Synthesis and biological evaluation of new cytotoxic indazolo[4,3-gh]isoquinolinone derivatives

A series of indazolo[4,3-gh]isoquinolinones derivatives have been synthesized to decrease cardiotoxic side effects in comparison to Mitoxantrone. The antiproliferative effects of different side chains were investigated and tested on at least four different cell lines of cervix, ovarian, CNS, NSCLC (non-small-cell lung cancer) and colon carcinoma. In addition to antiproliferative activities, influence on cell cycle and intercalation behavior have been tested.     

Synthesis and antitumor activity of a new class of pyrazolo[4,3-e]pyrrolo[1,2-a][1,4]diazepinone analogs of pyrrolo[1,4]benzodiazepines (PBDs)

A new class of Pyrrolo[1,4]benzodiazepines (PBDs) analogs featuring a pyrazolo[4,3-e]pyrrolo[1,2-a][1,4]diazepinone ring system has been designed and synthesized. In these compounds the A-benzene ring, characteristic of PBDs, has been replaced by a dimethylpyrazole ring, a modification suggested by modelling studies performed on the PBD base structure. Biological evaluation releaved appreciable antitumor activity for compounds 14 and 15 (8.84–22.4 μM) which encourages further investigation of the N⁶ and N⁷ alkyl pyrazole analogs.     

Synthesis,modeling and biological evaluation of some pyrazolo[3,4-d]pyrimidinones and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinones as anti-inflammatory agents

New pyrazolo[3,4-d]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed in vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity.     

Physiochemical characterization of substituted chromeno[4,3-b][1,5]benzodiazepine stereoisomers designed as cell membrane active antitumor agents

As an alternative to naturally occurring pyrrolo[2,1-c][1,4]benzodiazepines (e.g., antramycin) which possess properties of DNA alkylation, we have designed several antileukemic chromeno[4,3-b][1,5]benzodiazepine derivatives with potential activity toward leukemia cell membranes and the cyclic nucleotide system. The cis and trans diastereoisomers were characterized by NMR. The absolute configurations of the enantiomers were established by X-ray diffraction and circular dichroism (CD) measurements. By means of absorption spectroscopy and determinations of fluorescence and fluorescence decay, it was found that the cancerostatically active compound (+)(6aR, 13aS)-3,4-dimethoxy-10,11-dimethyl-6,6a,7,8,13, 13a-hexahydrochromeno[4,3-b][1,5]benzodiazepine (ZIMET 54/79) and its biologically inactive (-) enantiomer (ZIMET 55/79) interact with liposomal membranes. At pH values of 6.0 and 7.3 the long-wave absorption bands of these agents showed weak bathochromic and hypochromic effects upon addition of neutral, and positively and negatively charged phosphatidylcholine and phosphatidylcholine/cholesterol liposomes. Such spectral changes are interpreted as resulting from the binding of both agents to phospholipid bilayers. Steady-state determinations using the membrane probe 1-anilino-8-naphthalenesulfonic acid (1,8-ANS) led to the observation of a small decrease in fluorescence intensity in the presence of either agent. Time-resolved measurements demonstrate that the mechanism of action of the agents occurs mainly through the partial displacement of probe molecules from regions of hydrophobic binding to areas of greater solvent accessibility. No significant differences in binding between the cancerostatically active and inactive enantiomers with liposomes (archiral systems) were detectable on the basis of spectrophotometric and fluorescence determinations. Cell membrane bound adenylate cyclase is stimulated by ZIMET 54/79, resulting in an increase of 103% in the level of cAMP in mouse L1210 leukemia cells. On examination of structure-activity relationships, it was found that the biological activity (leukemia L1210, P388, Lewis lung carcinoma, melanoma B16, increase in cAMP) is correlated with the particular configuration (6aR,13aS) and type of substituent at positions 3 and 4 of the benzo ring in the case of alkoxy groups and positions 10 and 11 for methyl groups. No activity was detected toward DNA/RNA using microbial test systems.     

Synthesis and biological evaluation of cyclopenta[c]thiophene related compounds as new antitumor agents

A series of 22 cyclopenta[c]thiophene related compounds was obtained by the pharmacomodulation of 6-amino-5,6-dihydro-4H-cyclopenta[c]thiophen-4-ones 1a-g. All compounds were evaluated for potential anticancer activity in the NCI's in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Among these tested compounds, seven were found to be cytotoxic, especially against leukemia cell lines, allowing us to point out some structure-activity relationships. These derivatives were further evaluated for potential in vivo anticancer activity in the hollow fiber assay developed at the NCI, which selected two compounds, 1f and 3a for standard xenograft testing.     

Synthesis of N-substituted 5-[2-(N-alkylamino)ethyl]dibenzo[c,h][1,6]naphthyridines as novel topoisomerase I-targeting antitumor agents

Several N-alkyl and N,N-dialkyl 5H-8,9-dimethoxy-5-(2-aminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-ones have been identified as topoisomerase I-targeting agents with potent antitumor activity. In the present study, the impact on biological activity of substitution of a trifluoromethyl, cyano, aminocarbonyl, or ethynyl group on a N-methyl substituent of N,N-dimethyl-, N-methyl-N-ethyl-, and N-methyl-N-isopropyl 5H-8,9-dimethoxy-5-(2-aminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-ones was assessed.     

Synthesis and biological evaluation of novel steroidal[17,16-d][1,2,4]triazolo[1,5-a]pyrimidines

The preparation of steroidal[17,16-d][1,2,4]triazolo[1,5-a]pyrimidines and their biological evaluation as potential anticancer agents are herein reported. These novel heterosteroids (2, 4) were prepared through the condensation reaction of 3-amino-1,2,4-triazole with 16-arylidene-17-ketosteroids (1, 3). All the synthesized compounds were evaluated for their anticancer activity in vitro against PC-3 (human prostatic carcinoma), MCF-7 (human breast carcinoma) and EC9706 (human esophageal carcinoma) cell lines. Among the screened compounds, 2i, 2n and 4f showed significant inhibitory activity against all the three human cell lines.     

Synthesis and biological evaluation of novel isoxazolo[4,3-e]indoles as antibacterial agents

The synthesis of a new series of 8-bromo-6-alkyl-1-aryl-6H-isoxazolo[4,3-e]indole derivatives is described. All the newly synthesized compounds were screened for their antibacterial activity against Escherichia coli HB101, Staphylococcus aureus pathogens (methicillin resistant S. aureus and methicillin susceptible S. aureus), Pseudomonas aeruginosa, and Bacillus subtilis; also MIC values of these compounds were determined.     

Synthesis and biological evaluation of five-membered heterocycles fused to cyclopenta[c]thiophene as new antitumor agents

A series of 10 derivatives 2-6 issued from the fusion of various five-membered heterocycles to cyclopenta[c]thiophene were evaluated for potential anticancer activity in the NCI's in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Among these tested compounds, four were found to be cytotoxic allowing us to point out some structure-activity relationships. The oxazolidinone derivatives 2a-c displayed further in vivo antitumor activity in the hollow fiber assay and standard xenograft testing developed at the NCI.     

Synthesis and biological evaluation of new [1,2,4]triazolo[4,3-a]pyridine derivatives as potential c-Met inhibitors

A series of [1,2,4]triazolo[4,3-a]pyrazine derivatives (4a–4i) were designed, synthesized and evaluated for their c-Met kinase inhibition and antitumor activity against SNU5 gastric cell line in vitro. Among these compounds, 4d was found to show the highest activity against c-Met and high selectivity against the tumor cells which are believed to be dependent on the c-Met oncogene amplification, because 4d selectively inhibited c-Met while had no effect on other 59 kinases. In vivo efficacy study on human gastric (MKN-45) and human non-small cell lung (NCI-H1993) tumor xenograft in nude mouse demonstrated that 4d·CH₃SO₃H had a better inhibiting activity than SGX-523 in a dose-dependent manner. When tested in mice, compound 4d·CH₃SO₃H was found to have biological half-lives and plasma exposure values higher than those of JNJ-38877605, and its long-term toxicity and acute toxicity turned out to be acceptable, all of which indicates that 4d·CH₃SO₃H is a desirable drug candidate.     

Benzofuro[3,2-f][1]benzopyrans: a new class of antitubercular agents

Alkylation of 2-hydroxydibenzofuran with 3-chloro-3-methyl-1-butyne, followed by Claisen rearrangement, gave access to 3,3-dimethyl-3Hbenzofuro[3,2-f][1]-benzopyran. Several derivatives modified at the pyran 1,2-double bond were prepared, including the corresponding dihydro compound and (+/-)-cis-diol, which was converted into diacetate and cyclic carbonate upon acylation. Both 3,3-dimethyl-3Hbenzofuro[3,2-f][1]benzopyran and 1,2-dihydro-3,3-dimethyl-3Hbenzofuro[3,2-f][1]benzopyran displayed significant activities when tested against Mycobacterium tuberculosis H37Rv and Beijing strains, with MIC99 in the range of 1-10 microg/ml. Further biological studies demonstrated good activities against drug-resistant mycobacterial strains. These compounds appear as promising specific antitubercular agents, since they exhibited neither significant cytotoxicity against mammal cells, nor effect on the growth of various bacteria and fungi.     

Synthesis and biological evaluation of pyrano[4,3-b][1]benzopyranone derivatives as monoamine oxidase and cholinesterase inhibitors

A series of eighteen pyrano[4,3-b][1]benzopyranone derivatives (1a-9b) were synthesized, and structure-activity relationships of their monoamine oxidase (MAO) A and B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. Most of the synthesized compounds exhibited weak inhibitory activity toward MAO-A, whereas compounds 2a, 2b, 4a, 4b, 5a, 5b, 6a, 6b, 8a and 8b showed potent inhibitory activities toward MAO-B. Intriguingly, compounds 5a, 5b, and 8a showed inhibitory activities comparable to pargylin, used as a positive control for MAO-B. Substitution of butoxy at the C3 position or of chlorine at the C8 position of pyrano[4,3-b][1]benzopyranone increased the inhibitory activity of the compound toward MAO-B. The results of a molecular docking study supported this structural effect. Most of the compounds exhibited no or slight inhibitory activity toward AChE and BChE, with exo type compounds bearing a butoxy group, such as compounds 2b, 5b and 8b, showing weak but distinct inhibitory activities toward BChE. This report is the first to identify pyrano[4,3-b][1]benzopyranone derivatives as potent and selective MAO-B inhibitors. 3-Butoxy-8-chloro-pyrano[4,3-b][1]benzopyranone (5b) may be useful as a lead compound for the development of MAO-B inhibitors.     

Synthesis,biological evaluation,and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4–15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC₅₀ 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.     

Rational design,synthesis and biological evaluation of thiadiazinoacridines: a new class of antitumor agents

A series of potential DNA-binding antitumor agents, 3-[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 12 and 1,3-di[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 13, has been prepared by cyclization with SOCl(2) of 1-[[omega-(alkylamino)alkyl]amino]-9-imino-4-nitro-9,10-dihydroacridines 16 or 1-[[omega-(alkylamino)alkyl]amino]-9-[omega-(alkylamino)alkyl]imino-4-nitro-9,10-dihydroacridines 17, respectively. The non-covalent DNA-binding properties of 12, 13 have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward six tumor cell lines, including human colon adenocarcinoma (HT29) and human ovarian carcinoma (A2780 sensitive, A2780cisR cisplatin-resistant, CH1, CH1cisR cisplatin-resistant, and SKOV-3) cells, are described and compared to that of reference drugs. In vivo antitumor activity of some selected derivatives, endowed with relevant cytotoxic activity against murine leukemia P388 are reported. The 3-[2-(dimethylamino)ethyl]-6-nitro-2,7-dihydro-3H-2 lambda(4)-thiadiazino[3,4,5-kl]acridin-2-one (12d) has been identified as a new lead in the development of anticancer tetracyclic acridine derivatives.     

Synthesis of new indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones as potential antitumor agents

Novel racemic indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones 3-29 were obtained regioselectivily from the reaction of 5,6-diamino-3,4-dihydropyrimidin-4-ones 1 and 2-arylideneindandiones 2 as reagents. These compounds have been evaluated at the US National Cancer Institute (NCI) for their ability to inhibit approximately 60 different human tumor cell lines, where 5 and 6 presented remarkable activity against 57 and 48 cancer cell lines, respectively, with the most important GI(50) values ranging from 0.49 to 1.46 microM, in vitro assay.     

Synthesis,biological evaluation and molecular modeling study of [1,2,4]-Triazolo[4,3-c]quinazolines: New class of EGFR-TK inhibitors

New series of triazolo[4,3-c]quinazolines were designed, synthesized and their structures were elucidated using different spectroscopic techniques. They were evaluated for their in vitro antitumor activity against HepG2, MCF-7, PC-3, HCT-116 and HeLa cancer cell lines using MTT assay. It was found that all compounds showed variable in vitro cytotoxicity. Distinct derivatives exhibited higher inhibitory activity against the tested cell lines with IC₅₀ values ranging from 8.27 to 10.68 µM using DOX standard (IC₅₀ = 4.17–8.87 µM). In vitro epidermal growth factor receptor (EGFR) inhibition assay was performed. Results revealed that compounds 8, 19 and 21 exhibited worthy EGFR inhibitory activity with IC₅₀ values ranging from 0.69 to1.8 µM in comparison to the reference drug Gefitinib (IC₅₀ = 1.74 µM). Further investigation showed that active candidates 8, 19 and 21 caused cell cycle arrest at the G2/M phase, and interestingly, induced cell death by apoptosis of MCF-7 cells cumulatively with 7.14, 17.52 and 24.88%, respectively, compared with DOX as a positive reference (29.09%). Molecular modeling studies, including docking, flexible alignment and surface mapping, were also done to study the interaction mode into the active site of EGFR kinase domain. There was a good agreement between modeling results and biological results. ADMET analysis and parameters of Lipinski’s rule of five were calculated. Pharmacokinetic parameters showed that compound 8 had more expected penetration through blood brain barrier than Gefitinib. The present work displayed new triazoloquinazoline based derivatives with potent cytotoxicity and promising EGFR inhibition activity.     

Synthesis and biological evaluation of estradiol linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates as potential anticancer agents

A series of new estradiol linked pyrrolo[2,1-c][1,4]benzodiazepine (E(2)-PBD) conjugates (3a-f, 4a-f and 5a-f) with different linker architectures including a triazole moiety have been designed and synthesized. All the 18 compounds have been evaluated for their anticancer activity and it is observed that some of the compounds particularly 4c-e and 5c,d exhibited significant anticancer activity. The detailed biological aspects relating to the cell cycle effects and tubulin depolymerization activity have been examined with a view to understand the mechanism of action of these conjugates. Among all these conjugates, one of the compound 5c could be considered as the most effective compound particularly against MCF-7 breast cancer cell line.     

In vitro and in vivo antifilarial activity evaluation of 3,6-epoxy [1,5]dioxocines: a new class of antifilarial agents

A series of 3,6-epoxy [1,5]dioxocines were synthesized and evaluated for their antifilarial activity against adult parasites of human lymphatic filarial parasite Brugia malayi (sub-periodic strain) in vitro. Out of these, six compounds (4a-f) possessed improved in vitro anti-filarial activity and examples 4d and 4f were also found to be active in the in vivo experiments. These results demonstrate that 3,6-epoxy [1,5]dioxocines exhibits potent antifilarial activity and might be developed into a new class of antifilarial drug.     

Synthesis and biological evaluation of benzo[b]furo[3,4-e][1,4]diazepin-1-one derivatives as anti-cancer agents

A new series of novel Podophyllotoxin-like benzo[b]furo[3,4-e][1,4]diazepin-1-ones possessing structural elements of 4-aza-2,3-didehydropodophyllotoxins with central diazepine ring was designed and synthesized as anti-cancer agents. In initial assessment, the cytotoxic activity of the synthesized compounds was evaluated against three cancer cell lines including MCF-7, PC3 and B16-F10 employing the MTT assay. Some of compounds (12h, 13a, 13c and 14b) showed significant cytotoxic activity. So, we investigated the cytotoxicity of compounds 12h, 13a, 13c and 14b, along with podophyllotoxin as the reference drug in different cancer cell lines including A549, A2780, DU145, HeLa, and normal Huvec cell line. Among these four compounds, 13c showed promising antiproliferative activity against all cancer cells stronger than the other compounds and comparable to reference drug podophyllotoxin in some cancer cells. All these four compounds did not show significant cytotoxicity on normal Huvec cell line. The flow cytometry analysis of the MCF-7, PC3 and A2780 human cancer cell lines treated with 13c showed that 13c, induced apoptosis in the MCF-7, PC3 and A2780 human cancer cell lines, which is in good agreement to its cytotoxic activity as well. Compound 13c did not show significant influence on tubulin assembly and exert its cytotoxic effects via induction of apoptosis and has potent and selective cytotoxic effects in cancer cells.     

Synthesis and biological evaluation of indolyl glyoxylamides as a new class of antileishmanial agents

A series of indolylglyoxylamide derivatives have been synthesized and evaluated in vitro against amastigote form of Leishmania donovani. Compound 8c has been identified as the most active analog of the series with IC₅₀ value of 5.17 μM and SI value of 31.48, and is several folds more potent than the standard drugs sodium stilbogluconate and pentamidine.