An efficient one-pot synthesis and docking studies of bioactive new antiproliferative dispiro[oxindole/acenaphthylenone‒benzofuranone] pyrrolidine scaffolds.

A new and efficient method has been developed to synthesize dispiro[oxindole/acenaphthylenone-benzofuranone]pyrrolidine compounds. This is done by triggering the 1,3-dipolar cycloaddition reaction of azomethine ylides by reacting isatin/acenaphthoquinone with L-picolinic acid/L-proline/sarcosine/L-thioproline/tetrahydroisoquinolines, in a highly regioselective manner in an ionic liquid [DBU][Ac] with 4'-chloro-auron[2-(4-chlorobenzylidene)benzofuran-3(2H)-one]. Single-crystal X-ray diffraction data support the proposed structures of the new compounds. The heterocycles derived from amino acids such as L-picolinic acid, L-proline, and L-thioproline showed significant inhibitory effects against six human solid tumors, including lung, breast, cervix, colon, and others. These new structures were also tested in the active sites of the MDM2 receptor to further study their antiproliferative effects.

Design, synthesis and evaluation of 4,7-disubstituted 8-methoxyquinazoline derivatives as potential cytotoxic agents targeting ß-catenin/TCF4 signaling pathway.

Overactivation of Wnt/ß-catenin signaling by accumulated ß-catenin in the nucleus has been shown to play a crucial role in the etiology of cancer. Interaction of ß-catenin with Transcription factor 4 (TCF4) is a key step for the activation of Wnt genes in response to upstream signals of the Wnt/ß-catenin pathway. Hence, down regulation of Wnt/ß-catenin signaling or targeting downstream events by selective ß-catenin/TCF4 protein-protein interaction inhibitors could be a potential therapeutic strategy against such cancers. In this study structure-based drug design approach was followed to design novel 4,7-disubstituted 8-methoxyquinazoline-based derivatives which could act as potential cytotoxic agents inhibiting the ß-catenin/TCF4 protein-protein interactions. Fifteen compounds possessing 4,7-disubstituted 8-methoxyquinazoline scaffold were synthesized. Cytotoxic potential of the synthesised derivatives were determined against constitutively activated ß-catenin/TCF4 signaling pathway cancer cells (HCT116 and HepG2) using the sulforhodamine B assay. The most potent compound (18B) was selected for detailed biological evaluation. Cell morphology, Hoechst 33342 and Annexin V/PI staining were used to detect apoptosis, while inhibition of cell migration was assessed by in vitro wound healing assay against HCT116 and HepG2 cells. Effect on ß-catenin/TCF mediated transcriptional activity was assessed by TOPFlash/FOPFlash assay, TCF4 and ß-catenin protein expression by immunocytofluorescence, and Wnt target genes (like c-MYC and Cyclin D1) mRNA levels by RT-PCR against HCT116 cells. Cytotoxic potency of the most potential compound (18B) against primary human gallbladder cancer cells was also evaluated. The derivatives showed interactions with active site residues of ß-catenin and were capable of hindering the TCF4 binding, thereby disrupting ß-catenin/TCF4 interactions. Cytotoxic potencies (IC50) of these derivatives ranged from 5.64 ± 0.68 to 23.18 ± 0.45 µM against HCT116 and HepG2 cells respectively. Compound (18B), the most potent compound among the series, induced apoptosis and inhibited cell migration against HCT116 and HepG2 cells. Mechanistic studies indicated that compound (18B) downregulated ß-catenin/TCF4 signaling pathway, ß-catenin and TCF4 protein expression, and mRNA levels of c-MYC andCyclin D1 in HCT116 cells and showed cytotoxicity against primary human gallbladder cancer cells with IC50 value of 8.50 ± 1.44 µM. Thus, novel 4,7-disubstituted 8-methoxyquinazoline derivatives were identified as potential cytotoxic agents with potencies comparable to that of imatinib mesylate. Compound (18B) represents a promising lead molecule as anticancer agent against colon, hepatocellular and gallbladder cancers targeting ß-catenin/TCF4 signaling pathway.

Design and synthesis of novel N-[3-(benzimidazol-2-ylamino)phenyl]amine and N-[3-(benzoxazol-2-ylamino)phenyl]amine derivatives as potential anticancer agents.

In this contribution, we report the design, synthesis and cytotoxicity studies of a series of N-[3-(benzimidazol-2-yl-amino)phenyl]amine and N-[3-(benzoxazol-2-ylamino)phenyl]amine derivatives. In vitro cytotoxicity assay of 26 selected compounds was carried out at National Cancer Institute (NCI), USA. Out of them, compounds 10e (NSC D-762842/1) and 11s (NSC D-764942/1) have shown remarkable cytotoxicity with GI50 values ranging between "0.589-14.3 µM" and "0.276-12.3 µM," respectively, in the representative nine subpanels of human tumor cell lines. Further, flow cytometry analysis demonstrated that compound 10e exerted cell cycle arrest at G2/M phase and showed dose-dependent enhancement in apoptosis in K-562 leukemia cancer cells.

Recent developments and strategies for the discovery of TACE inhibitors.

INTRODUCTION: TNF-α plays a central role in certain autoimmune diseases as well as in inflammation. The current strategy for excluding TNF-α from circulation is to selectively inhibit TNF-α converting enzyme (TACE), an enzyme that cleaves mTNF-α to active TNF-α. Various TACE inhibitors have been discovered by using different strategies to control inflammatory diseases, cancer, and cardiac hypertrophy. AREAS COVERED: The present article summarizes the design and discovery of novel TACE inhibitors that have been reported in the literature since 2012 onwards. It also includes some reports concerning the new role that TACE plays in cancer and cardiac hypertrophy. EXPERT OPINION: So far, undertaken studies that have looked to design and develop small TACE inhibitors have been discouraging due to the failure of any TACE inhibitors to hit the market. However, some of the latest developments, such as with tartrate-based inhibitors, has given hope to the potentiality of a viable novel selective TACE inhibitor therapeutic in the future. Indeed, some of the novel peptidomimetics and monoclonal antibodies have great potential to pave the way for an effective and safe therapy by selectively inhibiting TACE enzyme.

New pyrazolyl-dibenzo[b,e][1,4]diazepinones: room temperature one-pot synthesis and biological evaluation.

Several new (5-aryloxy-pyrazolyl)- and (5-aryl/olefin-sulfanyl-pyrazolyl)-dibenzo[b,e] [1,4] diazepinone scaffolds have been synthesized, by assembling 5-substituted 3-methyl-1-phenyl-pyrazole-4-carbaldehydes of varied nature with different cyclic diketones and aromatic diamines successfully in the presence of indium chloride in acetonitrile, at room temperature. Desired products are excellent in the purity and isolated without chromatography. All new structures are confirmed, on the basis of single-crystal X-ray diffraction data of representative 29e. Compounds reported in the present work revealed good antioxidant, antimicrobial and antiproliferative activities with promising FRAP (ferric reducing antioxidant power), bacterial resistance and human solid tumor cell growth inhibitory values, respectively. Compounds 25c and 29e, overall, registered good to moderate activity against A549 (lung), HeLa (cervix), SW1573 (lung) T-47D (breast) and WiDr (colon) cell lines, with GI50 values in the 2.6-5.1 µM and 1.8-7.5 µM ranges, respectively. Molecular docking was carried out to elucidate the binding modes of the compounds (25c, 29e) to topoisomerase I and II.

Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents.

The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound 23e showed an IC50 value of 0.56 ± 0.02 µM for AChE and an IC50 value of 1.17 ± 0.09 µM for BuChE. These derivatives are also endowed with potent antioxidant activity. To understand the plausible binding mode of the compound 23e, molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H2O2-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aß-induced toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore, it did not show any significant toxicity in neuronal SH-SY5Y cells in the cytotoxicity assay. Compound 23e did not show any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly reversed scopolamine-induced memory deficit in mice model. Additionally, compound 23e showed notable in silico ADMET properties. Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD drugs.

Benzylpiperidine-Linked Diarylthiazoles as Potential Anti-Alzheimer's Agents: Synthesis and Biological Evaluation.

A novel series of hybrid molecules were designed and synthesized by fusing the pharmacophoric features of cholinesterase inhibitor donepezil and diarylthiazole as potential multitarget-directed ligands for the treatment of Alzheimer's disease (AD). The compounds showed significant in vitro anticholinesterase (anti-ChE) activity, the most potent compound (44) among them showing the highest activity (IC50 value of 0.30 ± 0.01 µM) for AChE and (1.84 ± 0.03 µM) for BuChE. Compound 44 showed mixed inhibition of AChE in the enzyme kinetic studies. Some compounds exhibited moderate to high inhibition of AChE-induced Aß1-42 aggregation and noticeable in vitro antioxidant and antiapoptotic properties. Compound 44 showed significant in vivo anti-ChE and antioxidant activities. Furthermore, compound 44 demonstrated in vivo neuroprotection by decreasing Aß1-42-induced toxicity by attenuating abnormal levels of Aß1-42, p-Tau, cleaved caspase-3, and cleaved PARP proteins. Compound 44 exhibited good oral absorption and was well tolerated up to 2000 mg/kg, po, dose without showing toxic effects.

Medicinal Chemistry Perspective of Fused Isoxazole Derivatives.

Nitrogen containing heterocyclic rings with an oxygen atom is considered as one of the best combination in medicinal chemistry due to their diversified biological activities. Isoxazole, a five membered heterocyclic azole ring is found in naturally occuring ibetonic acid along with some of the marketed drugs such as valdecoxib, flucloxacillin, cloxacillin, dicloxacillin, and danazol. It is also significant for showing antipsychotic activity in risperidone and anticonvulsant activity in zonisamide, the marketed drugs. This review article covers research articles reported till date covering biological activity along with SAR of fused isoxazole derivatives.

Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer.

Breast cancer, an emerging disease among the women population, occurs due to overexpression of estrogens. The enzyme aromatase plays a key rate limiting role in the biosynthesis of estrogens. Certain clinical advantages of the use of exemestane, a steroidal aromatase inhibitor over non-steroidal aromatase inhibitors have drawn the attention of researchers for the development of novel steroidal aromatase inhibitors.The current review is a humble attempt to compile the reports by various researchers till date on the synthesis of steroidal aromatase inhibitors. It has been tried to encompass the structural modifications carried out by various researchers in the steroid ring system by taking up the functional group modifications on rings A, B, ring A/B junction, ring-D, ring modifications, bridged derivatives and heterocyclic ring-fused derivatives in a systematic way.

Synthesis and biological evaluation of some novel pyrido[1,2-a]pyrimidin-4-ones as antimalarial agents.

Novel pyrido[1,2-a]pyrimidin-4-ones have been synthesized and evaluated for their antimalarial activity by SYBR Green I assay against erythrocytic stages of chloroquine (CQ) sensitive Pf 3D7 strain. The antimalarial screening of 42 different compounds revealed that 3-Fluorobenzyl(4-oxo-4H-pyrido [1,2-a]pyrimidin-3-yl)carbamate (21, IC50 value 33 µM) and 4-Oxo-N-[4-(trifluoromethyl)benzyl]-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (37, IC50 value 37 µM) showed moderate antimalarial activity. Cytotoxicity study was performed against mammalian cell line (Huh-7) by using the MTT assay for the moderately active compounds. Structural activity relationship (SAR) studies displayed that B-ring unsubstituted pyrido[1,2-a]pyrimidine scaffold is responsible for the antimalarial activities of the evaluated derivatives. This SAR based antimalarial screening supported that pyrido[1,2-a]pyrimidin-4-one can be considered as a lead heterocyclic structure for further development of more potent derivatives for antimalarial activity.

Unequivocal role of pyrazine ring in medicinally important compounds: a review.

Pyrazine is one of the important class of heterocyclic compounds that can be obtained naturally or synthesized chemically. Pyrazine ring has got importance in exhibiting various biological activities in association with other scaffolds like pyrrole, pyrazole, imidazole, triazole, tetrazole, thiophene, oxazole, pyridine, piperidine and piperazine. Presence of pyrazine ring as a basic scaffold in various clinically used drugs exhibits its importance in drug design. In this review, attempt has been made to disclose various therapeutic applications of pyrazine derivatives reported during the last decade.

Novel methods and strategies in the discovery of TACE inhibitors.

INTRODUCTION: Tumor necrosis factor-α (TNF-α) is a key player in inflammation and joint damage in rheumatoid arthritis (RA). One treatment approach to exclude TNF-α from the biological system is by inhibiting tumor necrosis factor-alpha converting enzyme (TACE), the enzyme responsible for the production of its active form. To date, a number of TACE inhibitors have been reported in the literature from various strategies and methods. AREAS COVERED: The following article presents the design and development strategies for the discovery of novel TACE inhibitors which could be of therapeutic utility for the alleviation of inflammatory conditions. The review is based on literature of the subject from 2005 onward. EXPERT OPINION: Discovery of a selective TACE inhibitor has remained a major goal for many academic and pharmaceutical industrial research laboratories for quite some time. Identification of selective TACE inhibitors has proved elusive until recently due to structural similarities between TACE and MMPs. The differences in the shape and size of the S1' pocket of TACE and MMPs could be exploited to design selective TACE inhibitors devoid of any MMP inhibitory activity in the near future. It would be a Herculean task to develop a specific TACE inhibitor for clinical treatment of RA because binding subsites of TACE and MMPs are quite similar. However, developments taking place currently in the field as well as in the application of molecular modeling techniques at a wider scale could yet provide clinically useful selective TACE inhibitors in the not too distant future.

Synthesis, preliminary biological evaluation and molecular modeling of some new heterocyclic inhibitors of TACE.

Central heteroaryl ring analogues belonging to a series of potent hydroxamate TACE inhibitors were synthesized. The TACE inhibitory activities of these compounds were evaluated by in vitro WBA and in silico molecular modeling studies using crystal structure of human TACE. Compound 14 showed very good in vitro inhibition, supported by the in silico docking studies.

Development of highly predictive 3D-QSAR CoMSIA models for anthraquinone and acridone derivatives as telomerase inhibitors targeting G-quadruplex DNA telomere.

G-quadruplex structures of DNA represent a potentially useful target for anticancer drugs. Telomerase enzyme, involved in immortalization of cancer cells is inhibited by stabilization of G-quadruplex at the ends of chromosomes. Anthraquinone and acridone derivatives are promising G-quadruplex ligands as telomerase inhibitors. So far, optimization of these ligands remained hampered due to the lack of creditable quantitative structure-activity relationships. To understand the structural basis of anthraquinone and acridone derivatives, a predictive 3D-QSAR model has been developed for the first time for telomerase inhibitory activity of G4 ligands, employing comparative molecular similarity indices analysis (CoMSIA). Considering the proposition that the basic nitrogens in these compounds should exist in protonated form at physiological pH the protonated forms of the reported compounds were analyzed and investigated. The QSAR model from conformational template Conf1 exhibited best correlative and predictive properties. The actual predictive abilities of the QSAR model were thoroughly validated through an external validation test set of compounds. The statistics indicate a significantly high prediction power of the best model (r(2), 0.721), supporting the proposed molecular mechanism of DNA G-quadruplex ligands.

Development of predictive pharmacophore model for in silico screening, and 3D QSAR CoMFA and CoMSIA studies for lead optimization, for designing of potent tumor necrosis factor alpha converting enzyme inhibitors.

A chemical feature-based pharmacophore model was developed for Tumor Necrosis Factor-alpha converting enzyme (TACE) inhibitors. A five point pharmacophore model having two hydrogen bond acceptors (A), one hydrogen bond donor (D) and two aromatic rings (R) with discrete geometries as pharmacophoric features was developed. The pharmacophore model so generated was then utilized for in silico screening of a database. The pharmacophore model so developed was validated by using four compounds having proven TACE inhibitory activity which were grafted into the database. These compounds mapped well onto the five listed pharmacophoric features. This validated pharmacophore model was also used for alignment of molecules in CoMFA and CoMSIA analysis. The contour maps of the CoMFA/CoMSIA models were utilized to provide structural insight for activity improvement of potential novel TACE inhibitors. The pharmacophore model so developed could be used for in silico screening of any commercial/in house database for identification of TACE inhibiting lead compounds, and the leads so identified could be optimized using the developed CoMSIA model. The present work highlights the tremendous potential of the two mutually complementary ligand-based drug designing techniques (i.e. pharmacophore mapping and 3D-QSAR analysis) using TACE inhibitors as prototype biologically active molecules.

Novel TACE inhibitors in drug discovery: a review of patented compounds.

TNF-alpha converting enzyme (TACE), a pro-inflammatory cytokine, catalyzes the formation of TNF-alpha from membrane bound TNF-alpha precursor protein. TNF-alpha is believed to play pathophysiological roles in inflammation, anorexia, cachexia, septic shock, viral replication and so on. TNF-alpha is a key player in inflammation and joint damage in rheumatoid arthritis. While a variety of TACE inhibitors have been reported in the literature, a vast majority of these compounds are peptidic and peptide-like compounds that are expected to have bioavailability and pharmacokinetic problems, common to such compounds, limiting their clinical effectiveness. Low molecular mass, long acting, orally bioavailable inhibitors of TACE are, therefore, highly desirable for the treatment of potential chronic diseases mentioned above. A review of patented compounds as TACE inhibitors in drug discovery is given. A selection of interesting patents recorded from 2001 to 2009 is presented. Various novel TACE inhibitors developed by different companies have been discussed.

Structural investigations of acridine derivatives by CoMFA and CoMSIA reveal novel insight into their structures toward DNA G-quadruplex mediated telomerase inhibition and offer a highly predictive 3D-model for substituted acridines.

Stabilization of G-quadruplex structures formed from telomeric DNA, by means of G-quadruplex selective ligands, is a means of inhibiting the telomerase enzyme. This makes G-quadruplex an emerging target for cancer therapy. The objective of the current 3D QSAR study is to uncover structural requirements for acridine derivatives, which would eventually assist and complement the rational drug-design attempts. Various protonation strategies were investigated to check in situ protonation sites present on ligands when they bind to G-quadruplex, and predictive 3D-QSAR CoMFA and CoMSIA models have been developed. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were carried out on substituted acridines as telomerase inhibitors. Molecular models with good predictive power were derived using steric, electrostatic, hydrophobic, and H-bond donor fields of the compounds. The CoMSIA coefficient contour plots identified several key features explaining the wide range in activities. The present study not only offers a highly significant predictive CoMSIA model for trisubstituted acridine derivatives as telomerase inhibitors but also throws more light on the molecular structure of these compounds at physiological pH.

Studies on novel 2-imidazolidinones and tetrahydropyrimidin-2(1H)-ones as potential TACE inhibitors: design, synthesis, molecular modeling, and preliminary biological evaluation.

Compounds belonging to the class of 2-imidazolidinones and tetrahydropyrimidin-2(1H)-ones were synthesized and evaluated for their TACE inhibitory activity. Most of the compounds showed very good TACE inhibitory activity. Docking study clearly indicates importance of the P1' group of the inhibitor for the TACE inhibitory activity. This work proves that these two classes of molecules could be used as potential leads for the development of TACE inhibitors.

Development of predictive 3D-QSAR CoMFA and CoMSIA models for beta-aminohydroxamic acid-derived tumor necrosis factor-alpha converting enzyme inhibitors.

A three-dimensional quantitative structure-activity relationship study was performed on a series of beta-aminohydroxamic acid-derived tumor necrosis factor-alpha converting enzyme inhibitors employing comparative molecular field analysis and comparative molecular similarity indices analysis techniques to investigate the structural requirements for the inhibitors, and derive a predictive model that could be used for the design of novel tumor necrosis factor-alpha converting enzyme inhibitors. log P was used as an additional descriptor in the comparative molecular field analysis analysis to study the effects of lipophilic parameters on activity. Inclusion of log P did not improve the models significantly. The statistically significant model was established with 45 molecules, which were validated by a test set of 11 compounds. Ligand molecular superimposition on the template structure was performed by the atom-/shape-based root mean square fit and database alignment methods. Docked conformer based alignment (V) yielded the best predictive comparative molecular field analysis model = 0.673, = 0.860, F-value = 86.073, predictive r (2) = 0.642, with two components, standard error of prediction = 0.394 and standard error of estimates = 0.243 while the comparative molecular similarity indices analysis model yielded = 0.635, = 0.858, F-value = 84.451, predictive r (2) = 0.441 with three components, standard error of prediction = 0.393 and standard error of estimates = 0.245. The contour maps obtained from three-dimensional quantitative structure-activity relationship studies were appraised for activity trends for the molecules analyzed. The comparative molecular field analysis models exhibited good external predictivity as compared with that of comparative molecular similarity indices analysis models. The model generated through comparative molecular field analysis was validated with the IK-682. The data generated from this study may guide our efforts in designing and predicting the tumor necrosis factor-alpha converting enzyme inhibitory activity of novel molecules.

Current perspective of TACE inhibitors: a review.

Rheumatoid Arthritis (RA) is one of the most common autoimmune inflammatory conditions, affecting approximately 1% of the adult population worldwide. TNF-alpha is a pleitropic, pro-inflammatory cytokine which plays a pivotal role in the origin and progression of RA and other immune mediated disorders. The success of anti-TNF-alpha biological agents proved that inhibition of TNF-alpha could result in effective control of RA. Since the discovery of anti-TNF-alpha biologicals, much efforts have gone into developing an orally bioavailable small size TNF-alpha antagonist. One of the ways to block TNF-alpha in biological fluids is to inhibit TNF-alpha converting enzyme (TACE). This target has been validated in preclinical trials using TACE inhibitors. But, even after more than a decade no single TACE inhibitor has passed the Phase II clinical trials. Very recently, it has been shown that TACE inhibitors could also be used for inhibition of pathogenic EGFR signaling in cancer. Hence, TACE inhibitors could perform a dual role, in curing not only RA but also certain cancerous conditions. Developments in the field have prompted us to review the research work on TACE inhibitors, especially their structure activity relationships and molecular modeling studies.