Pharmacophore For Inhibition Research Articles

Inhibitory effects of flavonoids on glucose transporter 1 (GLUT1): From library screening to biological evaluation to structure-activity relationship

Glucose transporter 1 (GLUT1) is mainly responsible for glucose uptake and energy metabolism, especially in the aerobic glycolysis process of tumor cells, which is closely associated with the advancement of tumors. Numerous studies have demonstrated that the inhibition of GLUT1 can decrease the growth of tumor cells and enhance drug sensitivity, so GLUT1 is considered to be a promising therapeutic target for cancer treatment. Flavonoids are a group of phenolic secondary metabolites present in vegetables, fruits, and herbal products, some of which were reported to increase cancer cells' sensitivity to sorafenib by inhibiting GLUT1. Our objective was to screen potential inhibitors of GLUT1 from 98 flavonoids and assess the sensitizing effect of sorafenib on cancer cells. and illuminate the structure–activity relationships of flavonoids with GLUT1. Eight flavonoids, including apigenin, kaempferol, eupatilin, luteolin, hispidulin, isosinensetin, sinensetin, and nobiletin exhibited significant inhibition (>50%) on GLUT1 in GLUT1-HEK293T cells. Among them, sinensetin and nobiletin showed stronger sensitizing effects and caused a sharp downward shift of the cell viability curves in HepG2 cells, illustrating these two flavonoids might become sensitizers to enhance the efficacy of sorafenib by inhibiting GLUT1. Molecular docking analysis elucidated inhibitory effect of flavonoids on GLUT1 was related to conventional hydrogen bonds, but not Pi interactions. The pharmacophore model clarified the critical pharmacophores of flavonoids inhibitors are hydrophobic groups in 3’positions and hydrogen bond acceptors. Thus, our findings would provide useful information for optimizing flavonoid structure to design novel GLUT1 inhibitors and overcome drug resistance in cancer treatment.

Discovery of potential FGFR3 inhibitors via QSAR, pharmacophore modeling, virtual screening and molecular docking studies against bladder cancer

BackgroundFibroblast growth factor receptor 3 is known as a favorable aim in vast range of cancers, particularly in bladder cancer treatment. Pharmacophore and QSAR modeling approaches are broadly utilized for developing novel compounds for the determination of inhibitory activity versus the biological target. In this study, these methods employed to identify FGFR3 potential inhibitors.MethodsTo find the potential compounds for bladder cancer targeting, ZINC and NCI databases were screened. Pharmacophore and QSAR modeling of FGFR3 inhibitors were utilized for dataset screening. Then, with regard to several factors such as Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties and Lipinski’s Rule of Five, the recognized compounds were filtered. In further step, utilizing the flexible docking technique, the obtained compounds interactions with FGFR3 were analyzed.ResultsThe best five compounds, namely ZINC09045651, ZINC08433190, ZINC00702764, ZINC00710252 and ZINC00668789 were selected for Molecular Dynamics (MD) studies. Off-targeting of screened compounds was also investigated through CDD search and molecular docking. MD outcomes confirmed docking investigations and revealed that five selected compounds could make steady interactions with the FGFR3 and might have effective inhibitory potencies on FGFR3.ConclusionThese compounds can be considered as candidates for bladder cancer therapy with improved therapeutic properties and less adverse effects.

Novel Benzo[4,5]imidazo[1,2-a]pyrimidine derivatives as selective Cyclooxygenase-2 Inhibitors: Design, synthesis, docking studies, and biological evaluation

The present study was aimed at the synthesis and evaluation of a new series of benzo[4,5]imidazo[1,2-a]pyrimidine having a methylsulfonyl group as COX-2 (cyclooxygenase-2) inhibitor pharmacophore. Molecular modeling studies were performed using the Autodock program, and the results demonstrated that methylsulfonyl pharmacophore was adequately placed into the COX-2 active site. The in vitro and in vivo COX-2 inhibitory effects were also evaluated. In the in vitro assay, all newly synthesized compounds showed moderate to good selectivity for the inhibition of the COX-2 enzyme. However, compound 2-(4-(methylsulfonyl) phenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (5a) showed the highest COX-2 inhibitory effect (IC50: 0.05 μM) even more than celecoxib as the reference drug (IC50: 0.06 μM). For the in vivo study, the writing reflex test was used, and the results indicated that all synthesized compounds had well dose-dependent anti-nociceptive activity. The in vivo evaluation also showed that compound 2-(4-(methylsulfonyl)phenyl)-4-(p-tolyl)benzo[4,5]imidazo[1,2-a]pyrimidine (5d) had the highest activity in the writing reflex test (ED50: 5.75 mg/kg). In addition, the cytotoxicity effects of the synthesized compounds were tested on MCF-7 breast cancer cells, and all compounds showed considerable inhibitory results.

Rationally designed donepezil-based hydroxamates modulate Sig-1R and HDAC isoforms to exert anti-glioblastoma effects

The pursuit of activating the HDAC inhibitory template towards additional mechanisms spurred us to design dual modulators (Sig-1R agonist - HDAC inhibitor) via utilization of the core structural unit of donepezil (an FDA-approved anti-Alzheimer's agent) as a surface recognition part. Literature precedents coupled with our experience rendered us with several insights that led to the inclusion of chemically diverse linkers and hydroxamic acid (zinc-binding motif) as the other components of HDAC inhibitory pharmacophore. With this envisionment and clarity, donepezil-based HDAC inhibitory adducts were furnished and exhaustively explored for their anti-GBM efficacy. Resultantly, a magnificently potent HDAC inhibitor 10 [IC50 (HDAC6) = 2.7 nM, IC50 (HDAC2) = 0.71 μM] was pinpointed that was endowed with the ability to: i) exert cell growth inhibitory effects against Human U87MG GBM cells ii) cause death in TMZ-resistant GBM cells iii) induce subG1 arrest in GBM cells iv) prolong the survival of TMZ-resistant U87MG inoculated orthotopic mice (in-vivo studies) v) induce GBM cell apoptosis via binding to Sig-1R. Collectively, the results led to the identification of compound 10 as a tractable anti-GBM agent that deserves detailed investigation for the accomplishment of its candidature as a GBM therapeutic.

Synthesis, ADMT prediction, and in vitro and in silico α-glucosidase inhibition evaluations of new quinoline-quinazolinone-thioacetamides.

In this work, a new series of quinoline-quinazolinone-thioacetamide derivatives 9a-p were designed using a combination of effective pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized by simple chemical reactions and evaluated for their anti-α-glucosidase activity. Among the tested compounds, compounds 9a, 9f, 9g, 9j, 9k, and 9m demonstrated significant inhibition effects in comparison to the positive control acarbose. Particularly, compound 9g with inhibitory activity around 83-fold more than acarbose exhibited the best anti-α-glucosidase activity. Compound 9g showed a competitive type of inhibition in the kinetic study, and the molecular simulation studies demonstrated that this compound with a favorable binding energy occupied the active site of α-glucosidase. Furthermore, in silico ADMET studies of the most potent compounds 9g, 9a, and 9f were performed to predict their drug-likeness, pharmacokinetic, and toxicity properties.

Discovery of potent Plasmodium falciparum protein kinase 6 (PfPK6) inhibitors with a type II inhibitor pharmacophore

Malaria is a devastating disease that causes significant global morbidity and mortality. The rise of drug resistance against artemisinin-based combination therapy demonstrates the necessity to develop alternative antimalarials with novel mechanisms of action. We report the discovery of Ki8751 as an inhibitor of essential kinase PfPK6. 79 derivatives were designed, synthesized and evaluated for PfPK6 inhibition and antiplasmodial activity. Using group efficiency analyses, we established the importance of key groups on the scaffold consistent with a type II inhibitor pharmacophore. We highlight modifications on the tail group that contribute to antiplasmodial activity, cumulating in the discovery of compound 67, a PfPK6 inhibitor (IC50 = 13 nM) active against the P. falciparum blood stage (EC50 = 160 nM), and compound 79, a PfPK6 inhibitor (IC50 < 5 nM) with dual-stage antiplasmodial activity against P. falciparum blood stage (EC50 = 39 nM) and against P. berghei liver stage (EC50 = 220 nM).

Structural Determinants of Indole-2-carboxamides: Identification of Lead Acetamides with Pan Antimycobacterial Activity.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is one of the leading causes of death in developing countries. Non-tuberculous mycobacteria (NTM) infections are rising and prey upon patients with structural lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. All mycobacterial infections require lengthy treatment regimens with undesirable side effects. Therefore, new antimycobacterial compounds with novel mechanisms of action are urgently needed. Published indole-2-carboxamides (IC) with suggested inhibition of the essential transporter MmpL3 showed good potency against whole-cell M.tb, yet had poor aqueous solubility. This project focused on retaining the required MmpL3 inhibitory pharmacophore and increasing the molecular heteroatom percentage by reducing lipophilic atoms. We evaluated pyrrole, mandelic acid, imidazole, and acetamide functional groups coupled to lipophilic head groups, where lead acetamide-based compounds maintained high potency against mycobacterial pathogens, had improved in vitro ADME profiles over their indole-2-carboxamide analogs, were non-cytotoxic, and were determined to be MmpL3 inhibitors.

Over 40 Years of Fosmidomycin Drug Research: A Comprehensive Review and Future Opportunities.

To address the continued rise of multi-drug-resistant microorganisms, the development of novel drugs with new modes of action is urgently required. While humans biosynthesize the essential isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) via the established mevalonate pathway, pathogenic protozoa and certain pathogenic eubacteria use the less well-known methylerythritol phosphate pathway for this purpose. Important pathogens using the MEP pathway are, for example, Plasmodium falciparum, Mycobacterium tuberculosis, Pseudomonas aeruginosa and Escherichia coli. The enzymes of that pathway are targets for antiinfective drugs that are exempt from target-related toxicity. 2C-Methyl-D-erythritol 4-phosphate (MEP), the second enzyme of the non-mevalonate pathway, has been established as the molecular target of fosmidomycin, an antibiotic that has so far failed to be approved as an anti-infective drug. This review describes the development and anti-infective properties of a wide range of fosmidomycin derivatives synthesized over the last four decades. Here we discuss the DXR inhibitor pharmacophore, which comprises a metal-binding group, a phosphate or phosphonate moiety and a connecting linker. Furthermore, non-fosmidomycin-based DXRi, bisubstrate inhibitors and several prodrug concepts are described. A comprehensive structure-activity relationship (SAR) of nearly all inhibitor types is presented and some novel opportunities for further drug development of DXR inhibitors are discussed.

B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that regulates the differentiation of B lymphocytes and mediates the formation of germinal centers (GCs) by recruiting corepressors through the BTB domain of BCL6. Physiological processes regulated by BCL6 involve cell activation, differentiation, DNA damage, and apoptosis. BCL6 is highly expressed when the gene is mutated, leading to the malignant proliferation of cells and drives tumorigenesis. BCL6 overexpression is closely correlated with tumorigenesis in diffuse large B-cell lymphoma (DLBCL) and other lymphomas, and BCL6 inhibitors can effectively inhibit some lymphomas and overcome resistance. Therefore, targeting BCL6 might be a promising therapeutic strategy for treating lymphomas. Herein, we comprehensively review the latest development of BCL6 inhibitors in diffuse large B-cell lymphoma and discuss the overview of the pharmacophores of BCL6 inhibitors and their efficacies in vitro and in vivo. Additionally, the current advances in BCL6 degraders are provided.

Potent Alkaline Phosphatase Inhibitors, Pyrazolo-Oxothiazolidines: Synthesis, Biological Evaluation, Molecular Docking, and Kinetic Studies.

To develop new alkaline phosphatase inhibitors (ALP), a series of pyrazolo-oxothiazolidine derivatives were synthesized and biologically assessed, and the results showed that all of the synthesized compounds significantly inhibited ALP. Specifically, compound 7g displayed the strongest inhibitory activity (IC50 = 0.045 ± 0.004 μM), which is 116-fold more active than monopotassium phosphate (IC50 = 5.242 ± 0.472 μM) as a standard reference. The most potent compound among the series (7g) was checked for its mode of binding with the enzyme and shown as non-competitively binding with the target enzyme. The antioxidant activity of these compounds was examined to investigate the radical scavenging effect. Moreover, the MTT assay method was performed to evaluate their toxic effects on the viability of MG-63 human osteosarcoma cells, and all compounds have no toxic effect on the cells at 4 μM. Computational research was also conducted to examine the binding affinity of the ligands with alkaline phosphatase, and the results revealed that all compounds showed good binding energy values within the active site of the target. Therefore, these novel pyrazolo-oxothiazolidine derivatives might be employed as promising pharmacophores for potent and selective alkaline phosphatase inhibitors.

3-Substituted-2,3-Dihydrothiazole as a promising scaffold to design EGFR inhibitors

The overexpression of EGFR has been recognized as the driver mechanism in the development of several human malignancies and the clinical use of EGFR inhibitors currently constitutes the standard of care for a wide range of malignancies, including colorectal cancer. However, the clinical efficacy of EGFR targeted inhibitors is limited by the development of intrinsic or acquired resistance, requiring the discovery of new compounds with different structural characteristics from those already developed. In this context, we explored the replacement of the aminoquinazoline pharmacophore of several FDA-approved EGFR inhibitors by its bioisosteric hydrazinothiazole moiety. A series of 14 new compounds were designed, synthesized, and evaluated as potential EGFR inhibitors. Compound 5i was active against 12 different cell lines in the NCI-60 cell line panel and showed an IC50 of 6.9 ± 0.013 µM against HCT-116 cells, with no significant toxicity against normal human fibroblasts (WI-38). Further studies showed that this compound showed submicromolar activity against EGFR and was able to induce tumor cell cycle arrest and cell apoptosis. Additionally, docking experiments, molecular dynamics and binding free energy calculations were performed and confirmed the potential of 2-hydrazino-2,3-dihydrothiazole derivatives as new EGFR inhibitors.

Discovery of a Novel G-Quadruplex and Histone Deacetylase (HDAC) Dual-Targeting Agent for the Treatment of Triple-Negative Breast Cancer.

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (1). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, a6 significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.

Ynamide Electrophile for the Profiling of Ligandable Carboxyl Residues in Live Cells and the Development of New Covalent Inhibitors.

Covalent inhibitors with an electrophilic warhead have received considerable attention due to their remarkable pharmacological properties. However, the electrophilic warhead in covalent drugs is often an α, β-unsaturated amide, and the targets are mainly cysteine or lysine residues. Thus, the development of novel electrophiles that can target other amino acids is highly desirable. Ynamide, a useful and versatile building block, is commonly employed in the construction of various compounds in organic synthesis. The performance of this functional group in a proteome-wide environment has been studied here for the first time, and it has been shown that it can efficiently modify carboxyl residues in situ and in vitro. Upon incorporation of this ynamide warhead into the pharmacophores of kinase inhibitors, the resulting compound showed moderate inhibition against the EGFR L858R mutant but not against EGFR WT. This novel electrophilic group can be used in the development of new types of covalent inhibitors.

Accommodation of ring C expanded deoxyvasicinone in the HDAC inhibitory pharmacophore culminates into a tractable anti-lung cancer agent and pH-responsive nanocarrier

A fragment recruitment process was conducted to pinpoint a suitable fragment for installation in the HDAC inhibitory template to furnish agents endowed with the potential to treat lung cancer. Resultantly, Ring C expanded deoxyvasicinone was selected as an appropriate surface recognition part that was accommodated in the HDAC three-component model. Delightfully, fused quinazolinone 6 demonstrating a magnificent anticancer profile against KRAS and EGFR mutant lung cancer cell lines (IC50 = 0.80–0.96 μM) was identified. Results of the mechanistic studies confirmed that the cell growth inhibitory effects of compound 6 stems for HDAC6 (IC50 = 12.9 nM), HDAC1 (IC50 = 49.9 nM) and HDAC3 inhibition (IC50 = 68.5 nM), respectively. Compound 6 also suppressed the colony formation ability of A549 cells, induced apoptosis, and increased autophagic flux. Key interactions of HDAC inhibitor 6 within the active site of HDAC isoforms were figured out through molecular modeling studies. Furthermore, a pH-responsive nanocarrier (Hyaluronic acid - fused quinazolinone 6 nanoparticles) was designed and assessed using a dialysis bag approach under both normal and acidic circumstances that confirmed the pH-sensitive nature of NPs. Delightfully, the nanoparticles demonstrated selective cell viability reduction potential towards the lung cancer cell lines (A549 lung cancer cell lines) and were found to be largely devoid of cell growth inhibitory effects under normal settings (L929, mouse fibroblast cells).

Discovery of Indole-Containing Benzamide Derivatives as HDAC1 Inhibitors with In Vitro and In Vivo Antitumor Activities

Targeting histone deacetylases (HDACs) has become an important focus in cancer inhibition. The pharmacophore of HDAC inhibitors (HDACis) reported so far is composed of three parts: a zinc-binding group (ZBG), a hydrophobic cavity-binding linker, and a surface-recognition cap interacting with HDAC surface located at the rim of active site cavity. This study aims to discover novel HDAC1 inhibitors with potent antitumor activities through modifying the cap and ZBG based on the structures of two marketed oral HDACis: chidamide and entinostat (MS-275). In this work, a series of benzamide derivatives were designed, synthesized, and evaluated for their antitumor activity. The structures of novel compounds were confirmed by 1H NMR (nuclear magnetic resonance) and ESI-MS (electrospray ionization mass spectrometry), and all target compounds were tested in both HDAC1 enzymatic inhibitory activity and cellular antiproliferative activity. Our data showed that the potent compound 3j exhibited good HDAC1 enzyme inhibitory activity and high antitumor cell proliferation activity against a selected set of cancer cells (PC-3, HCT-116, HUT-78, Jurkat E6–1, A549, Colo205, and MCF-7 cells) with no observed effects on human normal cells. In particular, compound 3j inhibited HDAC1 over the other tested HDAC isoforms (HDAC2, HDAC6, and HDAC8). Encouraged by this, the safety characteristics, molecular docking, preliminary pharmacokinetic characteristics, and antitumor effect in vivo of compound 3j were further investigated. Our data showed that compound 3j demonstrated acceptable safety profiles and favorable oral pharmacokinetic properties. Moreover, compound 3j could bind well with HDAC1 and showed significant antitumor activity in a PC-3 tumor xenograft model in vivo, though not as potent as positive control entinostat (MS-275). In summary, 3j might have therapeutic potential for the treatment of human cancers.

IDENTIFICATION OF NEW CYCLOOXYGENASE-2 SELECTIVE INHIBITORS VIA VIRTUAL SCREENING AND COMPLEX-BASED PHARMACOPHORE MAPPING

Background: New and effective COX-2-targeted medications may cure cancer, inflammation, and other disorders.It’s difficult to produce druggable site inhibitors for target protein inhibition that are strong and selective. Such medications need a more informed structure-based or ligand-based drug discovery technique. MOE was used to create asix-point COX-2 selective inhibitor pharmacophore from 43 compounds. The structure includes three aromatic rings,one hydrophobic group (Hyd), one donor (Don), and three H-bond acceptors. A pharmacophore was used to digitallyfilter the Chembridge database to locate additional structural poses that fulfilled the model’s requirements. We found2090 structurally diverse hits after filtering. Molecular docking was performed on 767 hits after Lipinski’s rule of fivedetermined druggability. Twenty compounds with high active site amino acid residue interactions and diverse scaffoldswere chosen. The first COX-2 isoform-inhibiting medicines were discovered using structure-based pharmacophores.Objectives Using complex-based pharmacophore mapping and virtual screening, this research seeks novel selectiveCOX-2 inhibitors. This involves filtering through a chemical database, defining critical interactions, maximizing hits,and extending drug development for safer and more effective inflammation and pain managemStudy design : Employing Advanced Computational And Pharmacological Approaches StudyDuration and place of study :The study was conducted at Abdul Wali Khan University Mardan from jan2017 to jan 2018Methods: The investigation used a structure-based drug discovery methodology to find novel cyclooxygenase-2 (COX-2)selective inhibitors. The COX-2 crystal structure was used to create a pharmacophore model, which was then used tovirtually search a chemical database. In order to identify potential lead compounds based on interactions with importantCOX-2 residues, binding energies were computed, and molecular docking was used to refine hits.Results: The goal of the project was to use virtual screening and complex-based pharmacophore mapping to findnovel selective COX-2 inhibitors. After the COX-2 crystal structure was used to create a pharmacophore model,2090 hits were discovered in a database. Following the druggability assessment, 767 hits were chosen for moleculardocking. Ultimately, twenty compounds were found to be promising COX-2 inhibitors due to their strong interactionswith COX-2 and variety of scaffolds.Conclusion: This study found 20 possible lead drugs that selectively block cyclooxygenase-2 (COX-2) using complex-based pharmacophore mapping and virtual screening. These substances show a variety of scaffolds and robustinteractions with COX-2, making them attractive candidates for further research and development as anti-inflammatoryand anti-cancer medications with maybe fewer adverse effects.Keywords: Cyclooxygenase-2 (COX-2),Pharmacophore mapping,Virtual screening,Drug discovery

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New 8-methyl-4-oxo-1,4-dihydroquinoline-3-carbohydrazides as Potential Anti-HIV Agents.

BackgroundThe development of a highly safe and potent scaffold is a significant challenge in anti-HIV drug discovery. ObjectivesThis study aimed at developing a novel series of anti-HIV agents based on HIV integrase inhibitor pharmacophores.MethodsA novel series of 8-methyl-4-oxo-1,4-dihydroquinoline-3-carbohydrazide derivatives featuring various substituted benzoyl and N-phenyl carboxamide and carbothioamide moieties were designed and synthesized. ResultsAccording to the biological evaluation, all the developed compounds were effective against HIV at concentrations lower than 150 µM, associated with no significant cytotoxicity (CC50 > 500 µM). ConclusionsCompound 8b, possessing a 4-fluorobenzoyl group, was the most potent compound, with an EC50 of 75 µM. Docking studies revealed that the binding modes of designed compounds are similar to the known HIV integrase inhibitors.

Chrysosporazines Revisited: Regioisomeric Phenylpropanoid Piperazine P-Glycoprotein Inhibitors from Australian Marine Fish-Derived Fungi.

A library of fungi previously recovered from the gastrointestinal tract (GIT) of several fresh, commercially sourced Australian mullet fish was re-profiled for production of a rare class of phenylpropanoid piperazine alkaloids (chrysosporazines) using an integrated platform of; (i) miniaturized 24-well plate cultivation profiling (MATRIX), (ii) UPLC-DAD and UPLC-QTOF-MS/MS (GNPS) chemical profiling, and; (iii) precursor directed biosynthesis to manipulate in situ biosynthetic performance and outputs; to detect two new fungal producers of chrysosporazines. Chemical analysis of an optimized PDA solid phase cultivation of Aspergillus sp. CMB-F661 yielded the new regioisomeric chrysosporazine T (1) and U (2), while precursor directed cultivation amplified production and yielded the very minor new natural products azachrysosporazine T1 (3) and U1 (4), and the new unnatural analogues neochrysosporazine R (5) and S (6). Likewise, chemical analysis of an optimized M1 solid phase cultivation of Spiromastix sp. CMB-F455 lead to the GNPS detection of multiple chrysosporazines and brasiliamides, and the isolation and structure elucidation of chrysosporazine D (7) and brasiliamide A (8). Access to new chrysosporazine regioisomers facilitated structure activity relationship investigations to better define the chrysosporazine P-glycoprotein (P-gp) inhibitory pharmacophore, which is exceptionally potent at reversing doxorubrin resistance in P-gp over expressing colon carcinoma cells (SW600 Ad300).

Design, Synthesis and Evaluation of Benzimidazole Hybrids to Inhibit Acetylcholinesterase and COX for Treatment of Alzheimer's Disease.

A simultaneous administration of an acetylcholinesterase (AChE) inhibitor and a NSAID as a drug cocktail has been documented to exhibit significantly protective effects in AD patients. But it suffers from poor patent compliance, pharmacodynamics and pharmacokinetic issues. The present study is aimed to design and synthesize a hybrid molecule capable of exhibiting both AChE inhibition and anti-inflammatory activities for de-accelerating the progression of AD. The synthesized molecules will be evaluated for in vitro and in vivo models. The present study involves the coupling of ibuprofen or naproxen to varied disubstituted amines (AChE inhibitor pharmacophore) through benzimidazole to develop two series of compounds i.e. IB01-IB05 and NP01-NP05. The synthesized compounds were characterized using FTIR, 1H-NMR, 13C-NMR and MS. All compounds were evaluated for in vitro AChE inhibitory and COX inhibitory activities. The most active compound was taken for in vivo evaluation. Compounds of series IB01-IB05 are found more potent as compared to NP01-NP05. The maximally potent compound IB04 in in vitro evaluation is selected for in vivo evaluation of memory restoration activity using scopolamine-induced amnesia model in mice. It significantly reverses the scopolamine-induced changes (i.e., escape latency time, mean time spent in target quadrant, brain AChE activity and oxidative stress) in a dose-dependent manner. IB04 at 8 mg/kg is significantly effective in lowering AD manifestation in comparison to donepezil. The findings indicate that Benzimidazole hybrids utilizing ibuprofen and pyrrolidine moiety may prove a useful template for the development of new chemical moieties against AD with multiple potencies.

Novel strategies for targeting the thioredoxin system for cancer therapy

ABSTRACT Introduction The thioredoxin system is increasingly recognized as an important executor for maintaining cell redox homeostasis and regulating multiple cell signaling pathways. Targeting this system for cancer treatment has therefore attracted much attention. Areas covered The authors focus on providing coverage and emphasizing the strategy of targeting the thioredoxin system to develop anticancer therapeutics in the past five years, especially from the perspective of discovering novel protein functions or new downstream regulatory pathways, and designing new therapeutic reagents. The authors also provide the readers with their expert perspectives for future development. Expert opinion The limited pharmacophore of inhibitors and the slow progress of clinical research partially restrict the development of anticancer drugs targeting the thioredoxin system, necessitating thus novel strategies to accelerate the system for treating cancer. Nevertheless, the synergistic targeting of thioredoxin system for cancer therapy is a promising strategy, particularly with regards to chemotherapy resistance and/or sensitization immunotherapy.