevenagel-hetero-Diels-Alder reaction were functionalized at the nitrogen in position 3 via reactions of alkylation, cyanoethylation, and acylation. The synthesized compounds were evaluated for their anticancer activity in NCI60 cell lines. Among the tested compounds, 3f was found to be the most active candidate with the greatest influence on leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, prostate cancer, and breast cancer subpanel cell lines with GI₅₀ values over a range of 0.37–0.67 μM.     

Diuretika, 3. Mitt. 1-Carbocyclisch und heterocyclisch substituierte 4-Aminopyrazolo[3,4-d]pyrimidine

Diuretics, III: 4-Aminopyrazolo[3,4-d]pyrimidines with Carbocyclic or Heterocyclic Substituents at N-1 As analogues of the diuretically active 4,6-diamino-1-(2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidine, the 4-aminopyrazolo[3,4-d]pyrimidines 3a–g were prepared by condensation of the 5-amino-4-cyanopyrazoles 1a–g with formamide (2) .     

4‐Substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine Derivatives: Design,Synthesis, Antitumor and EGFR Tyrosine Kinase Inhibitory Activity

Four series of some 4‐substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine derivatives 5a – f , 6a – f , 8a – f , and 9a – f were designed to be screened for their antitumor activity. All compounds were evaluated against breast (MCF‐7) and lung (A‐549) cell lines. Six compounds 5a , 5b , 6b , 6e , 9e , and 9f displaying activity against both cell lines were further estimated for their EGFR‐TK inhibitory activity where they revealed 41–91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP‐binding site of EGFR‐TK demonstrated their binding mode where H‐bonding interaction with Met793 through N¹ of pyrimidine or N² of pyrazole was observed.