Retraction notice to "Design, synthesis, and biological evaluation of heterotetracyclic quinolinone derivatives as anticancer agents targeting topoisomerases" [Eur. J. Med. Chem. 190 (2020) 112074].
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors. The authors regret to inform that they would like to withdraw this accepted article, due to serious errors in authorship, affiliations, material sources and supporting grant names/numbers. The authors sincerely apologize for these oversights and miscommunications the study caused. PMID: 32546328 [PubMed - in process] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - June 18, 2020 Category: Chemistry Authors: Lee JF, Chang TY, Liu ZF, Lee NZ, Yeh YH, Chen YS, Chen TC, Chou HS, Li TK, Lee SB, Lin MH Tags: Eur J Med Chem Source Type: research

Corrigendum to"Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in  vitro and in vivo"[Eur. J. Med. Chem. 190 (2020 Mar 15) 112086].
Corrigendum to"Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in vitro and in vivo"[Eur. J. Med. Chem. 190 (2020 Mar 15) 112086]. Eur J Med Chem. 2020 Jun 08;201:112404 Authors: Ojha R, Nepali K, Chen CH, Chuang KH, Wu TY, Lin TE, Hsu KC, Chao MW, Lai MJ, Lin MH, Huang HL, Chang CD, Pan SL, Chen MC, Liou JP PMID: 32526554 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Ojha R, Nepali K, Chen CH, Chuang KH, Wu TY, Lin TE, Hsu KC, Chao MW, Lai MJ, Lin MH, Huang HL, Chang CD, Pan SL, Chen MC, Liou JP Tags: Eur J Med Chem Source Type: research

Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors.
ini O Abstract Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaf...
Source: European Journal of Medicinal Chemistry - June 5, 2020 Category: Chemistry Authors: Nizi MG, Desantis J, Nakatani Y, Massari S, Mazzarella MA, Shetye G, Sabatini S, Barreca ML, Manfroni G, Felicetti T, Rushton-Green R, Hards K, Latacz G, Satała G, Bojarski AJ, Cecchetti V, Kolář MH, Handzlik J, Cook GM, Franzblau SG, Tabarrini O Tags: Eur J Med Chem Source Type: research

Corrigendum to "Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors" [Eur. J. Med. Chem. 197 (2020) 112308].
Corrigendum to "Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors" [Eur. J. Med. Chem. 197 (2020) 112308]. Eur J Med Chem. 2020 Jun 05;200:112464 Authors: Shuai W, Li X, Li W, Xu F, Lu L, Yao H, Yang L, Zhu H, Xu S, Zhu Z, Xu J PMID: 32512484 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - June 5, 2020 Category: Chemistry Authors: Shuai W, Li X, Li W, Xu F, Lu L, Yao H, Yang L, Zhu H, Xu S, Zhu Z, Xu J Tags: Eur J Med Chem Source Type: research

Discovery of AdipoRon analogues as novel AMPK activators without inhibiting mitochondrial complex I.
Abstract Activation of AMPK emerges as a potential therapeutic approach to metabolic diseases. AdipoRon is claimed to be an adiponectin receptor agonist that activates AMPK through adiponectin receptor 1 (AdipoR1). However, AdipoRon also exhibits moderate inhibition of mitochondrial complex I, leading to increased risk of lactic acidosis. In order to find novel AdipoRon analogues that activate AMPK without inhibition of complex I, 27 analogues of AdipoRon were designed, synthesized and biologically evaluated. As results, benzyloxy arylamide B10 was identified as a potent AMPK activator without inhibition of comple...
Source: European Journal of Medicinal Chemistry - May 30, 2020 Category: Chemistry Authors: Sun G, You Y, Li H, Cheng Y, Qian M, Zhou X, Yuan H, Xu QL, Dai L, Wang P, Cheng K, Wen X, Chen C Tags: Eur J Med Chem Source Type: research

Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases.
Abstract Cancer is a multifactorial disorder involving multiplicity of interrelated signaling pathways and molecular targets. To that end, a multi-target design strategy was adopted to develop some 1,2,3-triazoles hybridized with some pharmacophoric anticancer fragments, as first-in-class simultaneous inhibitors of COX-2, 15-LOX and tumor associated carbonic anhydrase enzymes. Results revealed that compounds 5a, 5d, 8b and 8c were potent inhibitors of COX-2 and 15-LOX enzymes. COX-2 inhibitory activity was further demonstrated by the inhibition of the accumulation of 6-keto-PGF1α, a metabolite of COX-2 produ...
Source: European Journal of Medicinal Chemistry - May 25, 2020 Category: Chemistry Authors: Elzahhar PA, Abd El Wahab SM, Elagawany M, Daabees H, Belal ASF, El-Yazbi AF, Eid AH, Alaaeddine R, Hegazy RR, Allam RM, Helmy MW, Bahaa Elgendy, Angeli A, El-Hawash SA, Supuran CT Tags: Eur J Med Chem Source Type: research

Design and synthesis of novel SCM-198 analogs as cardioprotective agents: Structure-activity relationship studies and biological evaluations.
In this study, 35 analogs of SCM-198 were designed, synthesized and their cardioprotective effects were evaluated. The cell viability assay on cardiomyocyte cell line H9c2 challenged with H2O2 showed that several analogs exhibited more potent cytoprotective effects than SCM-198 at 1 μM and 10 μM concentrations. LDH release level in cells treated with 1 μM 14o was comparable with cells treated with 10 μM SCM-198. Results of Bcl-2 expression and caspase-3 activation accordingly indicated higher protective activity of 14o than SCM-198. Moreover, in a mouse model of MI, the mice pretreated with ...
Source: European Journal of Medicinal Chemistry - May 21, 2020 Category: Chemistry Authors: Luo S, Xu S, Liu J, Ma F, Zhu YZ Tags: Eur J Med Chem Source Type: research

Resveratrol - A comprehensive review of recent advances in anticancer drug design and development.
Abstract Resveratrol is a natural polyphenolic stilbene isolated from various plants, foods and beverages with a broad spectrum of biological and pharmacological properties through modulating diverse targets and signaling pathways. Particularly, it has attracted a great deal of attention as a promising and multitarget anticancer agent due to its potential use in chemoprevention and chemotherapy of various tumors. However, unfavorable pharmacokinetics/pharmacodynamics profile such as poor bioavailability restricted its applications. Therefore, medicinal chemists have synthesized a lot of novel derivatives and analo...
Source: European Journal of Medicinal Chemistry - May 19, 2020 Category: Chemistry Authors: Ahmadi R, Ebrahimzadeh MA Tags: Eur J Med Chem Source Type: research

Identification of benzothiazinones containing 2-benzyl-2,7-diazaspiro[3.5]nonane moieties as new antitubercular agents.
Abstract A series of new benzothiazinone derivatives containing a symmetric 2-benzyl-2,7-diazaspiro[3.5]nonane moiety, based on the structure of LK02 discovered in our lab, were designed and synthesized. With one exception 3, all of them show excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC:
Source: European Journal of Medicinal Chemistry - May 19, 2020 Category: Chemistry Authors: Wang A, Ma C, Chai Y, Liu X, Lv K, Fu L, Wang B, Jia X, Liu M, Lu Y Tags: Eur J Med Chem Source Type: research

Novel potent antiplatelet thrombotic agent derived from biguanide for ischemic stroke.
Abstract Platelet thrombosis is the main pathogeny resulting in the low curability of ischemic stroke, a leading cause of mortality and disability worldwide. Metformin, a biguanide derivative that is the first-line oral medicine for type 2 diabetes, alleviates the severity of ischemic stroke in diabetic patients and suppresses platelet activation in experimental animal model. However, the clinical implementation of commercial biguanide analogs for stroke related to platelet thrombosis remains challenging due to its weak potency, poor pharmacokinetic characteristics and possible hypoglycemia. Here, twenty-three big...
Source: European Journal of Medicinal Chemistry - May 18, 2020 Category: Chemistry Authors: Xin G, Ming Y, Ji C, Wei Z, Li S, Morris-Natschke SL, Zhang X, Yu K, Li Y, Zhang B, Zhang J, Xing Z, He Y, Chen Z, Yang X, Niu H, Lee KH, Huang W Tags: Eur J Med Chem Source Type: research

Synthesis of 1, 2, 4-triazole benzoyl arylamine derivatives and their high antifungal activities.
Abstract Two series of novel 1, 2, 4-triazole benzoyl arylamine derivatives were prepared and screened for their activities against three pathogens of Gaeumannomyces graminis var.tritici, Sclerotinia sclerotiorum and Fusarium graminearum using the mycelium growth inhibition method in vitro. The results indicated that most of the synthesized derivatives displayed antifungal activities. Compounds 6c-d and 6f-g exhibited lower EC50s against all the three pathogens. Among of them, the compound 6g displayed the most potent antifungal activities with EC50 values of 0.01, 0.19 and 0.12 μg mL-1 respectively. ...
Source: European Journal of Medicinal Chemistry - May 16, 2020 Category: Chemistry Authors: Cheng YN, Jiang ZH, Sun LS, Su ZY, Zhang MM, Li HL Tags: Eur J Med Chem Source Type: research

Simple analogues of natural product chelerythrine: Discovery of a novel anticholinesterase 2-phenylisoquinolin-2-ium scaffold with excellent potency against acetylcholinesterase.
Abstract As simple analogues of the natural compound chelerythrine, a novel anti-cholinesterase 2-phenylisoquinolin-2-ium scaffold was designed by structure imitation. The activity evaluation led to the discovery of seven compounds with potent anti-acetylcholinesterase activity with IC50 values of ≤0.72 μM, superior to chelerythrine and standard drugs galantamine. Particularly, compound 8y showed the excellent dual acetylcholinesterase-butyrylcholinesterase inhibition activity, superior to rivastigmine, a dual cholinesterase inhibitor drug. Furthermore, the compounds displayed a competitive anti-acetylc...
Source: European Journal of Medicinal Chemistry - May 16, 2020 Category: Chemistry Authors: Zhou B, Li H, Cui Z, Li D, Geng H, Gao J, Zhou L Tags: Eur J Med Chem Source Type: research

A comprehensive description of GluN2B-selective N-methyl-D-aspartate (NMDA) receptor antagonists.
Abstract l-glutamate is an excitatory neurotransmitter in the central nervous system (CNS), which can activate ionotropic receptors (iGluRs) and metabotropic (mGluRs) receptors. N-methyl-D-aspartate (NMDA) receptor is a ligand-gated ion channel belonging to the iGluRs family. Among NMDA receptor subtypes, GluN2B subtype plays a crucial role in CNS diseases. In this review, we summarize, classify and discuss the reports on GluN2B antagonists, published from the 1990s to 2020, to provide the therapeutic potential of GluN2B antagonists on various disorders. The GluN2B antagonists are broadly classified into two categ...
Source: European Journal of Medicinal Chemistry - May 16, 2020 Category: Chemistry Authors: Liu W, Jiang X, Zu Y, Yang Y, Liu Y, Sun X, Xu Z, Ding H, Zhao Q Tags: Eur J Med Chem Source Type: research

Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity.
Abstract Specific inhibition of CDK9 is considered a promising strategy for developing effective anticancer therapeutics. However, most of the reported CDK9 inhibitors are still at an early stage of development and lack selectivity against other CDKs. Herein, we discovered coumarin derivative 30i as a potent CDK9 inhibitor with high selectivity (8300-fold over CDK7). Binding mode analysis illustrated that the substituent coumarin moiety is a critical group for CDK9 selectivity by occupying a flexible hinge/αD region, which is sterically hindered in other CDKs. Compound 30i showed excellent cellular antiproli...
Source: European Journal of Medicinal Chemistry - May 15, 2020 Category: Chemistry Authors: Xu J, Li H, Wang X, Huang J, Li S, Liu C, Dong R, Zhu G, Duan C, Jiang F, Zhang Y, Zhu Y, Zhang T, Chen Y, Tang W, Lu T Tags: Eur J Med Chem Source Type: research

Optical control of muscular nicotinic channels with azocuroniums, photoswitchable azobenzenes bearing two N-methyl-N-carbocyclic quaternary ammonium groups.
ríguez-Franco MI Abstract By linking two N-methyl-N-carbocyclic quaternary ammonium groups to an azobenzene scaffold in meta- or para-positions we generated a series of photoswitchable neuromuscular ligands for which we coined the term "azocuroniums". These compounds switched between the (E)- and (Z)-isomers by light irradiation at 400-450 nm and 335-340 nm, respectively. Meta-azocuroniums were potent nicotinic ligands with a clear selectivity for the muscular nAChRs compared to neuronal α7 and α4β2 subtypes, showed good solubility in physiologic media, negligible cell t...
Source: European Journal of Medicinal Chemistry - May 13, 2020 Category: Chemistry Authors: Herrera-Arozamena C, Estrada-Valencia M, Martí-Marí O, Pérez C, de la Fuente Revenga M, Villalba-Galea CA, Rodríguez-Franco MI Tags: Eur J Med Chem Source Type: research

Chemical profiling of HIV-1 capsid-targeting antiviral PF74.
We report herein the design, synthesis, and evaluation of a large number of PF74 analogs aiming to provide a comprehensive chemical profiling of PF74 and advance the understanding on its detailed binding mechanism and pharmacophore. The analogs, containing structural variations mainly in the aniline domain and/or the indole domain, were assayed for their effect on stability of CA hexamers, antiviral activity, and cytotoxicity. Selected analogs were also tested for metabolic stability in liver microsomes, alone or in the presence of a CYP3A inhibitor. Collectively, our studies identified important pharmacophore elements and...
Source: European Journal of Medicinal Chemistry - May 12, 2020 Category: Chemistry Authors: Wang L, Casey MC, Vernekar SKV, Do HT, Sahani RL, Kirby KA, Du H, Hachiya A, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z Tags: Eur J Med Chem Source Type: research

Exploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect.
Abstract The development of new small molecules from known structural motifs through molecular hybridization is one of the trends in drug discovery. In this connection, we have combined the two pharmacophoric units (pyrimidine and thioindole) in a single entity via molecular hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates 12a-aa, compound 12k was found to exhibit significant IC50 values 5.85, 7.87, 6.41 and 10.43 μM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) ...
Source: European Journal of Medicinal Chemistry - May 12, 2020 Category: Chemistry Authors: Sana S, Reddy VG, Bhandari S, Reddy TS, Tokala R, Sakla AP, Bhargava SK, Shankaraiah N Tags: Eur J Med Chem Source Type: research

Design, synthesis, in  vitro and in vivo biological evaluation of 2-amino-3-aroylbenzo[b]furan derivatives as highly potent tubulin polymerization inhibitors.
Design, synthesis, in vitro and in vivo biological evaluation of 2-amino-3-aroylbenzo[b]furan derivatives as highly potent tubulin polymerization inhibitors. Eur J Med Chem. 2020 May 12;200:112448 Authors: Oliva P, Romagnoli R, Manfredini S, Brancale A, Ferla S, Hamel E, Ronca R, Maccarinelli F, Giacomini A, Rruga F, Mariotto E, Viola G, Bortolozzi R Abstract A new class of inhibitors of tubulin polymerization based on the 2-amino-3-(3',4',5'-trimethoxybenzoyl)benzo[b]furan molecular scaffold was synthesized and evaluated for in vivo and in vitro biological activity. These derivati...
Source: European Journal of Medicinal Chemistry - May 12, 2020 Category: Chemistry Authors: Oliva P, Romagnoli R, Manfredini S, Brancale A, Ferla S, Hamel E, Ronca R, Maccarinelli F, Giacomini A, Rruga F, Mariotto E, Viola G, Bortolozzi R Tags: Eur J Med Chem Source Type: research

CT1-3, a novel magnolol-sulforaphane hybrid suppresses tumorigenesis through inducing mitochondria-mediated apoptosis and inhibiting epithelial mesenchymal transition.
In this study, we successfully synthesized the magnolol-sulforaphane (MAG-SFN) hybrid CT1-3, showcasing more efficient anticancer activity than its lead compounds MAG and SFN with IC50 values ranging from 5.10 to 14.06 μM in multiple cancer cells. We also demonstrated that CT1-3 elicited a strong antitumor effect in vivo but has no hepatic and renal toxicity. Furthermore, we found out CT1-3 treatment resulted in reduction of Bcl-2 and XIAP levels, in addition to increase of phospho-JNK and Bax levels, leading to mitochondria-mediated apoptosis in human cancer cells. Moreover, we revealed that CT1-3 could reduc...
Source: European Journal of Medicinal Chemistry - May 11, 2020 Category: Chemistry Authors: Tao C, Chen J, Huang X, Chen Z, Li X, Li Y, Xu Y, Ma M, Wu Z Tags: Eur J Med Chem Source Type: research

Corrigendum to "N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN- γ induced PD-L1 expression"[Eur. J. Med. Chem. 2020 Jan 1;185:111725].
Corrigendum to "N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PD-L1 expression"[Eur. J. Med. Chem. 2020 Jan 1;185:111725]. Eur J Med Chem. 2020 May 11;199:112406 Authors: Mehndiratta S, Lin MH, Wu YW, Chen CH, Wu TY, Chuang KH, Chao MW, Chen YY, Pan SL, Chen MC, Liou JP PMID: 32408215 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - May 11, 2020 Category: Chemistry Authors: Mehndiratta S, Lin MH, Wu YW, Chen CH, Wu TY, Chuang KH, Chao MW, Chen YY, Pan SL, Chen MC, Liou JP Tags: Eur J Med Chem Source Type: research

Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency.
Abstract In this work, unique flavopiridol analogs bearing thiosugars, amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound 13c resulting from a structure-activity relationship (SAR) study and in silico docking showed the best antiproliferative activity and was more efficient than the refe...
Source: European Journal of Medicinal Chemistry - May 5, 2020 Category: Chemistry Authors: Ibrahim N, Bonnet P, Brion JD, Peyrat JF, Bignon J, Levaique H, Josselin B, Robert T, Colas P, Bach S, Messaoudi S, Alami M, Hamze A Tags: Eur J Med Chem Source Type: research

Identification and optimization of piperine analogues as neuroprotective agents for the treatment of Parkinson's disease via the activation of Nrf2/keap1 pathway.
Abstract Parkinson's disease (PD) is a slowly progressive and complex neurodegenerative disorder. Up to date, there are no approved drugs that could slow or reverse the neurodegenerative process of PD. Here, we reported the synthesis of series of piperine analogues and the evaluation of their neuroprotective effects against hydrogen peroxide (H2O2) induced damage in the neuron-like PC12 cells. Among these analogues, 3b exhibited the most potent protection effect and its underlying mechanism was further investigated. Further results indicated that the ROS scavenging and cytoprotection effect of 3b might be rel...
Source: European Journal of Medicinal Chemistry - May 5, 2020 Category: Chemistry Authors: Wang L, Cai X, Shi M, Xue L, Kuang S, Xu R, Qi W, Li Y, Ma X, Zhang R, Hong F, Ye H, Chen L Tags: Eur J Med Chem Source Type: research

Discovery of novel resorcinol diphenyl ether-based PROTAC-like molecules as dual inhibitors and degraders of PD-L1.
Abstract Novel resorcinol diphenyl ether-based PROTACs (PROteolysis TArgeting Chimeras) were designed and evaluated for their inhibitory activity against the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway and their ability to degrade PD-L1 protein. Most of the compounds displayed excellent inhibitory activities against PD-1/PD-L1, as assessed by the homogenous time-resolved fluorescence (HTRF) binding assay, with IC50 values ranging from 25 nM to 200 nM. Among them, compound P22 is one of the best with an IC50 value of 39.2 nM. In addition to inhibiting PD-1/PD-L1 intera...
Source: European Journal of Medicinal Chemistry - May 5, 2020 Category: Chemistry Authors: Cheng B, Ren Y, Cao H, Chen J Tags: Eur J Med Chem Source Type: research

Synthesis, characterization and carbonic anhydrase I and II inhibitory evaluation of new sulfonamide derivatives bearing dithiocarbamate.
In this study, novel dithiocarbamate-sulfonamide derivatives (3a-3k) were synthesized to investigate their inhibitory activity on purified human carbonic anhydrase (hCA) I and II. The IC50 and Ki values of the compounds were calculated to compare their inhibition profiles on hCA I and II isoenzymes. Acetazolamide was used as the standard inhibitor in the enzyme inhibition assay. Compounds 3a, 3e, 3g, 3h, 3j and 3k showed notable inhibitory effects against hCA I and II. Among these compounds, compound 3h was found to be the most active derivate against both the hCA I and II enzymes with Ki values of 0.032 ± ...
Source: European Journal of Medicinal Chemistry - May 4, 2020 Category: Chemistry Authors: Sağlık BN, Osmaniye D, Çevik UA, Levent S, Çavuşoğlu BK, Büyükemir O, Nezir D, Karaduman AB, Özkay Y, Koparal AS, Beydemir Ş, Kaplancıklı ZA Tags: Eur J Med Chem Source Type: research

Rational design and biological evaluation of gemfibrozil modified Xenopus GLP-1 derivatives as long-acting hypoglycemic agents.
Abstract Novel methods for peptides structural modification and bioactivity optimization are highly needed in peptide-based drug discovery. Herein, we explored the use gemfibrozil (GFZ) as an albumin binder to enhance the stability and improve the bioactivity of peptides. Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models...
Source: European Journal of Medicinal Chemistry - May 4, 2020 Category: Chemistry Authors: Han J, Fu J, Yang Q, Zhou F, Chen X, Li C, Yin J Tags: Eur J Med Chem Source Type: research

Discovery of bazedoxifene analogues targeting glycoprotein 130.
Abstract Deregulation of GP130 in signal transduction is involved in multiple types of human diseases, especially in cancers, indicating that GP130 is an attractive target for cancer therapy. However, GP130 was conventionally considered as an undruggable target thus the discovery of GP130 PPI inhibitors is extremely challenging. By the aid of structure-based drug design, in this study, two series of bazedoxifene based analogues were designed to target GP130 D1 domain and block the IL-6/GP130/STAT3 signaling pathway for antitumor treatment. Most of these designed compounds displayed potent anti-proliferative activi...
Source: European Journal of Medicinal Chemistry - May 4, 2020 Category: Chemistry Authors: Song D, Yu W, Ren Y, Zhu J, Wan C, Cai G, Guo J, Zhang W, Kong L Tags: Eur J Med Chem Source Type: research

Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines.
Abstract Targeting BCL-XL via PROTACs is a promising strategy in reducing BCL-XL inhibition associated platelet toxicity. Recently, we reported potent BCL-XL PROTAC degraders that recruit VHL or CRBN E3 ligase. However, low protein expression or mutation of the responsible E3 ligase has been known to result in decreased protein degradation efficiency of the corresponding PROTACs. To overcome these mechanisms of resistance, PROTACs based on recruiting alternative E3 ligases could be generated. Thus, we designed and synthesized a series of PROTACs that recruit IAP E3 ligases for BCL-XL degradation. Among those PROTA...
Source: European Journal of Medicinal Chemistry - May 4, 2020 Category: Chemistry Authors: Zhang X, He Y, Zhang P, Budamagunta V, Lv D, Thummuri D, Yang Y, Pei J, Yuan Y, Zhou D, Zheng G Tags: Eur J Med Chem Source Type: research

Monocarboxylate transporter 1 and 4 inhibitors as potential therapeutics for treating solid tumours: A review with structure-activity relationship insights.
Abstract Development of multidrug resistance (MDR) is one of the major causes leading to failure of cancer chemotherapy and radiotherapy. Monocarboxylate transporters (MCTs) MCT1 and MCT4, which are overexpressed in solid tumours, play a very important role in cancer cell survival and proliferation. These lactate transporters work complimentarily to drive lactate shuttle in tumour cells, which results in maintenance of H+ ion (pH) balance necessary for their survival. Inhibition of these transmembrane proteins has been demonstrated as a novel strategy to treat drug resistant solid cancers. Presently, only a few sm...
Source: European Journal of Medicinal Chemistry - May 1, 2020 Category: Chemistry Authors: Puri S, Juvale K Tags: Eur J Med Chem Source Type: research

Corrigendum to "A fluorine scan on the Zn2+-binding thiolate side chain of HDAC inhibitor largazole: Synthesis, biological evaluation, and molecular modeling" [Eur. J. Med. Chem. 182 (2019) 111672].
Corrigendum to "A fluorine scan on the Zn2+-binding thiolate side chain of HDAC inhibitor largazole: Synthesis, biological evaluation, and molecular modeling" [Eur. J. Med. Chem. 182 (2019) 111672]. Eur J Med Chem. 2020 May 01;198:112340 Authors: Zhang B, Liu J, Gao D, Yu X, Wang J, Lei X PMID: 32371332 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - May 1, 2020 Category: Chemistry Authors: Zhang B, Liu J, Gao D, Yu X, Wang J, Lei X Tags: Eur J Med Chem Source Type: research

Therapeutic potential of targeting α/β-Hydrolase domain-containing 6 (ABHD6).
Therapeutic potential of targeting α/β-Hydrolase domain-containing 6 (ABHD6). Eur J Med Chem. 2020 Apr 25;198:112353 Authors: Deng H, Li W Abstract α/β-Hydrolase domain 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes monoacylglycerol (MAG) lipids, particularly the endogenous cannabinoid 2-arachidonoylglycerol (2-AG), in both central and peripheral tissues. ABHD6 and its substrates have been shown to be involved in the modulation of various (patho)physiological processes, including neurotransmission, inflammation, insulin secretion, adipose browning, food intake, aut...
Source: European Journal of Medicinal Chemistry - April 25, 2020 Category: Chemistry Authors: Deng H, Li W Tags: Eur J Med Chem Source Type: research

Elephantopinolide A-P, germacrane-type sesquiterpene lactones from Elephantopus scaber induce apoptosis, autophagy and G2/M phase arrest in hepatocellular carcinoma cells.
Abstract Chromatographic purification of Elephantopus scaber led to 16 new germacrane-type sesquiterpene lactones (1-16), named elephantopinolide A-P, along with a known analogue (17). Their structures were confirmed by comprehensive spectroscopic analyses, single-crystal X-ray diffraction, and comparison between the experimental and calculated ECD spectra. Their hepatocellular inhibition activities against Hep3B and HepG2 cells were screened by MTT assay, and the structure-activity relationships were examined. The results revealed that 10 (IC50 value of 2.83 μM and 1.98 μM) is more potent than sor...
Source: European Journal of Medicinal Chemistry - April 25, 2020 Category: Chemistry Authors: Bai M, Chen JJ, Xu W, Dong SH, Liu QB, Lin B, Huang XX, Yao GD, Song SJ Tags: Eur J Med Chem Source Type: research

Discovery of novel NF- кB inhibitor based on scaffold hopping: 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidine.
In this study, a series of fluoro-substituted 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidines (PPMs, 31-57) were synthesized from 3,5-bis(arylidene)-4-piperidones (BAPs, 4-30) based on scaffold hopping. We successfully discovered the most potent 43 substituted by electron-withdrawing substitutes (3-F and 4-CF3) exhibited less toxicity and higher anti-inflammatory activity. Preliminary mechanistic studies revealed that 43 induced dose-dependent cell apoptosis at cell and protein level, while inhibited NF-κB activation by suppressing LPS-induced phosphorylation levels of p65, IκBα and Akt, and by indirectly s...
Source: European Journal of Medicinal Chemistry - April 24, 2020 Category: Chemistry Authors: Sun Y, Gao ZF, Yan WB, Yao BR, Xin WY, Wang CH, Meng QG, Hou GG Tags: Eur J Med Chem Source Type: research

Design, synthesis and biological evaluation of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent Kinase2 (CDK2) dual inhibitors against malignant cancer.
Abstract In the current study, we have designed and synthesized a series of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent kinase2 (CDK2) dual inhibitors by integrating purine-based pharmacophore into the recognition cap group of CS055. The representative compound 14d with excellent antiproliferative activities towards five solid cancer cells, showed potent inhibitory activities against HDAC1, HDAC2 and CDK2 with IC50 values of 70.7 nM, 23.1 nM and 0.80 μM, respectively. Besides, compound 14d could effectively block the cell cycle in the G2/M phase and induce apoptosis, which might b...
Source: European Journal of Medicinal Chemistry - April 23, 2020 Category: Chemistry Authors: Yun F, Cheng C, Ullah S, Yuan Q Tags: Eur J Med Chem Source Type: research

Synthesis and anticancer activity of thiourea derivatives bearing a benzodioxole moiety with EGFR inhibitory activity, apoptosis assay and molecular docking study.
Abstract New thiourea derivatives bearing a benzodioxole moiety were synthesized via the reaction of 5-isothiocyanatobenzodioxole with amino compounds such as aromatic amines, sulfa drugs, heterocyclic amines, hydrazines and hydrazides. The anticancer activity of the synthesized thiourea derivatives was examined against HCT116, HepG2 and MCF-7 cancer cell lines. Most of thiourea derivatives revealed significant cytotoxic effect, in some cases greater than the doxorubicin. As example, IC50 values of N1,N3-disubstituted-thiosemicarbazone 7 were 1.11, 1.74 and 7.0 μM for HCT116, HepG2 and MCF7, respectively; ...
Source: European Journal of Medicinal Chemistry - April 23, 2020 Category: Chemistry Authors: Abbas SY, Al-Harbi RAK, Sh El-Sharief MAM Tags: Eur J Med Chem Source Type: research

Indole chalcones: Design, synthesis, in  vitro and in silico evaluation against Mycobacterium tuberculosis.
Indole chalcones: Design, synthesis, in vitro and in silico evaluation against Mycobacterium tuberculosis. Eur J Med Chem. 2020 Apr 22;198:112358 Authors: Ramesh D, Joji A, Vijayakumar BG, Sethumadhavan A, Mani M, Kannan T Abstract Indole chalcones were designed and synthesized as a promising set of compounds against H37Rv strain of Mycobacterium tuberculosis. Within this library of compounds, (E)-1-(furan-3-yl)-3-(1H-indol-3-yl)prop-2-en-1-one (18), (E)-3-(1H-indol-3-yl)-1-(thiophen-2-yl)prop-2-en-1-one (20) and (E)-2-((1H-indol-2-yl)methylene)cyclopentan-1-one (24) displayed high anti-tubercula...
Source: European Journal of Medicinal Chemistry - April 22, 2020 Category: Chemistry Authors: Ramesh D, Joji A, Vijayakumar BG, Sethumadhavan A, Mani M, Kannan T Tags: Eur J Med Chem Source Type: research

Antioxidant activity of novel quinazolinones bearing sulfonamide: Potential radiomodulatory effects on liver tissues via NF- κB/ PON1 pathway.
Antioxidant activity of novel quinazolinones bearing sulfonamide: Potential radiomodulatory effects on liver tissues via NF-κB/ PON1 pathway. Eur J Med Chem. 2020 Apr 21;197:112333 Authors: Soliman AM, Karam HM, Mekkawy MH, Ghorab MM Abstract In order to discover new antioxidants, fifteen novel quinazolinone derivatives bearing benzenesulfonamide moiety with variable heterocyclic tail, were synthesized and their structures were established on the basis of spectral data. All the synthesized compounds were screened for their antioxidant potential using DPPH assay in comparison to ascorbic acid. Th...
Source: European Journal of Medicinal Chemistry - April 21, 2020 Category: Chemistry Authors: Soliman AM, Karam HM, Mekkawy MH, Ghorab MM Tags: Eur J Med Chem Source Type: research

Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors.
Abstract A series of novel isocombretapyridines were designed and synthesized based on a lead compound isocombretastatin A-4 (isoCA-4) by replacing 3,4,5-trimethoxylphenyl with substituent pyridine nucleus. The MTT assay results showed that compound 20a possessed the most potent activities against all tested cell lines with IC50 values at nanomolar concentration ranges. Moreover, 20a inhibited tubulin polymerization at a micromolar level and also displayed potent anti-vascular activity in vitro. Further mechanistic studies were conducted to demonstrate that compound 20a could bind to the colchicine site of tu...
Source: European Journal of Medicinal Chemistry - April 19, 2020 Category: Chemistry Authors: Shuai W, Li X, Li W, Xu F, Lu L, Yao H, Yang L, Zhu H, Xu S, Zhu Z, Xu J Tags: Eur J Med Chem Source Type: research

Synthesis and biological activities of drugs for the treatment of osteoporosis.
Abstract Osteoporosis is an asymptomatic progressive disease. With the improvement of people's living standard and the aging of population, osteoporosis and its fracture have become one of the main diseases threatening the aging society. The serious medical and social burden caused by this has aroused wide public concern. Osteoporosis is listed as one of the three major diseases of the elderly. At present, the drugs for osteoporosis include bone resorption inhibitors and bone formation promoters. The purpose of these anti-osteoporosis drugs is to balance osteoblast bone formation and osteoclast bone resorption. Wi...
Source: European Journal of Medicinal Chemistry - April 19, 2020 Category: Chemistry Authors: Zhou S, Huang G, Chen G Tags: Eur J Med Chem Source Type: research

Corrigendum to "Design, synthesis, and evaluation of N-phenyl-4-(2-phenylsulfonamido)-benzamides as microtubule-targeting agents in drug-resistant cancer cells, displaying HDAC inhibitory response" [Eur J Med Chem. 192 2020 112158].
Corrigendum to "Design, synthesis, and evaluation of N-phenyl-4-(2-phenylsulfonamido)-benzamides as microtubule-targeting agents in drug-resistant cancer cells, displaying HDAC inhibitory response" [Eur J Med Chem. 192 2020 112158]. Eur J Med Chem. 2020 Apr 17;196:112329 Authors: Wu WC, Liu YM, Lin MH, Liao YH, Lai MJ, Chuang HY, Hung TY, Chen CH, Liou JP PMID: 32311605 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - April 17, 2020 Category: Chemistry Authors: Wu WC, Liu YM, Lin MH, Liao YH, Lai MJ, Chuang HY, Hung TY, Chen CH, Liou JP Tags: Eur J Med Chem Source Type: research

Discovery and evaluation of new compounds targeting ribosomal protein S1 in antibiotic-resistant Mycobacterium Tuberculosis.
In this study, based on the structure of the RpsA C-terminal domain (RpsA-CTD) and POA complex, new compounds were designed. After being synthesized, the compounds were tested in vitro with saturation transfer difference (STD), fluorescence quenching titration (FQT) and chemical shift perturbation (CSP) experiments. Finally, six of the 17 new compounds have high affinity for both RpsA-CTD and its Ala438 deletion mutant. The active compounds provide new choices for targeting trans-translation in Mtb, and the analysis of the structure-activity relationships will be helpful for further structural modifications based on d...
Source: European Journal of Medicinal Chemistry - April 10, 2020 Category: Chemistry Authors: Dai Y, Xu Y, Guo C, Xue X, Lin D, Lin K Tags: Eur J Med Chem Source Type: research

Hybrids of MEK inhibitor and NO donor as multitarget antitumor drugs.
Abstract A series of hybrids of MEK inhibitor and nitric oxide donor have been designed and synthesized. Compound 18h [4-(3-((3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-methyl-2-oxo-2H-chromen-7-yl)oxy) propoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide] was proven to be more potent than the clinical compound RO5126766 in MDA-MB-231 cells. Compound 18h can significantly reduce the levels of pMEK and pERK, induce cell apoptosis in MDA-MB-231 cells, and release NO in cells efficiently, suggesting that these hybrids, while displaying the properties of both MEK inhibitors and NO donors have a mechan...
Source: European Journal of Medicinal Chemistry - April 9, 2020 Category: Chemistry Authors: Wang C, Xi D, Wang H, Niu Y, Liang L, Xu F, Peng Y, Xu P Tags: Eur J Med Chem Source Type: research

Discovery of a 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal-regulating kinase 1 (ASK1).
Abstract Inhibition of MAP3K kinase ASK1 has been an attractive strategy for the treatment of nonalcoholic steatohepatitis and multiple sclerosis, among others. Herein, we reported the discovery of 2-pyridinyl urea-containing compound 14l (YD57) as a potent, small-molecule inhibitor of ASK1. 14l was selective against MAP3K kinases ASK2 and TAK1 (>140-fold), while it also inhibited several cell cycle regulating kinases with IC50 values in a range of 90-400 nM (
Source: European Journal of Medicinal Chemistry - April 5, 2020 Category: Chemistry Authors: Zhang S, Huang C, Lyu X, Wang P, Zang Y, Wang Z, Wang H, Li J, Zhao Y Tags: Eur J Med Chem Source Type: research

Design, synthesis and biological evaluation of novel 3,4-dihydro-2(1H)-quinolinone derivatives as potential chitin synthase inhibitors and antifungal agents.
Abstract A series of 3,4-dihydro-2(1H)-quinolinone derivatives contained butenediamide fragment were designed and synthesized. Their inhibition potency against chitin synthase and antimicrobial activities were screened in vitro. The enzymatic assays showed that all the synthesized compounds had inhibition potency against chitin synthase at concentration of 300 μg/mL. Compound 2d displayed excellent potency with inhibition percentage (IP) value of 82.3%, while IP value of the control polyoxin B was 87.5%. Compounds 2b, 2e and 2s whose IP values were above 70% showed good inhibition potency against chit...
Source: European Journal of Medicinal Chemistry - April 4, 2020 Category: Chemistry Authors: Li B, Shen Y, Wu H, Wu X, Yuan L, Ji Q Tags: Eur J Med Chem Source Type: research

hERG toxicity assessment: Useful guidelines for drug design.
Abstract All along the drug development process, one of the most frequent adverse side effects, leading to the failure of drugs, is the cardiac arrhythmias. Such failure is mostly related to the capacity of the drug to inhibit the human ether-à-go-go-related gene (hERG) cardiac potassium channel. The early identification of hERG inhibition properties of biological active compounds has focused most of attention over the years. In order to prevent the cardiac side effects, a great number of in silico, in vitro and in vivo assays have been performed. The main goal of these studies is to understand th...
Source: European Journal of Medicinal Chemistry - April 3, 2020 Category: Chemistry Authors: Garrido A, Lepailleur A, Mignani SM, Dallemagne P, Rochais C Tags: Eur J Med Chem Source Type: research

Design, synthesis and biological evaluation of novel dual-acting modulators targeting both estrogen receptor α (ERα) and lysine-specific demethylase 1 (LSD1) for treatment of breast cancer.
In this study, we have developed a series of dual-acting agents targeting both estrogen receptor α (ERα) and histone demethylase based on a privileged OBHS pharmacophore scaffold developed previously by our laboratory. These novel OBHS-LSD1i conjugates showed excellent ERα binding affinity and selectivity, and exhibited potent inhibitory activity against lysine specific demethylase 1 (LSD1). Several conjugates showed higher antiproliferative efficacy in MCF-7 breast cancer cell line compared to 4-hydroxytamoxifen in vitro. Among them, the best compound 11g displayed potent inhibitory activity against...
Source: European Journal of Medicinal Chemistry - April 3, 2020 Category: Chemistry Authors: He M, Ning W, Hu Z, Huang J, Dong C, Zhou HB Tags: Eur J Med Chem Source Type: research

Synthesis of novel hybrid quinolino[4,3-b][1,5]naphthyridines and quinolino[4,3-b][1,5]naphthyridin-6(5H)-one derivatives and biological evaluation as topoisomerase I inhibitors and antiproliferatives.
nso C Abstract The topoisomerase I enzymatic inhibition of hybrid quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridines and quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-ones was investigated. First, the synthesis of these fused compounds was performed by intramolecular [4 + 2]-cycloaddition reaction of functionalized aldimines obtained by the condensation of 3-aminopyridine and unsaturated aldehydes affording corresponding hybrid 5-tosylhexahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,...
Source: European Journal of Medicinal Chemistry - April 3, 2020 Category: Chemistry Authors: Martín-Encinas E, Selas A, Tesauro C, Rubiales G, Knudsen BR, Palacios F, Alonso C Tags: Eur J Med Chem Source Type: research

Synthesis of novel monocarbonyl curcuminoids, evaluation of their efficacy against MRSA, including ex  vivo infection model and their mechanistic studies.
Synthesis of novel monocarbonyl curcuminoids, evaluation of their efficacy against MRSA, including ex vivo infection model and their mechanistic studies. Eur J Med Chem. 2020 Apr 03;195:112276 Authors: Gagandeep, Kumar P, Kandi SK, Mukhopadhyay K, Rawat DS Abstract In continuation of our effort to improve the physiological stability and the antibacterial activity of curcuminoids against drug-resistant bacteria, a series of novel monocarbonyl curcuminoids were synthesized and screened for antibacterial activity against S. aureus and E. coli strains. These curcuminoids showed potent antib...
Source: European Journal of Medicinal Chemistry - April 3, 2020 Category: Chemistry Authors: Gagandeep, Kumar P, Kandi SK, Mukhopadhyay K, Rawat DS Tags: Eur J Med Chem Source Type: research

Corrigendum to: Third-generation CDK inhibitors: A review on the synthesis and binding modes of Palbociclib, Ribociclib and Abemaciclib [Eur. J. Med. Chem. 172 (2019) 143-153].
PMID: 32251743 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - April 3, 2020 Category: Chemistry Authors: Poratti M, Marzaro G Tags: Eur J Med Chem Source Type: research

Targeting RAS-RAF pathway significantly improves antitumor activity of Rigosertib-derived platinum(IV) complexes and overcomes cisplatin resistance.
Abstract RAS-RAF pathway presents a valuable target for the cancer treatment due to its important roles in the regulation of tumor proliferation, apoptosis and the obtained resistance. To explore such target a RAS/CRAF interference agent, was therefore conjugated with Pt(IV) prodrugs via ester bond, resulting in total eleven multifunctional Pt(IV) complexes. The complexes could target genomic DNA and disrupt the signaling transduction from RAS protein to CRAF so that block the mitogen-activated protein kinase (MAPK) signaling pathway. Experiments in vitro indicated that all of the Pt(IV) complexes showed pote...
Source: European Journal of Medicinal Chemistry - March 25, 2020 Category: Chemistry Authors: Liu Z, Wang M, Wang H, Fang L, Gou S Tags: Eur J Med Chem Source Type: research

Corrigendum to "Design and synthesis of novel artemisinin hybrids with potent activities against human colorectal cancer cells in  vitro and in vivo" [Eur. J. Med. Chem. 182 (2019) 111665].
Corrigendum to "Design and synthesis of novel artemisinin hybrids with potent activities against human colorectal cancer cells in vitro and in vivo" [Eur. J. Med. Chem. 182 (2019) 111665]. Eur J Med Chem. 2020 Mar 25;194:112256 Authors: Wang LL, Kong L, Liu H, Zhang Y, Zhang L, Liu X, Yuan F, Li Y, Zuo Z PMID: 32220686 [PubMed - as supplied by publisher] (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - March 25, 2020 Category: Chemistry Authors: Wang LL, Kong L, Liu H, Zhang Y, Zhang L, Liu X, Yuan F, Li Y, Zuo Z Tags: Eur J Med Chem Source Type: research