Targeting KRAS mutant cancers by preventing signaling transduction in the MAPK pathway.
Abstract KRAS genes are the most commonly mutated oncogenes in cancer. Unfortunately, effective therapeutic strategies for targeting KRAS mutant cancers have proven to be difficult to obtain. A key reason for this setback is due to the lack of success direct KRAS mutant inhibitors have received. Researchers have turned their efforts away from targeting the KRAS nucleotide-binding site directly and towards targeting other areas of the MAPK signaling pathway to block KRAS function. Researchers found that inhibiting enzymes and protein-protein interactions involved in the MAPK signaling pathway inhibit the activation...
Source: European Journal of Medicinal Chemistry - November 17, 2020 Category: Chemistry Authors: Korzeniecki C, Priefer R Tags: Eur J Med Chem Source Type: research

Uncompetitive nanomolar dimeric indenoindole inhibitors of the human breast cancer resistance pump ABCG2.
e M Abstract Multidrug resistance membrane pumps reduce the efficacy of chemotherapies by exporting a wide panel of structurally-divergent drugs. Here, to take advantage of the polyspecificity of the human Breast Cancer Resistance Protein (BCRP/ABCG2) and the dimeric nature of this pump, new dimeric indenoindole-based inhibitors from the monomeric α,β-unsaturated ketone 4b and phenolic derivative 5a were designed. A library of 18 homo/hetero-dimers was synthesised. Homo-dimerization shifted the inhibition efficacy from sub-micromolar to nanomolar range, correlated with the presence of 5a, linked by a 2-...
Source: European Journal of Medicinal Chemistry - November 12, 2020 Category: Chemistry Authors: Guragossian N, Belhani B, Moreno A, Nunes MT, Gonzalez-Lobato L, Marminon C, Berthier L, Rocio Andrade Pires AD, Özvegy-Laczka C, Sarkadi B, Terreux R, Bouaziz Z, Berredjem M, Jose J, Di Pietro A, Falson P, Le Borgne M Tags: Eur J Med Chem Source Type: research

Development of programmable gemcitabine-GnRH pro-drugs bearing linker controllable "click" oxime bond tethers and preclinical evaluation against prostate cancer.
Development of programmable gemcitabine-GnRH pro-drugs bearing linker controllable "click" oxime bond tethers and preclinical evaluation against prostate cancer. Eur J Med Chem. 2020 Nov 12;:113018 Authors: Vrettos EI, Karampelas T, Sayyad N, Kougioumtzi A, Syed N, Crook T, Murphy C, Tamvakopoulos C, Tzakos AG Abstract Peptide-drug conjugates (PDCs) are gaining considerable attention as anti-neoplastic agents. However, their development is often laborious and time-consuming. Herein, we have developed and preclinically evaluated three PDCs with gemcitabine as the anticancer cytotoxic unit and...
Source: European Journal of Medicinal Chemistry - November 12, 2020 Category: Chemistry Authors: Vrettos EI, Karampelas T, Sayyad N, Kougioumtzi A, Syed N, Crook T, Murphy C, Tamvakopoulos C, Tzakos AG Tags: Eur J Med Chem Source Type: research

Dispirotripiperazine-core compounds, their biological activity with a focus on broad antiviral property, and perspectives in drug design (mini-review).
Abstract Viruses are obligate intracellular parasites and have evolved to enter the host cell. To gain access they come into contact with the host cell through an initial adhesion, and some viruses from different genus may use heparan sulfate proteoglycans for it. The successful inhibition of this early event of the infection by synthetic molecules has always been an attractive target for medicinal chemists. Numerous reports have yielded insights into the function of compounds based on the dispirotripiperazine scaffold. Analysis suggests that this is a structural requirement for inhibiting the interactions between...
Source: European Journal of Medicinal Chemistry - November 12, 2020 Category: Chemistry Authors: Egorova A, Bogner E, Novoselova E, Zorn KM, Ekins S, Makarov V Tags: Eur J Med Chem Source Type: research

Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment.
In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-α release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Ove...
Source: European Journal of Medicinal Chemistry - November 7, 2020 Category: Chemistry Authors: Zhang R, Li H, Zhang X, Li J, Su H, Lu Q, Dong G, Dou H, Fan C, Gu Z, Mu Q, Tang W, Xu Y, Liu H Tags: Eur J Med Chem Source Type: research

Novel quinolone-based potent and selective HDAC6 inhibitors: Synthesis, molecular modeling studies and biological investigation.
Abstract In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products was performed by employing computational studies which led to the discovery of the diethylaminomethyl derivatives 7g and 7k as the most promising hit molecules. These compounds were investigated in cellular studies to evaluate their anticancer effect against colon...
Source: European Journal of Medicinal Chemistry - November 7, 2020 Category: Chemistry Authors: Relitti N, Saraswati AP, Chemi G, Brindisi M, Brogi S, Herp D, Schmidtkunz K, Saccoccia F, Ruberti G, Ulivieri C, Vanni F, Sarno F, Altucci L, Lamponi S, Jung M, Gemma S, Butini S, Campiani G Tags: Eur J Med Chem Source Type: research

Discovery and optimization of novel pyrazole-benzimidazole CPL304110, as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1-3).
rek M Abstract The FGFR family is characterized by four receptors (FGFR 1-4), binding to 18 ligands called fibroblast growth factors (FGFs). Aberrant activation of FGFs and their FGFRs has been implicated in a broad spectrum of human tumors. We employed the scaffolds hybridization approach, scaffold-hopping concept to synthesize a series of novel pyrazole-benzimidazole derivatives 56 (a-x). Compound 56q (CPL304110) was identified as a selective and potent pan-FGFR inhibitor for FGFR1, -2, -3 with IC50s of 0.75 nM, 0.50 nM, 3.05 nM respectively, whereas IC50 of 87.90 nM for FGFR4. Due to its fav...
Source: European Journal of Medicinal Chemistry - November 7, 2020 Category: Chemistry Authors: Yamani A, Zdżalik-Bielecka D, Lipner J, Stańczak A, Piórkowska N, Stańczak PS, Olejkowska P, Hucz-Kalitowska J, Magdycz M, Dzwonek K, Dubiel K, Lamparska-Przybysz M, Popiel D, Pieczykolan J, Wieczorek M Tags: Eur J Med Chem Source Type: research

Insight into the binding mode of HIF-2 agonists through molecular dynamic simulations and biological validation.
This study provides deep insight into the binding mode of such HIF-2 agonists, which would be useful for designing novel agonists for HIF-2. PMID: 33189439 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - November 7, 2020 Category: Chemistry Authors: Yu Y, Yu Q, Liu S, Wu C, Zhang X Tags: Eur J Med Chem Source Type: research

ROS-responsive and multifunctional anti-Alzheimer prodrugs: Tacrine-ibuprofen hybrids via a phenyl boronate linker.
Abstract Current drugs available in clinic for Alzheimer's disease (AD) treatment can only alleviate disease symptoms without clearly curing or delaying the process of AD. And some AD drugs failed in Phase III clinical trials are only focused on targeting amyloid-β (Aβ). Therefore, an alternative strategy in AD drug design is meaningful to be involved in the multiple pathogenic factors which can affect each other at multiple levels. Herein, we report a series of ROS-responsive prodrugs based on multi-target-directed ligands (MTDLs) approach, which can specifically release tacrine derivatives and ibuprofe...
Source: European Journal of Medicinal Chemistry - November 6, 2020 Category: Chemistry Authors: Liu Z, Zhang B, Xia S, Fang L, Gou S Tags: Eur J Med Chem Source Type: research

Synthesis and evaluation of new quinazoline-benzimidazole hybrids as potent anti-microbial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis.
Abstract Owing to the rapid rise in antibiotic resistance, infectious diseases have become serious threat to public health. There is an urgent need to develop new antimicrobial agents with diverse chemical structures and novel mechanisms of action to overcome the resistance. In recent years, Quinazoline-benzimidazole hybrids have emerged as a new class of antimicrobial agents active against S. aureus and M. tuberculosis. In the current study, we designed and synthesized fifteen new Quinazoline-benzimidazole hybrids and evaluated them for their antimicrobial activity against S. aureus ATCC 29213 and ...
Source: European Journal of Medicinal Chemistry - November 6, 2020 Category: Chemistry Authors: Malasala S, Ahmad MN, Akunuri R, Shukla M, Kaul G, Dasgupta A, Madhavi YV, Chopra S, Nanduri S Tags: Eur J Med Chem Source Type: research

Novel naphthylamide derivatives as dual-target antifungal inhibitors: Design, synthesis and biological evaluation.
Abstract Fungal infections have become a serious medical problem due to the high infection rate and the frequent emergence of drug resistance. Squalene epoxidase (SE) and 14α-demethylase (CYP51) are considered as the important antifungal targets, they can show the synergistic effect on antifungal therapy. In the study, a series of active fragments were screened through the method of De Novo Link, and these active fragments with the higher Ludi_Scores were selected, which can show the obvious binding ability with the dual targets (SE, CYP51). Subsequently, three series of target compounds with naphthyl amide ...
Source: European Journal of Medicinal Chemistry - November 5, 2020 Category: Chemistry Authors: An Y, Dong Y, Liu M, Han J, Zhao L, Sun B Tags: Eur J Med Chem Source Type: research

PROTACs to address the challenges facing small molecule inhibitors.
iao X Abstract Small molecule inhibitors of proteins represent important medicines and critical chemical tools to investigate the biology of the target proteins. Advances in various -omics technologies have fueled the pace of discovery of disease-relevant proteins. Translating these discoveries into human benefits requires us to develop specific chemicals to inhibit the proteins. However, traditional small molecule inhibitors binding to orthosteric or allosteric sites face significant challenges. These challenges include drug selectivity, therapy resistance as well as drugging undruggable proteins and multi-domain...
Source: European Journal of Medicinal Chemistry - November 5, 2020 Category: Chemistry Authors: Martín-Acosta P, Xiao X Tags: Eur J Med Chem Source Type: research

2-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives: Simplification and modification of aconitine scaffold for the discovery of novel anticancer agents.
In this study, we designed and synthesized a series of 2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC50 value of 0.02 μM and a significant Hsp90α inhibitory activity with an IC50 value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycl...
Source: European Journal of Medicinal Chemistry - November 5, 2020 Category: Chemistry Authors: Zhang Y, Zhang TJ, Li XY, Liang JW, Tu S, Xu HL, Xue WH, Qian XH, Zhang ZH, Zhang X, Meng FH Tags: Eur J Med Chem Source Type: research

How to determine the mechanism of action of CFTR modulator compounds: A gateway to theranostics.
In conclusion, the most powerful approach to determine the MoA of a compound is to understand the underlying biology. Novel large datasets of intervenients in most biological processes, namely those emerging from the post-genomic era tools, are available and should be used to help in this task. PMID: 33190956 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - November 5, 2020 Category: Chemistry Authors: Amaral MD Tags: Eur J Med Chem Source Type: research

Design, synthesis and evaluation of calix[4]arene-based carbonyl amide derivatives with antitumor activities.
Abstract Calixarenes, with potential functionalization on the upper and lower rim, have been explored in recent years for the design and construction of anticancer agents in the field of drugs and pharmaceuticals. Herein, optimization of bis [N-(2-hydroxyethyl) aminocarbonylmethoxyl substituted calix [4] arene (CLX-4) using structure-based drug design and traditional medicinal chemistry led to the discovery of series of calix [4]arene carbonyl amide derivatives 5a-5t. Evaluation of the cytotoxicity of 5a-5t employing MTT assay in MCF-7, MDA-MB-231 (human breast cancer cells), HT29 (human colon carcinoma cells), He...
Source: European Journal of Medicinal Chemistry - November 4, 2020 Category: Chemistry Authors: An L, Wang C, Zheng YG, Liu JD, Huang TH Tags: Eur J Med Chem Source Type: research

Exploring the ability of dihydropyrimidine-5-carboxamide and 5-benzyl-2,4-diaminopyrimidine-based analogues for the selective inhibition of L.  major dihydrofolate reductase.
Exploring the ability of dihydropyrimidine-5-carboxamide and 5-benzyl-2,4-diaminopyrimidine-based analogues for the selective inhibition of L. major dihydrofolate reductase. Eur J Med Chem. 2020 Nov 04;:112986 Authors: Bibi M, Qureshi NA, Sadiq A, Farooq U, Hassan A, Shaheen N, Asghar I, Umer D, Ullah A, Khan FA, Salman M, Bibi A, Rashid U Abstract To tackle leishmaniasis, search for efficient therapeutic drug targets should be pursued. Dihydrofolate reductase (DHFR) is considered as a key target for the treatment of leishmaniasis. In current study, we are interested in the design and synthesis o...
Source: European Journal of Medicinal Chemistry - November 4, 2020 Category: Chemistry Authors: Bibi M, Qureshi NA, Sadiq A, Farooq U, Hassan A, Shaheen N, Asghar I, Umer D, Ullah A, Khan FA, Salman M, Bibi A, Rashid U Tags: Eur J Med Chem Source Type: research

Alkylated monoterpene indole alkaloid derivatives as potent P-glycoprotein inhibitors in resistant cancer cells.
ra MU Abstract Aiming at generating a series of monoterpene indole alkaloids with enhanced multidrug resistance (MDR) reversing activity in cancer, two major epimeric alkaloids isolated from Tabernaemontana elegans, tabernaemontanine (1) and dregamine (2), were derivatized by alkylation of the indole nitrogen. Twenty-six new derivatives (3-28) were prepared by reaction with different aliphatic and aromatic halides, whose structures were elucidated mainly by NMR, including 2D NMR experiments. Their MDR reversal ability was evaluated through a functional assay, using as models resistant human colon adenocarcinoma an...
Source: European Journal of Medicinal Chemistry - November 4, 2020 Category: Chemistry Authors: Cardoso DSP, Kincses A, Nové M, Spengler G, Mulhovo S, Aires-de-Sousa J, Dos Santos DJVA, Ferreira MU Tags: Eur J Med Chem Source Type: research

Discovery and optimization of withangulatin A derivatives as novel glutaminase 1 inhibitors for the treatment of triple-negative breast cancer.
Abstract To develop novel GLS1 inhibitors as effective therapeutic agents for triple-negative breast cancer (TNBC), 25 derivatives were synthesized from the natural inhibitor withangulatin A (IC50 = 18.2 μM). Bioassay optimization identified a novel and selective GLS1 inhibitor 7 (IC50 = 1.08 μM). In MDA-MB-231 cells, 7 diminished cellular glutamate levels by blocking glutaminolysis pathway, further triggering the generation of reactive oxygen species to induce caspase-dependent apoptosis. Molecular docking indicated that 7 interacted with a new reacting site of allosteric ...
Source: European Journal of Medicinal Chemistry - November 1, 2020 Category: Chemistry Authors: Zhou WX, Chen C, Liu XQ, Li Y, Lin YL, Wu XT, Kong LY, Luo JG Tags: Eur J Med Chem Source Type: research

Therapeutic potential for coxibs-nitric oxide releasing hybrids in cystic fibrosis.
Abstract This review discusses the rational for further studies of COX-2 inhibitors-NO releaser hybrids (NO-Coxibs) in the pharmacological treatment of the airway inflammation in Cystic Fibrosis (CF). Our research group developed several classes of NO-Coxibs for the pharmacological treatment of arthritis, and among them several compounds showed an outstanding in vivo efficacy and good pharmacokinetic properties. The good antiinflammatory properties displayed by these compounds during the previous screening could, by itself, suggest appropriate candidates for further testing in CF. PMID: 33168231 [PubMed ...
Source: European Journal of Medicinal Chemistry - October 31, 2020 Category: Chemistry Authors: Consalvi S, Poce G, Ghelardini C, Di Cesare Mannelli L, Patrignani P, Bruno A, Anzini M, Calderone V, Martelli A, Testai L, Giordani A, Biava M Tags: Eur J Med Chem Source Type: research

Deep learning enables discovery of highly potent anti-osteoporosis natural products.
Abstract A pre-trained self-attentive message passing neural network (P-SAMPNN) model was developed based on our anti-osteoclastogenesis dataset for virtual screening purpose. Validation processes proved that P-SAMPNN model was significantly superior to the other base line models. A commercially available natural product library was virtually screened by the P-SAMPNN model and resulted in confirmed 5 hits from 10 selected virtual hits. Among the confirmed hits, compounds AP-123/40765213 and AE-562/43462182 are the nanomolar inhibitors against osteoclastogenesis with a new scaffold. Further studies indicate that AP...
Source: European Journal of Medicinal Chemistry - October 31, 2020 Category: Chemistry Authors: Liu Z, Huang D, Zheng S, Song Y, Liu B, Sun J, Niu Z, Gu Q, Xu J, Xie L Tags: Eur J Med Chem Source Type: research

Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges.
Abstract Proteolysis targeting chimera (PROTAC), hijacking protein of interest (POI) and recruiting E3 ligase for target degradation via the ubiquitin-proteasome pathway, is a novel drug discovery paradigm which has been widely used as biological tools and medicinal molecules with the potential of clinical application value. Currently, ARV-110, an orally small molecule PROTAC was designed to specifically target Androgen receptor (AR), firstly enters clinical phase I trials for the treatment of metastatic castration-resistant prostate cancer, which turns a new avenue for the development of PROTAC. We herein provide...
Source: European Journal of Medicinal Chemistry - October 31, 2020 Category: Chemistry Authors: Zeng S, Huang W, Zheng X, Liyan Cheng, Zhang Z, Wang J, Shen Z Tags: Eur J Med Chem Source Type: research

Recent research progress of Uncaria spp. based on alkaloids: phytochemistry, pharmacology and structural chemistry.
Abstract Medicinal plants are well-known in affording clinically useful agents, with rich medicinal values by combining with disease targets through various mechanisms. Plant secondary metabolites as lead compounds lay the foundation for the discovery and development of new drugs in disease treatment. Genus Uncaria from Rubiaceae family is a significant plant source of active alkaloids, with anti-hypertensive, sedative, anti-Alzheimer's disease, anti-drug addiction and anti-inflammatory effects. This review summarizes and discuss the research progress of Uncaria based on alkaloids in the past 15 years, mainly in t...
Source: European Journal of Medicinal Chemistry - October 31, 2020 Category: Chemistry Authors: Qin N, Lu X, Liu Y, Qiao Y, Qu W, Feng F, Sun H Tags: Eur J Med Chem Source Type: research

2-Aminothiazole: A privileged scaffold for the discovery of anti-cancer agents.
Abstract Cancer has been the second heath killer being next only to cardiovascular diseases in human society. Although many efforts have been taken for cancer therapy and many achievements have been yielded in the diagnosis and treatment of cancer, the current first-line anti-cancer agents are insufficient owing to the emergence of multi-drug resistance and side effects. Therefore, it is urgent to develop new anti-cancer agents with high activity and low toxicity. 2-Aminothiazole is a class of important scaffold which widely distributes in many natural and synthetic compounds with many pharmacological effects incl...
Source: European Journal of Medicinal Chemistry - October 29, 2020 Category: Chemistry Authors: Wan Y, Long J, Gao H, Tang Z Tags: Eur J Med Chem Source Type: research

Preparation of new 1,3-dibenzyl tetrahydropyridinylidene ammonium salts and their antimicrobial and anticellular activities.
Weis R Abstract New 1,3 dibenzyl -tetrahydropyridinylidene ammonium salts have been prepared from unsubstituted or N-benzylated tetrahydropyridinylidene ammonium salts. The antiplasmodial and antitrypanosomal activities as well as their cytotoxic effects were determined using microplate assays. In addition, their activities against two gram positive and two gram negative bacteria strains and a yeast strain were examined. Furthermore, anticancer effects against two cell lines were investigated. Physicochemical parameters were calculated and structure-activity-relationships discussed. One compound showed antip...
Source: European Journal of Medicinal Chemistry - October 29, 2020 Category: Chemistry Authors: Petritsch M, Seebacher W, Mohsin NU, Dolensky J, Hochegger P, Kaiser M, Mäser P, Belaj F, Saf R, Kretschmer N, Alajlani M, Brantner A, Bauer R, Schühly W, Weis R Tags: Eur J Med Chem Source Type: research

Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosis.
Martinez A Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Aggregates of the nuclear protein TDP-43 have been recognized as a hallmark of proteinopathy in both familial and sporadic cases of ALS. Post-translational modifications of this protein, include hyperphosphorylation, cause disruption of TDP-43 homeostasis and as a consequence, promotion of its neurotoxicity. Among the kinases involved in these changes, cell division cycle kinase 7 (CDC7) plays an important role by directly phosphorylating TDP-43. In the present manuscript the discovery, synthesis, and ...
Source: European Journal of Medicinal Chemistry - October 28, 2020 Category: Chemistry Authors: Rojas-Prats E, Martinez-Gonzalez L, Gonzalo-Consuegra C, Liachko NF, Perez C, Ramírez D, Kraemer BC, Martin-Requero Á, Perez DI, Gil C, de Lago E, Martinez A Tags: Eur J Med Chem Source Type: research

Di-aryl guanidinium derivatives: Towards improved α2-Adrenergic affinity and antagonist activity.
Di-aryl guanidinium derivatives: Towards improved α2-Adrenergic affinity and antagonist activity. Eur J Med Chem. 2020 Oct 24;:112947 Authors: McMullan M, Kelly B, Mihigo HB, Keogh AP, Rodriguez F, Brocos-Mosquera I, García-Bea A, Miranda-Azpiazu P, Callado LF, Rozas I Abstract Compounds with excellent receptor engagement displaying α2-AR antagonist activity are useful not only for therapeutic purposes (e.g. antidepressants), but also to help in the crystallization of this particular GPCR. Therefore, based on our broad experience in the topic, we have prepared eighteen di-aryl (phen...
Source: European Journal of Medicinal Chemistry - October 24, 2020 Category: Chemistry Authors: McMullan M, Kelly B, Mihigo HB, Keogh AP, Rodriguez F, Brocos-Mosquera I, García-Bea A, Miranda-Azpiazu P, Callado LF, Rozas I Tags: Eur J Med Chem Source Type: research

Potent antiproliferative activity of bradykinin B2 receptor selective agonist FR-190997 and analogue structures thereof: A paradox resolved?
Abstract Βradykinin stimulation of B2 receptor is known to activate the oncogenic ERK pathway and overexpression of bradykinin receptors B1 and B2 has been reported to occur in glioma, colorectal and cervical cancers. B1R and B2R antagonists have been shown to reverse tumor proliferation and invasion. Paradoxically, B1R and B2R agonism has also been reported to elicit antiproliferative benefits. In order to complement the data accumulated to date with the natural substrate bradykinin and peptidic B2R antagonists, we decided to examine for the first time the response elicited by B2R stimulation in breast cance...
Source: European Journal of Medicinal Chemistry - October 23, 2020 Category: Chemistry Authors: Rassias G, Leonardi S, Rigopoulou D, Vachlioti E, Afratis K, Piperigkou Z, Koutsakis C, Karamanos NK, Gavras H, Papaioannou D Tags: Eur J Med Chem Source Type: research

Structure-activity relationship (SAR) studies of N-(3-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (SRI-22819) as NF- ҡB activators for the treatment of ALS.
Structure-activity relationship (SAR) studies of N-(3-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (SRI-22819) as NF-ҡB activators for the treatment of ALS. Eur J Med Chem. 2020 Oct 22;:112952 Authors: Mathew B, Ruiz P, Dutta S, Entrekin JT, Zhang S, Patel KD, Simmons MS, Augelli-Szafran CE, Cowell RM, Suto MJ Abstract ALS is a rare type of progressive neurological disease with unknown etiology. It results in the gradual degeneration and death of motor neurons responsible for controlling the voluntary muscles. Identification of mutations in the superoxide dismutase (SOD) 1 gene has been the mo...
Source: European Journal of Medicinal Chemistry - October 22, 2020 Category: Chemistry Authors: Mathew B, Ruiz P, Dutta S, Entrekin JT, Zhang S, Patel KD, Simmons MS, Augelli-Szafran CE, Cowell RM, Suto MJ Tags: Eur J Med Chem Source Type: research

An insight into the recent development of the clinical candidates for the treatment of malaria and their target proteins.
Abstract Malaria is an endemic disease, prevalent in tropical and subtropical regions which cost half of million deaths annually. The eradication of malaria is one of the global health priority nevertheless, current therapeutic efforts seem to be insufficient due to the emergence of drug resistance towards most of the available drugs, even first-line treatment ACT, unavailability of the vaccine, and lack of drugs with a new mechanism of action. Intensification of antimalarial research in recent years has resulted into the development of single dose multistage therapeutic agents which has advantage of overcoming th...
Source: European Journal of Medicinal Chemistry - October 22, 2020 Category: Chemistry Authors: Madhav H, Hoda N Tags: Eur J Med Chem Source Type: research

Design, synthesis and bioevaluation of inhibitors targeting HSP90-CDC37 protein-protein interaction based on a hydrophobic core.
Abstract HSP90-CDC37 protein-protein interaction (PPI) works as a kinase specific-molecular chaperone system to regulate the maturation of kinases. Currently, selectively disrupting HSP90-CDC37 PPI, rather than the direct inhibition of the ATPase function of HSP90, is emerging as a promising strategy for cancer therapy by specifically blocking the maturation of kinases. However, due to the limited understanding of HSP90-CDC37 binding interface, design of small molecule inhibitors targeting HSP90-CDC37 PPI is challenging. In this work, based on the binding mode of compound 11 (previously reported by our group), we ...
Source: European Journal of Medicinal Chemistry - October 22, 2020 Category: Chemistry Authors: Zhang Q, Wu X, Zhou J, Zhang L, Xu X, Zhang L, You Q, Wang L Tags: Eur J Med Chem Source Type: research

Design, synthesis, biological activity evaluation of 3-(4-phenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives as potent JAK 2/3 and aurora A/B kinases multi-targeted inhibitors.
In this study, a series of 3-(4-phenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives were designed, synthesized, and evaluated for their biological activities. Upon performing kinase assays, most of the compounds exhibited potent inhibition against JAK2/3 and Aurora A/B with the IC50 values ranging from 0.008 to 2.52 μM. Among these derivatives, compound 10e expressed the most moderate inhibiting activities against all the four kinases with the IC50 values of 0.166 μM (JAK2), 0.057 μM (JAK3), 0.939 μM (Aurora A), and 0.583 μM (Aurora B), respectively. Moreover, most of the derived compou...
Source: European Journal of Medicinal Chemistry - October 21, 2020 Category: Chemistry Authors: Zheng YG, Wang JA, Meng L, Pei X, Zhang L, An L, Li CL, Miao YL Tags: Eur J Med Chem Source Type: research

Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors.
Abstract In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Kα inhibitor (IC50 = 5.9 nM, β/α, δ/α,γ/α = 101-, 13-, 38-fold). Western blot analysis confirmed that compound 37 could inhibit phosphorylation of AKT in human cancer cells to modulate the cellular PI3K/AKT/mTOR pathway. And furthe...
Source: European Journal of Medicinal Chemistry - October 21, 2020 Category: Chemistry Authors: Xiang HY, Wang X, Chen YH, Zhang X, Tan C, Wang Y, Su Y, Gao ZW, Chen XY, Xiong B, Gao ZB, Chen Y, Ding J, Meng LH, Yang CH Tags: Eur J Med Chem Source Type: research

Corrigendum to "From irreversible to reversible covalent inhibitors: Harnessing the andrographolide scaffold for anti-inflammatory action" [Eur. J. Med. Chem. 204 (2020) 112481].
Corrigendum to "From irreversible to reversible covalent inhibitors: Harnessing the andrographolide scaffold for anti-inflammatory action" [Eur. J. Med. Chem. 204 (2020) 112481]. Eur J Med Chem. 2020 Oct 20;:112943 Authors: Tran QTN, Tan DWS, Wong WSF, Chai CLL PMID: 33097302 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - October 20, 2020 Category: Chemistry Authors: Tran QTN, Tan DWS, Wong WSF, Chai CLL Tags: Eur J Med Chem Source Type: research

PROTACs suppression of GSK-3 β, a crucial kinase in neurodegenerative diseases.
In this study, a series of heterobifunctional small molecule proteolysis targeting chimera (PROTAC) were designed and synthesized based on E3 ubiquitin ligase cereblon (CRBN). Most of PROTACs displayed good inhibitory activity, with the IC50 values at the double-digits nanomolar levels and moderate protein degradation ability against GSK-3β. Western-blot data showed compound PG21 can effectively degrade GSK-3β in a dose-dependent manner, which can induce 44.2% protein degradation at 2.8 μM. Further pharmacological experiments revealed that the ability of PG21 to degrade GSK-3β is mediated by the ubiq...
Source: European Journal of Medicinal Chemistry - October 17, 2020 Category: Chemistry Authors: Jiang X, Zhou J, Wang Y, Liu X, Xu K, Xu J, Feng F, Sun H Tags: Eur J Med Chem Source Type: research

Synthesis and identification of a novel derivative of salidroside as a selective, competitive inhibitor of monoamine oxidase B with enhanced neuroprotective properties.
Abstract Salidroside [(2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-hydroxyphenethoxy)tetrahy-dro-2H-pyran-3,4,5-triol] is an antioxidant, anti-inflammatory and neuroprotective agent, but its drug-like properties are unoptimized and its mechanism of actions is uncertain. We synthesized twenty-six novel derivatives of salidroside and examined them in CoCl2-treated PC12 cells using MTT assay. pOBz, synthesized by esterifying the phenolic hydroxyl group of salidroside with benzoyl chloride, was one of five derivatives that were more cytoprotective than salidroside, with an EC50 of 0.038 μM versus 0.30 &mu...
Source: European Journal of Medicinal Chemistry - October 15, 2020 Category: Chemistry Authors: Yang Z, Huang X, Lai W, Tang Y, Liu J, Wang Y, Chu K, Brown J, Hong G Tags: Eur J Med Chem Source Type: research

An update into the medicinal chemistry of translocator protein (TSPO) ligands.
Abstract The Translocator Protein 18 kDa (TSPO) has been discovered in 1977 as an alternative binding site for the benzodiazepine diazepam. It is an evolutionary well-conserved and tryptophan-rich 169-amino acids protein with five alpha helical transmembrane domains stretching the outer mitochondrial membrane, with the carboxyl-terminus in the cytosol and a short amino-terminus in the intermembrane space of mitochondrion. At this level, together with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocase (ANT), it forms the mitochondrial permeability transition pore (MPTP). TSPO exp...
Source: European Journal of Medicinal Chemistry - October 14, 2020 Category: Chemistry Authors: Barresi E, Robello M, Costa B, Da Pozzo E, Baglini E, Salerno S, Da Settimo F, Martini C, Taliani S Tags: Eur J Med Chem Source Type: research

Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes.
This study provides support for selective HDAC/BRD4 dual inhibitors as epigenetic probes based on pyrrolopyridone core for the future biological evaluation in different cancer cell lines. PMID: 33077265 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - October 13, 2020 Category: Chemistry Authors: Chen J, Li Y, Zhang J, Zhang M, Wei A, Liu H, Xie Z, Ren W, Duan W, Zhang Z, Shen A, Hu Y Tags: Eur J Med Chem Source Type: research

Lipolytic enzymes inhibitors: A new way for antibacterial drugs discovery.
Abstract Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains the deadliest infectious disease worldwide with 1.5 million deaths in 2018, of which about 15% are attributed to resistant strains. Another significant example is Mycobacterium abscessus (M. abscessus), a nontuberculous mycobacteria (NTM) responsible for cutaneous and pulmonary infections, representing up to 95% of NTM infections in cystic fibrosis (CF) patients. M. abscessus is a new clinically relevant pathogen and is considered one of the most drug-resistant mycobacteria for which standardized chemotherapeutic r...
Source: European Journal of Medicinal Chemistry - October 12, 2020 Category: Chemistry Authors: Cavalier JF, Spilling CD, Durand T, Camoin L, Canaan S Tags: Eur J Med Chem Source Type: research

Non-invasive intranasal administration route directly to the brain using dendrimer nanoplatforms: An opportunity to develop new CNS drugs.
Abstract There are several routes of administration to the brain, including intraparenchymal, intraventricular, and subarachnoid injections. The blood-brain barrier (BBB) impedes the permeation and access of most drugs to the central nervous system (CNS), and consequently, many neurological diseases remain undertreated. For past decades, to circumvent this effect, several nanocarriers have been developed to deliver drugs to the brain. Importantly, intranasal (IN) administration can allow direct delivery of drugs into the brain through the anatomical connection between the nasal cavity and brain without crossing th...
Source: European Journal of Medicinal Chemistry - October 11, 2020 Category: Chemistry Authors: Mignani S, Shi X, Karpus A, Majoral JP Tags: Eur J Med Chem Source Type: research

Design, synthesis, and evaluation of substituted 2-acylamide-1,3-benzo[d]zole analogues as agents against MDR- and XDR-MTB.
In this study, a series of substituted 2-acylamide-1,3-zole analogues were designed and synthesized, and their anti-Mtb activities were analyzed. In total, 17 compounds were found to be potent anti-Mtb agents, especially against the MDR- and XDR-MTB strains, with MIC values 
Source: European Journal of Medicinal Chemistry - October 10, 2020 Category: Chemistry Authors: Li D, Liu C, Jiang X, Lin Y, Zhang J, Li Y, You X, Jiang W, Chen M, Xu Y, Si S Tags: Eur J Med Chem Source Type: research

SP1-independent inhibition of FOXM1 by modified thiazolidinediones.
artínez CA Abstract This research article describes an approach to modify the thiazolidinedione scaffold to produce test drugs capable of binding to, and inhibit, the in vitro transcriptional activity of the oncogenic protein FOXM1. This approach allowed us to obtain FOXM1 inhibitors that bind directly to the FOXM1-DNA binding domain without targeting the expression levels of Sp1, an upstream transcription factor protein known to activate the expression of FOXM1. Briefly, we modified the chemical structure of the thiazolidinedione scaffold present in anti-diabetic medications such as pioglitazone, rosi...
Source: European Journal of Medicinal Chemistry - October 10, 2020 Category: Chemistry Authors: Tabatabaei Dakhili SA, Pérez DJ, Gopal K, Haque M, Ussher JR, Kashfi K, Velázquez-Martínez CA Tags: Eur J Med Chem Source Type: research

Synthesis and evaluation of new compounds bearing 3-(4-aminopiperidin-1-yl)methyl magnolol scaffold as anticancer agents for the treatment of non-small cell lung cancer via targeting autophagy.
Abstract Magnolol and honokiol are the two major active ingredients with similar structure and anticancer activity from traditional Chinese medicine Magnolia officinalis, and honokiol is now in a phase I clinical trial (CTR20170822) for advanced non-small cell lung cancer (NSCLC). In search of potent lead compounds with better activity, our previous study has demonstrated that magnolol derivative C2, 3-(4-aminopiperidin-1-yl)methyl magnolol, has better activity than honokiol. Here, based on the core of 3-(4-aminopiperidin-1-yl)methyl magnolol, we synthesized fifty-one magnolol derivatives. Among them, compound 30 ...
Source: European Journal of Medicinal Chemistry - October 10, 2020 Category: Chemistry Authors: Zhao M, Zheng YH, Zhao QY, Zheng W, Yang JH, Pei HY, Liu L, Liu KJ, Xue LL, Deng DX, Wang L, Ma X, Fu SH, Peng AH, Tang MH, Luo YZ, Ye HY, Chen LJ Tags: Eur J Med Chem Source Type: research

Thymosin alpha 1 exerts beneficial extrapulmonary effects in cystic fibrosis.
Abstract Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding for the ion channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Long considered a lung disease for the devastating impact on the respiratory function, the recent diagnostic and therapeutic advances have shed the light on the extra-pulmonary manifestations of CF, including gastrointestinal, hepatobiliary and pancreatic symptoms. We have previously demonstrated that thymosin alpha1 (Tα1), a naturally occurring immunomodulatory peptide, displays multi-sided beneficial effects in CF that conc...
Source: European Journal of Medicinal Chemistry - October 9, 2020 Category: Chemistry Authors: Bellet MM, Borghi M, Pariano M, Renga G, Stincardini C, D'Onofrio F, Brancorsini S, Garaci E, Costantini C, Romani L Tags: Eur J Med Chem Source Type: research

Design, synthesis and biological assessment of new selective COX-2 inhibitors including methyl sulfonyl moiety.
aplancıklı ZA Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spec...
Source: European Journal of Medicinal Chemistry - October 9, 2020 Category: Chemistry Authors: Sağlık BN, Osmaniye D, Levent S, Çevik UA, Çavuşoğlu BK, Özkay Y, Kaplancıklı ZA Tags: Eur J Med Chem Source Type: research

Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity.
bri M Abstract Structurally diverse heterotricyclic compounds are recognized as monoamine oxidase (MAO) inhibitors and thus represent an appealing scaffold in development and optimization of novel MAO inhibitors. Herein we explored the chemical space of pyrimido[1,2-b]indazoles as MAO inhibitors by preparing a small library of (hetero)aryl derivatives. An efficient synthetic strategy was developed starting from commercially available 1H-indazol-3-amines, which were converted to various 3-bromoheterotricyclic derivatives and further functionalized via Suzuki-Miyaura coupling reaction. Derivatives 4a-t selectively i...
Source: European Journal of Medicinal Chemistry - October 8, 2020 Category: Chemistry Authors: Jismy B, El Qami A, Pišlar A, Frlan R, Kos J, Gobec S, Knez D, Abarbri M Tags: Eur J Med Chem Source Type: research

Cytotoxic triterpenoid-safirinium conjugates target the endoplasmic reticulum.
Abstract Safirinium P and Q fluorescence labels were synthesized and conjugated with spacered triterpenoic acids to access hybrid structures. While the parent safirinium compounds were not cytotoxic at all, many triterpenoid safirinium P and Q conjugates showed moderate cytotoxicity. An exception, however, was safirinium P derived compound 30 holding low EC50 = 5.4 μM (for A375 cells) to EC50 = 7.5 μM (for FaDu cells) as well as EC50 = 6.6 μM for non-malignant fibroblasts NIH 3T3. Fluorescence imaging showed that the safirinium core structures cannot enter...
Source: European Journal of Medicinal Chemistry - October 8, 2020 Category: Chemistry Authors: Kraft O, Kozubek M, Hoenke S, Serbian I, Major D, Csuk R Tags: Eur J Med Chem Source Type: research

Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.
Abstract An interesting enzyme of the endocannabinoid system is monoacylglycerol lipase (MAGL). This enzyme, which metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG), has attracted great interest due to its involvement in several physiological and pathological processes, such as cancer progression. Experimental evidences highlighted some drawbacks associated with the use of irreversible MAGL inhibitors in vivo, therefore the research field concerning reversible inhibitors is rapidly growing. In the present manuscript, the class of benzoylpiperidine-based MAGL inhibitors was further expanded and opt...
Source: European Journal of Medicinal Chemistry - October 7, 2020 Category: Chemistry Authors: Granchi C, Bononi G, Ferrisi R, Gori E, Mantini G, Glasmacher S, Poli G, Palazzolo S, Caligiuri I, Rizzolio F, Canzonieri V, Perin T, Gertsch J, Sodi A, Giovannetti E, Macchia M, Minutolo F, Tuccinardi T, Chicca A Tags: Eur J Med Chem Source Type: research

Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator.
Abstract Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the disc...
Source: European Journal of Medicinal Chemistry - October 7, 2020 Category: Chemistry Authors: Luo G, Lin X, Li Z, Xiao M, Li X, Zhang D, Xiang H Tags: Eur J Med Chem Source Type: research

Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σ2R/TMEM97 ligands.
Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σ2R/TMEM97 ligands. Eur J Med Chem. 2020 Oct 07;209:112906 Authors: Xie XY, Li YY, Ma WH, Chen AF, Sun YT, Lee JY, Riad A, Xu DH, Mach RH, Huang YS Abstract Sigma-2 receptor (σ2R/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective σ2 ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of ...
Source: European Journal of Medicinal Chemistry - October 7, 2020 Category: Chemistry Authors: Xie XY, Li YY, Ma WH, Chen AF, Sun YT, Lee JY, Riad A, Xu DH, Mach RH, Huang YS Tags: Eur J Med Chem Source Type: research

Protease activated receptor 4 (PAR4) antagonists: Research progress on small molecules in the field of antiplatelet agents.
This article provides an overview of the discovery and development of small-molecule antagonists of PAR4 as novel antiplatelet agents, including structure-activity relationship (SAR) analysis, progress of structure and bioassay optimization, and the latest structural and/or clinical information of representative small-molecule antagonists of PAR4. PMID: 33049608 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - October 7, 2020 Category: Chemistry Authors: Liu S, Li S, Yuan D, Wang E, Xie R, Zhang W, Kong Y, Zhu X Tags: Eur J Med Chem Source Type: research