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In this work, we describe an improved series of N -phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC 50 values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a , 6d , 6e and 6f show MIC values between 0.031 and 0.0625 μg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 μg/mL and against the E. faecalis strain with a MIC of 0.125 μg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line. [Display omitted] • An improved series of N -phenylpyrrolamide DNA gyrase inhibitors has been developed. • The compounds show low nanomolar IC 50 values against E. coli DNA gyrase and topoisomerase IV. • The MIC values are between 0.031 and 0.0625 μg/mL against MRSA, VISA and E. faecalis strains. • The time-kill curve, the PAE and the development of resistance to MRSA were determined. • The compounds were not cytotoxic at effective concentrations. [ABSTRACT FROM AUTHOR]

Class I histone deacetylases (HDACs) are closely associated with the development of a diverse array of diseases, including cancer, neurodegenerative disorders, HIV, and inflammatory diseases. Considering the essential roles in tumorigenesis, class I HDACs have emerged as highly desirable targets for therapeutic strategies, particularly in the field of anticancer drug development. However, the conventional class I HDAC inhibitors faced several challenges such as acquired resistance, inherent toxicities, and limited efficacy in inhibiting non-enzymatic functions of HDAC. To address these problems, novel strategies have emerged, including the development of class I HDAC dual-acting inhibitors, targeted protein degradation (TPD) technologies such as PROTACs, molecular glues, and HyT degraders, as well as covalent inhibitors. This review provides a comprehensive overview of class I HDAC enzymes and inhibitors, by initially introducing their structure and biological roles. Subsequently, we focus on the recent advancements of class I HDAC modulators, including isoform-selective class I inhibitors, dual-target inhibitors, TPDs, and covalent inhibitors, from the perspectives of rational design principles, pharmacodynamics, pharmacokinetics, and clinical progress. Finally, we also provide the challenges and outlines future prospects in the realm of class I HDAC-targeted drug discovery for cancer therapeutics. This review summarizes the recent progress in the development of class I histone deacetylase (HDAC) modulators encompassing isoform-selective inhibitors, dual-target inhibitors, targeted protein degradation (TPD) technologies, and covalent inhibitors, with deep insights into the potential challenges and corresponding remedies. [Display omitted] • The structure and biological functions of class I HDAC were elucidated. • Class I HDAC modulators (inhibitors, degraders, and covalent inhibitors) were overviewed. • Prospects and future directions of class I HDAC-targeting cancer therapy were discussed. [ABSTRACT FROM AUTHOR]

Herein, we describe the design and synthesis of novel aryl pyrimidine benzenesulfonamides APBSs 5a-n , 6a-c , 7a-b , and 8 as pazopanib analogues to explore new potent and selective inhibitors for the CA IX. All APBSs were examined in vitro for their promising inhibition activity against a small panel of hCAs (isoforms I, II, IX, and XII). The X-ray crystal structure of CA I in adduct with a representative APBS analogue was solved. APBS - 5m , endowed with the best hCA IX inhibitory efficacy and selectivity, was evaluated for antiproliferative activity against a small panel of different cancer cell lines, SK-MEL-173, MDA-MB-231, A549, HCT-116, and HeLa, and it demonstrated one-digit IC 50 values range from 2.93 μM (MDA-MB-231) to 5.86 μM (A549). Furthermore, compound APBS - 5m was evaluated for its influence on hypoxia-inducible factor (HIF-1α) production, apoptosis induction, and colony formation in MDA-MB-231 cancer cells. The in vivo efficacy of APBS - 5m as an antitumor agent was additionally investigated in an animal model of Solid Ehrlich Carcinoma (SEC). In order to offer perceptions into the conveyed hCA IX inhibitory efficacy and selectivity in silico , a molecular docking investigation was also carried out. [Display omitted] • Aryl pyrimidine benzene sulfonamides (APBSs) were synthesized and characterized. • APBS - 5m showed top inhibitory activity towards CA IX (K I = 2.7 nM). • The anticancer activity of APBS - 5m was superior against MDA-MB-231 cancer cells. • APBS - 5m displayed potent proapoptotic activity on hypoxia sensitized MDA-MB-231. • X-ray crystal structure of CA I- APBS - 5b adduct was solved (PDB code: 8QUN). [ABSTRACT FROM AUTHOR]

Secondary alkylcarbamic acid biphenyl-3-yl esters are a class of Fatty Acid Amide Hydrolase (FAAH) inhibitors, which include the reference compounds URB597 and URB694. Given the intrinsic reactivity of the carbamate group, the in vivo potency of these molecules in rats is strongly affected by their hydrolysis in plasma or hepatic metabolism. In the present study, in vitro chemical and metabolic stability assays (rat plasma and rat liver S(9) fraction) were used to investigate the structure-property relationships (SPRs) for a focused series of title compounds, where lipophilicity and steric hindrance of the carbamate N-substituent had been modulated. The resulting degradation rates indicate that a secondary or tertiary alkyl group at the carbamate nitrogen atom increases hydrolytic stability towards rat plasma esterases. The calculated solvent accessible surface area (SASA) of the carbamate fragment was employed to describe the differences observed in rate constants of hydrolysis in rat plasma (log k(plasma)), suggesting that stability in plasma increases if the substituent exerts a shielding effect on the carbamate carbonyl. Stability in rat liver S(9) fraction is increased when a tertiary carbon is bound to the carbamate nitrogen atom, while other steric effects showed complex relationships with degradation rates. The SPRs here described may be applied at the pharmacokinetic optimization of other classes of carbamate FAAH inhibitors.

As an essential form of lipid modification for maintaining vital cellular functions, palmitoylation plays an important role in in the regulation of various physiological processes, serving as a promising therapeutic target for diseases like cancer and neurological disorders. Ongoing research has revealed that palmitoylation can be categorized into three distinct types: N-palmitoylation, O-palmitoylation and S-palmitoylation. Herein this paper provides an overview of the regulatory enzymes involved in palmitoylation, including palmitoyltransferases and depalmitoylases, and discusses the currently available broad-spectrum and selective inhibitors for these enzymes. [Display omitted] • The types of palmitoylation and regulatory enzymes. • Modulators of palmitoylation-related enzymes and their biological activities. • The key structure-activity relationships and binding details of the modulators in the resolved crystal structures. [ABSTRACT FROM AUTHOR]

This study explores the potential of CSF-1R inhibitors as therapeutic agents for neurodegenerative diseases. CSF-1R, a receptor tyrosine kinase primarily expressed in macrophage lineages, plays a pivotal role in regulating various cellular processes. Recent research highlights the significance of CSF-1R inhibition in mitigating neuroinflammation, particularly in Alzheimer's disease, where microglial overactivation contributes to neurodegeneration. The research reveals a series of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide CSF-1R inhibitors, where compounds 7d, 7e, and 9a exhibit outstanding inhibitory activities and selectivity, with IC 50 values of 33, 31, and 64 nM, respectively. These most promising compounds in this series were profiled for cellular potency and subjected to in vitro pharmacokinetic profiling. These inhibitors exhibit minimal cytotoxicity, even at higher concentrations, and possess promising blood-brain barrier permeability, making them potential candidates for central nervous system diseases. The investigation into the in vitro ADME properties, including plasma and microsomal stability, reveals that these CSF-1R inhibitors maintain their structural integrity and plasma concentration. This resilience positions them for further development as therapeutic agents for neurodegenerative diseases., Competing Interests: Declaration of Competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jung-Mi Hah reports financial support was provided by National Research Foundation., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

In this review, we present the latest advances in the field of multi-target-directed ligand (MTDL) design for the treatment of various complex pathologies of multifactorial origin. In particular, latest findings in the field of MTDL design targeting both an enzyme and a receptor are presented for different diseases such as Alzheimer's disease (AD), depression, addiction, glaucoma, non-alcoholic steatohepatitis and pain and inflammation. The ethology of the diseases is briefly described, with special emphasis on how the MTDL can evolve into novel therapies that replace the classic pharmacological dogma "one target one disease". Considering the current needs for therapy adherence improvement, it is exposed as from the medicinal chemistry, different molecular scaffolds are studied. With the use of structure activity relationship studies and molecular optimization, new hybrid molecules are generated with improved biological properties acting at two biologically very distinct targets. Image 1 • Multi-target-directed ligands addressing both an enzyme and a receptor are comprehensively reviewed. • Applications are Alzheimer's disease, depression, addiction, glaucoma, and inflammatory diseases among others. • Successful combination is possible and the approach is generally applicable. [ABSTRACT FROM AUTHOR]

The superfamily of adenylate-forming enzymes all share a common chemistry. They activate a carboxylate group, on a specific substrate, by catalyzing the formation of a high energy mixed phosphoanhydride-linked nucleoside intermediate. Members of this diverse enzymatic family play key roles in a variety of metabolic pathways and therefore many have been regarded as drug targets. A generic approach to inhibit such enzymes is the use of non-hydrolysable sulfur-based bioisosteres of the adenylate intermediate. Here we compare the activity of compounds containing a sulfamoyl and sulfonamide linker respectively. An improved synthetic strategy was developed to generate inhibitors containing the latter that target isoleucyl- (IleRS) and seryl-tRNA synthetase (SerRS), two structurally distinct representatives of Class I and II aminoacyl-tRNA synthetases (aaRSs). These enzymes attach their respective amino acid to its cognate tRNA and are indispensable for protein translation. Evaluation of the ability of the two similar isosteres to inhibit serRS revealed a remarkable difference, with an almost complete loss of activity for seryl-sulfonamide 15 (SerSoHA) compared to its sulfamoyl analogue (SerSA), while inhibition of IleRS was unaffected. To explain these observations, we have determined a 2.1 Å crystal structure of Klebsiella pneumoniae SerRS in complex with SerSA. Using this structure as a template, modelling of 15 in the active site predicts an unfavourable eclipsed conformation. We extended the same modelling strategy to representative members of the whole adenylate-forming enzyme superfamily, and were able to disclose a new classification system for adenylating enzymes, based on their protein fold. The results suggest that, other than for the structural and functional orthologues of the Class II aaRSs, the O to C substitution within the sulfur-sugar link should generally preserve the inhibitory potency. Image 1 • Improved synthesis strategy of N -acylated sulfonamide adenosines developed. • Two aminoacylated compounds evaluated as aminoacyl-tRNA synthetase (aaRS) inhibitors. • Inhibitory activity depends on the aaRS structural class. • Structural studies suggest an unfavorable pose of the compound in class II aaRS. • Modelling suggests a general targeting potential towards adenylate-forming enzymes. [ABSTRACT FROM AUTHOR]

The last decade has witnessed the peculiarities of metabolic reprogramming in tumour onset and progression, and their relevance in cancer therapy. Also, it has been indicated that the metastatic process may depend on the metabolic rewiring and adaptation of cancer cells to the pressure of tumour microenvironment and limiting nutrient availability. The present review gatherers the existent knowledge on the influence of tumour microenvironment and metabolic routes driving metastasis. A focus will be given to glycolysis, fatty acid metabolism, glutaminolysis, and amino acid handling. In addition, the role of metabolic waste driving metastasization will be explored. Finally, we discuss the status of cancer treatment approaches targeting metabolism. This knowledge revision will highlight the critical metabolic targets in metastasis and the chemicals already used in preclinical studies and clinical trials, providing clues that would be further exploited in medicinal chemistry research. Image 1 • Metabolic reprogramming is a hallmark of cancer. • Glucose, fatty acids, glutamine, and amino acids fuel tumour cell invasiveness. • Metastasization depends on the metabolic rewiring of cancer cells. • Several metabolic targets have potential as anti-cancer therapies. • Medicinal chemistry research can improve the effectiveness of metabolic inhibitors. [ABSTRACT FROM AUTHOR]

Abstract The histone lysine specific demethylase 1 (LSD1/KDM1A) is implicated in the development of cancers, targeting LSD1 has been recognized as a promising strategy for cancer therapy. To date, some small-molecule inhibitors are currently being investigated in clinical trials. Herein we report the design, synthesis and biochemical characterization of [1,2,4]triazolo[1,5- a ]pyrimidine derivatives as new LSD1 inhibitors. Of these compounds, compound C26 inhibited LSD1 in a reversible manner (IC 50 = 1.72 μM) and showed selectivity to LSD1 over MAO-A/B. Besides, compound C26 displayed FAD-competitive binding to LSD1. Interestingly, C26 did not inhibit horseradish peroxidase (HRP) and quench H 2 O 2 , thus excluding the possibility that LSD1 inhibition by C26 was due to the HRP inhibition and consumption of H 2 O 2. In LSD1 overexpressed A549 cells, compound C26 concentration-dependently induced accumulation of H3K4me1/me2 and H3K9me2 and showed cellular target engagement to LSD1. Additionally, compound C26 significantly inhibited migration of A549 cells in a concentration-dependent manner, further western blot analysis showed that C26 increased expression levels of epithelial cell markers E-Cadherin and Claudin-1, down-regulated mesenchymal cell marker N-Cadherin and the upstream transcription factors Snail and Slug. Docking studies were also performed to rationalize the potency of C26 toward LSD1. To conclude, the [1,2,4]triazolo[1,5- a ]pyrimidine could serve as a promising scaffold for the development of new LSD1 inhibitors. Graphical abstract Image 1 Highlights • A new series of [1,2,4]triazolo[1,5- a ]pyrimidine derivatives were designed as new LSD1 inhibitors. • C26 inhibited LSD1 reversibly and showed selectivity to LSD1 over MAO-A/B. • C26 concentration-dependently induced accumulation of H3K4/9 substrates and showed cellular target engagement to LSD1 in A549 cells. • C26 significantly inhibited migration of A549 cells in a concentration-dependent manner. • The [1,2,4]triazolo[1,5- a ]pyrimidine could serve as a promising scaffold for the development of new LSD1 inhibitors. [ABSTRACT FROM AUTHOR]

Abstract The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N -benzylpiperidine analogs (17 – 31 and 32 – 46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets. Compounds 40 and 41 exhibited high brain permeability in the PAMPA-BBB assay, significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE, and were devoid of neurotoxicity towards SH-SY5Y neuroblastoma cell lines up to the maximum tested concentration of 80 μM. Meanwhile, both these compounds inhibited self- and AChE-induced Aβ aggregation in thioflavin T assay, which was also re-affirmed by morphological characterization of Aβ aggregates using atomic force microscopy (AFM). Moreover, 40 and 41 ameliorated the scopolamine-induced cognitive impairment in elevated plus and Y-maze experiments. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of these compounds. Further, improvement in Aβ 1-42 -induced cognitive impairment was also observed by compound 41 in the Morris water maze experiment with significant oral absorption characteristics ascertained by the pharmacokinetic studies. Graphical abstract Image 1 Highlights • Design and synthesis of a series of N -benzylpiperidine analogs (17 – 46). • Compounds 25, 26, 40, and 41 exhibited balanced inhibition of AChE and BACE-1. • Propidium iodide displacement and inhibition of Aβ aggregation by 40 and 41. • Biochemical analysis of rat brain homogenates suggested antioxidant potential. • Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models. [ABSTRACT FROM AUTHOR]

Abstract Heme oxygenases (HOs) are a family of enzymes involved in the selective catabolism of free circulating heme. While HO-2 is constitutively expressed, HO-1 is strongly overexpressed under stressful stimuli (e. g., oxidative stress). Under these conditions, HO-1 exerts its strong cytoprotective activities and plays a crucial role in stimulating cell survival by removing the pro-oxidant heme and by producing carbon monoxide and biliverdin (promptly reduced to bilirubin). Unfortunately, the broad spectrum of HO-1 cytoprotective effects has been well experimentally documented both in normal and tumor cells, where the enzyme can be overexpressed, making it an exciting target in the management of some type of tumors. Development of non-competitive HO-1 inhibitors dates back in 2002 with the discovery of Azalanstat. Since then, many efforts have been devoted to the identification of selective HO-1 and HO-2 inhibitors and to unravel the molecular determinants responsible for selectivity. Molecular modeling studies supported the identification of chemical features involved in the recognition and inhibition of these enzymes. Herein, medicinal chemistry aspects and in silico studies related to the development of HO inhibitors will be discussed. The purpose of this review is to highlight recent advances in the development of new selective HO-1 and HO-2 inhibitors and covers the last six years (2013–2018). Graphical abstract Image 1 Highlights • HO-1 is an emerging target in cancer therapy. • New and selective azole-based HO-1 inhibitors have been identified and optimized. • SAR studies of HO-1 and HO-2 inhibitors are comprehensively discussed. • In silico studies for the most relevant HO-1 inhibitors are revised. [ABSTRACT FROM AUTHOR]

Abstract Tuberculosis (TB) caused by the pathogen Mycobacterium tuberculosis , represents one of the most challenging threat to public health worldwide, and with the increasing resistance to approved TB drugs, it is needed to develop new strategies to address this issue. Ethionamide is one of the most widely used drugs for the treatment of multidrug-resistant TB. It is a prodrug that requires activation by mycobacterial monooxygenases to inhibit the enoyl-ACP reductase InhA, which is involved in mycolic acid biosynthesis. Very recently, we identified that inhibition of a transcriptional repressor, termed EthR2, derepresses a new bioactivation pathway that results in the boosting of ethionamide activation. Herein, we describe the identification of potent EthR2 inhibitors using fragment-based screening and structure-based optimization. A target-based screening of a fragment library using thermal shift assay followed by X-ray crystallography identified 5 hits. Rapid optimization of the tropinone chemical series led to compounds with improved in vitro potency. Graphical abstract Image 1 Highlights • Fragment-based approach to discover new M. tb EthR2 inhibitors. • X-ray structures of EthR2 with fragments. • Straightforward synthesis of N-alkylated nortropinones and derivatives. [ABSTRACT FROM AUTHOR]

Abstract A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors. Graphical abstract Image 1 Highlights • A series of B and C-rings truncated deguelin derivatives were designed and synthesized. • Their structure-activity relationships were investigated in a systematic manner. • Compound 21c was identified to have high Hsp90 binding potency. • Compound 21c caused apoptosis of MCF-7 cells. [ABSTRACT FROM AUTHOR]

Abstract MutT homologue 1 (MTH1) protects the nucleotide pool from oxidative stress by hydrolyzing oxidized nucleoside triphosphates and prevents their incorporation into DNA. Cancer cells are dependent on the MTH1 activity for survival due to the high-level of reactive oxygen species in cancer cells; therefore, MTH1 is considered to be a novel target for treatment of various cancers. Here, we show by X-ray crystallographic screening using an in-house cocktail library that α-mangostin, a natural xanthone from mangosteen pericarp, binds to the active site of MTH1. A subsequent inhibition assay revealed that 3-isomangostin, a cyclized derivative of α-mangostin, was the most potent MTH1 inhibitor, with an IC 50 value of 0.052 μM. Detailed structural analyses of the MTH1-3-isomangostin complex showed the novel binding mode of 3-isomangostin. Our results demonstrate that X-ray crystallographic screening is useful for the lead discovery for MTH1, and suggest that 3-isomangostin would be an attractive chemical tool for the development of anticancer agents. Graphical abstract Image 1 Highlights • X-ray crystallographic screening identified α-mangostin as an MTH1 inhibitor. • 3-isomangostin present strong MTH1 inhibitory activity. • Crystallographic analysis revealed the novel binding mode of 3-isomangostin. [ABSTRACT FROM AUTHOR]

Abstract A class of 36 new 2-(6-phenylimidazo[2,-1- b ][1,3,4]thiadiazol-2-yl)-1 H -indoles was efficiently synthesized and evaluated for their anti-biofilm properties against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 25923, S. aureus ATCC 6538 and Staphylococcus epidermidis ATCC 12228, and the Gram-negative strains Pseudomonas aeruginosa ATCC 15442 and Escherichia coli ATCC 25922. Many of these new compounds, were able to inhibit biofilm formation of the tested staphylococcal strains showing BIC 50 lower than 10 μg/ml. In particular, derivatives 9c and 9h showed remarkable anti-biofilm activity against S. aureus ATCC 25923 with BIC 50 values of 0.5 and 0.8 μg/ml, respectively, whereas compound 9aa was the most potent against S. aureus ATCC 6538, with a BIC 50 of 0.3 μg/ml. Remarkably, these compounds showed effects in the early stages of the biofilm formation without affecting the mature biofilm of the same strains and the viability of the planktonic form. Their ability in counteracting a virulence factor (biofilm formation) without interfering with the bacterial growth in the free life form make them novel valuable anti-virulence agents. Graphical abstract Image 1 Highlights • New 2-(6-phenylimidazo[2,-1- b ][1,3,4]thiadiazol-2-yl)-1 H -indoles with anti-biofilm properties were synthesized. • Many compounds inhibited staphylococcal biofilm formation with BIC 50 lower than 10 μg/ml. • Compounds 9c and 9h showed BIC 50 values of 0.5 and 0.8 μg/ml, respectively, against S. aureus ATCC 25923. • The new derivatives showed a typical anti-virulence profile. [ABSTRACT FROM AUTHOR]

Abstract ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N -phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC 50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1–50 μM range, one of which inhibited the growth of Enterococcus faecalis , Enterococcus faecium , S. aureus and Streptococcus pyogenes with MIC values of 1.56 μM, 1.56 μM, 0.78 μM and 0.72 μM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 μM on both strains, and MIC value of 32 μM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action. Graphical abstract Image 1 Highlights • A series of optimised DNA gyrase B inhibitors were designed and prepared. • Compounds displayed low nanomolar IC 50 values against DNA gyrase. • Compound 9d displayed IC 50 values of 6.9 nM against Escherichia coli DNA gyrase. • Compound 57 inhibited the growth of several Gram-positive bacteria with low micromolar MIC values. • Compound 57 inhibited MRSA and MRSA VISA strains with MIC values of 2.5 μM. [ABSTRACT FROM AUTHOR]

Abstract To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3β inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3β with weak Cu2+, Zn2+ and Al3+ chelating ability. The imine derivatives 9a , 9b and 9e were potent GSK-3β inhibitors and selective Cu2+and Al3+ chelators. The 1,2-diamine derivatives 10a-e were strong metal-chelators, but decreased or lost their GSK-3β inhibitory potency. In vitro, compounds 9a , 9b and 9e , especially 9b , exhibited good Cu2+-induced Aβ aggregation inhibition, Cu2+-Aβ complex disaggregation, ROS formation inhibition, and antioxidant activities. In cells, compounds 9a , 9b and 9e can inhibit tau protein phosphorylation and protect neuro cells against Cu2+-Aβ 1–42 and H 2 O 2 -induced cell damage. Furthermore, compound 9b was predicted to have the ability to pass the BBB with drug likeness properties. Therefore, compound 9b might be a good lead for the development of novel GSK-3β inhibitors targeting multi-facets of AD. Graphical abstract Image 1 Highlights • Novel multifunctional GSK-3β inhibitors were designed and synthesized. • 9a , 9b and 9e displayed Cu2+-Aβ aggregation inhibition and complex disaggregation. • 9a , 9b and 9e inhibited ROS formation and displayed antioxidant activities. • 9a , 9b and 9e had low neurotoxicity and great neuroprotection. • 9a , 9b and 9e could inhibit tau protein hyperphosphorylation (Ser396). [ABSTRACT FROM AUTHOR]

Abstract A series of aminothiazolyl norfloxacin analogues as a new type of potential antimicrobial agents were synthesized and screened for their antimicrobial activities. Most of the prepared compounds exhibited excellent inhibitory efficiencies. Especially, norfloxacin analogue II - c displayed superior antimicrobial activities against K. pneumoniae and C. albicans with MIC values of 0.005 and 0.010 mM to reference drugs, respectively. This compound not only showed broad antimicrobial spectrum, rapid bactericidal efficacy and strong enzymes inhibitory potency including DNA gyrase and chitin synthase (CHS), low toxicity against mammalian cells and no obvious propensity to trigger the development of bacterial resistance, but also exerted efficient membrane permeability, and could effectively intercalate into K. pneumoniae DNA to form a steady supramolecular complex, which might block DNA replication to exhibit their powerful antimicrobial activity. Quantum chemical studies were also performed to explain the high antimicrobial activities. Molecular docking showed that compound II - c could bind with gyrase–DNA and topoisomerase IV–DNA through hydrogen bonds and π-π stacking. Graphical abstract Image 1 Highlights • Novel aminothiazolyl norfloxacin analogues with broad antimicrobial spectrum were developed. • Compound II-c displayed low MIC values of 0.005 and 0.010 mM against K. pneumoniae and C. albicans. • Compound II-c showed strong enzyme inhibition, low toxicity and slow development of resistance. • Molecule II - c could bind with DNA gyrase and topoisomerase IV via hydrogen bonds and π-π stacking. • Compound II - c could intercalate DNA and disturb the K. pneumoniae membrane. [ABSTRACT FROM AUTHOR]

Abstract Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme in many bacterial pathogens and is considered as a potential drug target for the development of new antibacterial agents. Our recent work has revealed the crucial role of one of the two structural domains (i.e. Bateman domain) in the regulation of the quaternary structure and enzymatic activity of bacterial IMPDHs. Thus, we have screened chemical libraries to search for compounds targeting the Bateman domain and identified first in-class allosteric inhibitors of a bacterial IMPDH. These inhibitors were shown to counteract the activation by the natural positive effector, MgATP, and to block the enzyme in its apo conformation (low affinity for IMP). Our structural studies demonstrate the versatility of the Bateman domain to accommodate totally unrelated chemical scaffolds and pave the way for the development of allosteric inhibitors, an avenue little explored until now. Graphical abstract Image 1 Highlights • Four chemical series identified as novel allosteric IMPDH inhibitors by HTS. • Original binding mode in the Bateman domain solved by X-ray structure. • First in-class inhibitors trap IMPDH in its apo conformation. [ABSTRACT FROM AUTHOR]

Abstract Numerous metal-containing enzymes (metalloenzymes) have been considered as drug targets related to diseases such as cancers, diabetes, anemia, AIDS, malaria, bacterial infection, fibrosis, and neurodegenerative diseases. Inhibitors of the metalloenzymes have been developed independently, most of which are mimics of substrates of the corresponding enzymes. However, little attention has been paid to the interactions between inhibitors and active site metal ions. This review is focused on different metal binding fragments and their chelating properties in the metal-containing active binding pockets of metalloenzymes. We have enumerated over one hundred of inhibitors targeting various metalloenzymes and identified over ten kinds of fragments with different binding patterns. Furthermore, we have investigated the inhibitors that are undergoing clinical evaluation in order to help looking for more potential scaffolds bearing metal binding fragments. This review will provide deep insights for the rational design of novel inhibitors targeting the metal-containing binding sites of specific proteins. Graphical abstract Image 1 Highlights • Various metalloenzymes and their representative inhibitors are reviewed. • Major structural properties that reflect chelating ability are provided. • Inhibitors undergoing clinical evaluation are included. [ABSTRACT FROM AUTHOR]

Abstract Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G 0 /G 1 phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC 50 values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a c ompound that in hibits Cd k4 and t ubulin. Its IC 50 value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC 50 of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G 0 /G 1 and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle. Graphical abstract Image 1 Highlights • Dual inhibitors of Cdk4 & tubulin polymerization (TP) identified employing HTVS. • Quinazolinone scaffold selected from the hits of ligand-.→ structure-based HTVS • Four dual inhibitors (29 , 34 , 40 & 50) were identified from enumerated library. • Cink4T (40) , inhibited Cdk4 & TP with IC 50 of 0.47 and 0.6 μM, respectively. [ABSTRACT FROM AUTHOR]

Clinically used pan and class I HDACi cause severe side effects, whereas class IIa HDACi are less cytotoxic. Here, we present the synthesis and anticancer effects of a series of 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO)-based amides and alkoxyamides derived from the previously reported class IIa HDACi YAK540. The most active class IIa inhibitor 1a showed nanomolar inhibition of the class IIa enzymes 4, 5, 7 (IC 50 HDAC4: 12 nM) and high selectivity (selectivity index >318 for HDAC4) over non-class IIa HDACs. Instead of a hydroxamic acid group, 1a has a trifluoromethyloxadiazolyl (TFMO) moiety as a non-chelating Zinc-binding group (ZBG). Applying the Chou-Talalay-method we found an increased synergistic cytotoxic effect of 1a in combination with bortezomib in THP1 cells. 1a in combination with bortezomib enhanced expression of p21 leading to increased caspase-induced apoptosis. Eventually, growth inhibition by 1a of the head-neck cancer cell line Cal27 was increased upon HDAC4 overexpression in Cal27 in cell culture and using the in vivo chorioallantoic membrane model. The class IIa HDACi 1a outperforms previously described HDAC class IIa inhibitor YAK540 regarding anticancer effects and may constitute a novel option compared to pan and class I HDACi in anticancer combination treatments. [Display omitted] • Class IIa HDAC inhibitor 1a shows synergistic anticancer activity with bortezomib. • 1a induces strong caspase 3/7 mediated apoptosis and increased p21 expression. • Structure-activity-relationship analysis of TFMO-based HDAC class IIa -Inhibitors. [ABSTRACT FROM AUTHOR]

Dual cyclooxygenase 2/15-lipoxygenase inhibitors constitute a valuable alternative to classical non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 (cyclooxygenase-2) inhibitors for the treatment of inflammatory diseases, as well as preventing the cancer. Indeed, these latter present diverse side effects, which are reduced or absent in dual-acting agents. In this review, COX-2 and 15-LOX (15-lipoxygenase) pathways are first described in order to highlight the therapeutic interest of designing such compounds. Various structural families of dual inhibitors are illustrated. This study discloses various structural families of dual 15-LOX/COX-2 inhibitors, thus pave the way to design potentially-active anticancer agents with balanced dual inhibition of these enzymes. [Display omitted] • Cancer is a complex process, produces a number of inflammatory mediators. • Dual-acting COX-2/5-LOX inhibitors may treat cancer by suppressing COX-2 and 5-LOX enzymes. • 15-LOX inhibitors lack some of the side effects of 5-LOX inhibitors. • Implications of novel synthetic analogs as dual COX-2/15-LOX inhibitors are addressed in the present review paper. [ABSTRACT FROM AUTHOR]

The cytoplasmic steps of peptidoglycan synthesis represent an important targeted pathway for development of new antibiotics. Herein, we report the synthesis of novel 3-oxopyrazolidin-4-carboxamide derivatives with variable amide side chains as potential antibacterial agents targeting MurA enzyme, the first committed enzyme in these cytosolic steps. Compounds 15 (isoindoline-1,3-dione-5-yl), 16 (4-(1 H -pyrazol-4-yl)phenyl), 20 (5-cyanothiazol-2-yl), 21 and 31 (5-nitrothiazol-2-yl derivatives) exhibited the most potent MurA inhibition, with IC 50 values of 9.8–12.2 μM. Compounds 15 , 16 and 21 showed equipotent inhibition of the C115D MurA mutant developed by fosfomycin–resistant Escherichia coli. NMR binding studies revealed that some of the MurA residues targeted by 15 also interacted with fosfomycin, but not all, indicating an overlapping but not identical binding site. The antibacterial activity of the compounds against E. coli Δ tolC suggests that inhibition of MurA accounts for the observed effect on bacterial growth, considering that a few potent MurA inhibitors could not penetrate the bacterial outer membrane and were therefore inactive as proven by the bacterial cell uptake assay. The most promising compounds were also evaluated against a panel of Gram-positive bacteria. Remarkably, compounds 21 and 31 (MurA IC 50 = 9.8 and 10.2 μM respectively) exhibited a potent activity against Clostridioides difficile strains with MIC values ranging from 0.125 to 1 μg/mL, and were also shown to be bactericidal with MBC values between 0.25 and 1 μg/mL. Furthermore, both compounds were shown to have a limited activity against human normal intestinal flora and showed high safety towards human colon cells (Caco-2) in vitro. The thiolactone derivative (compound 5) exhibited an interesting broad spectrum antibacterial activity despite its weak MurA inhibition. Altogether, the presented series provides a promising class of antibiotics that merits further investigation. [Display omitted] • 15 , 16 and 21 could equally inhibit wildtype and C115D MurA mutant developed by fosfomycin-resistant E. coli. • NMR studies revealed partial overlap between 15 and fosfomycin in binding to MurA. • 21 and 31 were 2–8 folds more potent than vancomycin against some C. difficile clinical strains. • 21 and 31 exhibited a bactericidal action and showed high stability in culture media and bacterial cell lysate. • 21 and 31 exhibited restricted activity against representatives of the human normal microbiota. [ABSTRACT FROM AUTHOR]

Abstract A novel chemotype topologically similar to known influenza virus PA endonuclease inhibitors has been designed. It was aimed to reproduce the extended topology of the known metal-chelating ligands with a p -phenylidene-linked bis-imidazoline scaffold. It was envisioned that aromatic groups introduced to this scaffolds via metal-catalyzed N -arylation (Buchwald-Hartwig or Chan-Evans-Lam) would contribute to lipophilic binding to the target and one of the imidazoline nitrogen atoms would ensure non-chelating coordination to the prosthetic divalent metal ion. The compounds displayed appreciable anti-influenza activity in vitro and substantial concentration window from the general cytotoxicity range. Docking analysis of low-energy poses of the most active compound (as well as their comparison to the binding of an inactive compound) revealed that these compounds reproduced similar binding components to a known PA endonuclease inhibitor and displayed similar binding pose and desired monodentate metal coordination, as was initially envisioned. These findings warrant further investigation of the mechanism of action of the newly discovered series. Graphical abstract Image 1 Highlights • Novel series was seen as similar to known influenza virus PA endonuclease inhibitors. • It was envisioned to reproduce extended topology of the inhibitor molecule. • No obvious metal-chelating motifs were employed. • Compounds were shown to possess anti-influenza virus activity and low cytotoxicity. • Biological data are in accord with docking results suggesting mechanism of action. [ABSTRACT FROM AUTHOR]

Abstract A number of new F-triazolequinolones (FTQs) and alkoxy-triazolequinolones (ATQs) were designed, synthesized and evaluated for their activity against Mycobacterium tuberculosis H37Rv. Five out of 21 compounds exhibited interesting minimum inhibitory concentration (MIC) values (6.6–57.9 μM), ATQs generally being more potent than FTQs. Two ATQs, 21a and 30a , were endowed with the best anti-Mtb potency (MIC = 6.9 and 6.6 μM, respectively), and were not cytotoxic in a Vero cell line. Tested for activity against M. tuberculosis DNA gyrase in a DNA supercoiling activity assay, 21a and 30a showed IC 50 values (27–28 μM) comparable to that of ciprofloxacin (10.6 μM). 21a was next selected for screening against several Mtb strains obtained from clinical isolates, including multi-drug-resistant (MDR) variants. Importantly, this compound was effective in all cases, with very promising MIC values (4 μM) in the case of some isoniazid/rifampicin-resistant Mtb strains. Finally, computer-based simulations revealed that the binding mode of 21a in the Mtb gyrase cleavage core complexed with DNA and the relevant network of intermolecular interactions are utterly similar to those described for ciprofloxacin, yielding a molecular rationale for the comparable anti-mycobacterial and DNA gyrase inhibition activity of this quinolone. Graphical abstract Two alkoxy-triazolequinolones, 21a and 30a , showed selective inhibition against Mycobacterium tuberculosis H37Rv and a set of Mtb strains obtained from clinical isolates. They were assessed for their ability to inhibit Mtb DNA gyrase in a DNA supercoiling activity assay, when compared to ciprofloxacin they were found to be equally active. Image 1 Highlights • Triazole derivatives are of great interest in medicinal chemistry. • We have synthesized 4-alkoxy-triazoloquinolones endowed with antitubercular activity. • 4-alkoxy-triazoloquinolones inhibit the M. tuberculosis DNA gyrase in a different way compared to the classic quinolones. • We have shown that these derivatives are selective for M. tuberculosis and inactive against the other bacteria. [ABSTRACT FROM AUTHOR]

Abstract Antimicrobial resistance resulting in ineffective treatment of infectious diseases is an increasing global problem, particularly in infections with pathogenic bacteria. In some bacteria, such as Streptococcus pyogenes , the pathogenicity is strongly linked to the attachment of virulence factors. Their attachment to the cellular membrane is a transpeptidation reaction, catalyzed by sortase enzymes. As such, sortases pose an interesting target for the development of new antivirulence strategies that could yield novel antimicrobial drugs. Using the substitution-oriented fragment screening (SOS) approach, we discovered a potent and specific inhibitor (C10) of sortase A from S. pyogenes. The inhibitor C10 showed high specificity towards S. pyogenes sortase A, with an IC 50 value of 10 μM and a K d of 60 μM. We envision that this inhibitor could be employed as a starting point for further exploration of sortase's potential as therapeutic target for antimicrobial drug development. Graphical abstract Image 1 Highlights • Sortase A is used as a target for the development of new antivirulence drugs. • A focused library of small, indole-based molecules was designed. • Substitution-oriented fragment screening was applied to find a potent inhibitor. • Molecular modeling was performed to propose binding of the inhibitor and the enzyme. [ABSTRACT FROM AUTHOR]

Abstract c-Jun N-terminal kinases (JNKs) play a central role in many physiologic and pathologic processes. We synthesized novel 11 H -indeno[1,2- b ]quinoxalin-11-one oxime analogs and tryptanthrin-6-oxime (indolo[2,1- b ]quinazoline-6,12-dion-6-oxime) and evaluated their effects on JNK activity. Several compounds exhibited sub-micromolar JNK binding affinity and were selective for JNK1/JNK3 versus JNK2. The most potent compounds were 10c (11 H -indeno[1,2- b ]quinoxalin-11-one O -(O -ethylcarboxymethyl) oxime) and tryptanthrin-6-oxime, which had dissociation constants (K d) for JNK1 and JNK3 of 22 and 76 nM and 150 and 275 nM, respectively. Molecular modeling suggested a mode of binding interaction at the JNK catalytic site and that the selected oxime derivatives were potentially competitive JNK inhibitors. JNK binding activity of the compounds correlated with their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation in human monocytic THP-1Blue cells and interleukin-6 (IL-6) production by human MonoMac-6 cells. Thus, oximes with indenoquinoxaline and tryptanthrin nuclei can serve as specific small-molecule modulators for mechanistic studies of JNK, as well as potential leads for the development of anti-inflammatory drugs. Graphical abstract Image 1 Highlights • New c-Jun N-terminal kinase (JNK) inhibitors were synthesized. • Compounds 10c and tryptanthrin-6-oxime were the most potent JNK inhibitors. • Compounds 6i , 10c , and tryptanthrin-6-oxime exhibited high selectivity for JNK1/JNK3 versus JNK2. • The active JNK inhibitors inhibited NF-κB/AP-1 activation and IL-6 production by human monocytic cells. [ABSTRACT FROM AUTHOR]

Abstract No antiviral drugs to treat or prevent life-threatening flavivirus infections such as those caused by mosquito-borne Dengue (DENV) and more recently Zika (ZIKV) viruses are yet available. We aim to develop, through a structure-based drug design approach, novel inhibitors targeting the NS5 AdoMet-dependent mRNA methyltransferase (MTase), a viral protein involved in the RNA capping process essential for flaviviruses replication. Herein, we describe the optimization of a hit (5) identified using fragment-based and structure-guided linking techniques, which binds to a proximal site of the AdoMet binding pocket. X-ray crystallographic structures and computational docking were used to guide our optimization process and lead to compounds 30 and 33 (DENV IC 50 = 26 μM and 23 μM; ZIKV IC 50 = 28 μM and 19 μM, respectively), two representatives of novel non-nucleoside inhibitors of flavivirus MTases. Graphical abstract Image 1 Highlights • A fragment-based drug design approach on flavivirus methyltransferase. • Optimization of non-nucleosidique methyltransferase inhibitors by fragment-growing. • Validation of Dengue and Zika viruses methyltransferases inhibition. [ABSTRACT FROM AUTHOR]

Abstract The conjugated system of cinnamic acid, α-substituted with a phosphonoalkyl residue, was previously validated as a scaffold that provided one of the most potent organophosphorus inhibitors of bacterial urease. Following the idea of using Morita-Baylis-Hillman adducts to introduce the terminal phosphonic side chain functionality to the α,β-unsaturated system, we currently report the synthesis and activity of an extended series of compounds. Cinnamates modified with 3-phosphonopropyl and 4-phosphonobutyl side chains were obtained in a convenient two-step procedure, which involved Pd-mediated transformations of the Morita-Baylis-Hillman bromides as the key substrates. The introduction of a terminal alkenyl fragment, which was achieved by Stille coupling with stannanes, was followed by a tandem C-P bond formation/oxidation process. A submicromolar ligand of Sporosarcina pasteurii urease (K i = 0.509 μM) was identified among the active molecules. In addition, inhibitors of Proteus mirabilis urease affected bacterial growth at the micromolar level. Based on the structure-activity relationship and the mechanism of inhibition, we suggest a nontypical mixed mode of action for the slow binding compounds. We presume that the molecular distance between the phosphonic group and the backbone double bond allows a dual activity: complexation of the acidic group with nickel ions and Michael addition of a cysteine forming the active site lid. Graphical abstract Image 1 Highlights • Multistep synthesis of organophosphorus cinnamic acid-based compounds was elaborated. • The most potent compounds showed slow-binding mechanism of inhibition and submicromolar activity. • Molecular modeling indicated mode of binding based on interaction with metal ions and reaction with cysteine residue. [ABSTRACT FROM AUTHOR]

Abstract Chalcones and 1,2-benzothiazines are two important classes of bioactive compounds, each scaffold endowed with diverse pharmacological activities. Combining both of these pharmacophores in a single molecule was aimed to yield multi-modal agents. Herein, we report a series of hybrid compounds 3a – 3o derived from chalcones and 1,2-benzothiazine cores. They were synthesized from commercially available sodium saccharin, and the resulting 1,2-benzothiazine-derived ketone was then condensed with aromatic aldehydes in an aldol condensation to obtain the respective chalcones. The compounds were characterized using different analytical techniques including FT-IR, NMR spectroscopy, mass spectrometry and X-ray crystallography. Some synthesized chalcones revealed potent and/or selective inhibitory properties towards alkaline phosphatase isozymes transiently expressed in COS-7 cells. A detailed structure-activity and selectivity study was carried out with regard to the effect of different substituents at ortho -, meta - and para -positions of the phenyl residue. Compound 3c was the most effective human intestinal alkaline phosphatase (h -IAP) inhibitor (IC 50 value of 1.04 μM), while it was not active against human tissue non-specific alkaline phosphatase (h -TNAP) isozyme. In contrast, 3i was a selective inhibitor of h -TNAP with IC 50 values of 0.25 ± 0.01 μM. The possible binding interactions of the most effective inhibitors of h -TNAP and h -IAP were obtained from molecular docking studies. Graphical abstract Image 1 Highlights • synthesis of hybride compounds derived from chalcone and 1,2-benzothiazine pharmacophores. • Potent and/or selective inhibitors of alkaline phosphatase isozymes. • Structure-activity and selectivity study with regard to different substituents at the phenyl residue. • Molecular docking studies of the most effective inhibitors of h -TNAP and h -IAP. [ABSTRACT FROM AUTHOR]

Abstract In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]⋅CH 3 OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4′-dimethyl-2,2′-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1 Pt7 exhibited cytotoxic activity against the tested NCI H460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity. Pt5 exhibited an IC 50 value of 0.13 ± 0.16 μM against SK-OV-3/DDP cancer cells and significantly reduced tumor growth in a Hep-G2 xenograft mouse model (tumor growth inhibition (TGI) = 40.8%, p < 0.05) at a dose of 15.0 mg/kg. Interestingly, Pt1 Pt7 displayed low cytotoxicity against normal HL-7702 cells. Mechanistic studies revealed that these compounds caused cell cycle arrest at the G2/M and S phases, and regulated the expression of CDK2, cyclin A, p21, p53 and p27. Further mechanistic studies showed that Pt5 induced SK-OV3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity by directly targeting the c-myc promoter, and activation of the p53 signaling pathway. Taken together, Pt5 has the potential to be further developed as a new antitumor drug. Graphical abstract Pt5 induced SK-OV-3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity and activation of the p53 signaling pathway. Image 1 Highlights • We designed and synthesized tacrine platinum(II) complexes Pt1 Pt7 as telomerase inhibitors and p53 activators. • Pt5 display high in vivo and in vitro anticancer activity. • Pt5 may trigger cell apoptosis via a mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

Abstract Frequent oncogenic mutations have been identified in MAPK (mitogen-activated protein kinase) signaling pathway components. As a result, MAPK pathway is associated with human cancer initiation, in particular RAF (rapidly accelerated fibrosarcoma) component. The mutation in RAF component leads to auto-activation of MAPK signaling pathway, stimulating the uncontrolled cell growth and proliferation. In last few years, diverse chemical scaffolds have been identified as RAF inhibitors. Most of these scaffolds show potent anti-cancer activity. The present review highlights the recent investigations of RAF inhibitors during the last five years. Graphical abstract Image 1 Highlights • MAPK signaling pathway activation contributes to stimulation of cell proliferation. • RAF kinases are considered as key components in MAPK signaling pathway. • RAF protein kinase mutation triggers the auto-activation of MAPK signaling pathway. • RAF inhibitors exhibit potent anti-cancer activity. • The present review provides the recent progress in RAF inhibitors identification. [ABSTRACT FROM AUTHOR]

Abstract SCD1 is a rate-limiting enzyme in the conversion of saturated fatty acids to monounsaturated fatty acids. SCD1 inhibitors have potential effects on obesity, diabetes, acne, and cancer, but the adverse effects associated with SCD1 inhibition in the skin and eyelids are impediments to clinical development. To avoid mechanism-based adverse effects, we explored the compounds that selectively inhibit SCD1 in the liver in an ex vivo assay. Starting from a systemically active lead compound, we focused on the physicochemical properties tPSA and cLogP to minimize exposure in the off-target tissues. This effort led to the discovery of thiazole-4-acetic acid analog 48 as a potent and liver-selective SCD1 inhibitor. Compound 48 exhibited significant effects in rodent models of diabetes, hepatic steatosis, and obesity, with sufficient safety margins in a rat toxicology study with repeated dosing. Graphical abstract Image 1 Highlights • Lead compound 4 was developed as a potent, systemically distributed SCD1 inhibitor. • Modifying 4 's physicochemical properties could change the tissue distribution pattern. • SCD1 activity in the liver/eyelid was measured in an ex vivo assay. • Thiazole-4-acetic acid analog 48 is potent, orally active, and liver-selective. • SCD1 inhibitor 48 could have a sufficient therapeutic window for chronic treatment. [ABSTRACT FROM AUTHOR]

Abstract Phosphatidylinositol 3-kinase α (PI3Kα) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kα H1047R mutant inhibitor Hit-02 (EC 50 = 115.3 μM), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h , which strongly inhibited PI3Kα H1047R mutant with an EC 50 value of 0.55 μM, over 200-fold more potent than Hit-02 , while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3Kα H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC 50 value of 10.9 μM. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti-proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3Kα inhibitor. Graphical abstract Image 1 Highlights • Compound 7h displays a potent PI3Kα H1047R inhibitory activity with EC 50 value of 0.55 μM. • Compound 7h reduces HCT-116 cells growth. • Compound 7h is a selective PI3Kα inhibitor. [ABSTRACT FROM AUTHOR]

Abstract The trans -sialidase protein expressed by Trypanosoma cruzi is an important enzyme in the life cycle of this human pathogenic parasite and is considered a promising target for the development of new drug treatments against Chagas' disease. Here we describe α-amino phosphonates as a novel class of inhibitor of T. cruzi trans -sialidase. Molecular modelling studies were initially used to predict the active-site binding affinities for a series of amino phosphonates, which were subsequently synthesised and their IC 50 s determined in vitro. The measured inhibitory activities show some correlation with the predictions from molecular modelling, with 1-napthyl derivatives found to be the most potent inhibitors having IC 50 s in the low micromolar range. Interestingly, kinetic analysis of the mode of inhibition demonstrated that the α-aminophosphonates tested here operate in a non-competitive manner. Graphical abstract Image 1 Highlights • Aryl α-aminophosphonates are effective inhibitors of T. cruzi trans -sialidase. • Inhibition of trans -sialidase is improved using substituted aryl α-aminophosphonates. • Aryl α-aminophosphonates inhibit trans -sialidase in a non-competitive manner. [ABSTRACT FROM AUTHOR]

Abstract ATP citrate lyase (ACLY) is a cytosolic homotetrameric enzyme that catalyzes the conversion of citrate and coenzyme A (CoA) to acetyl-CoA and oxaloacetate, with the simultaneous hydrolysis of ATP to ADP and phosphate. Interestingly, ACLY is a strategic enzyme linking both the glycolytic and lipidic metabolism. In tumour cells characterized by an altered energetic metabolism, an increased glucose uptake and an accelerated glycolytic flux lead to an intensified production of mitochondrial citrate. Once transported to the cytosol, citrate is here converted by ACLY to acetyl-CoA, an essential biosynthetic precursor for fatty acid synthesis and mevalonate pathway. ACLY expression and activity proved to be aberrantly expressed in many types of tumours, and its pharmacological or genetic inhibition significantly inhibited cancer cell proliferation and induced apoptosis. Increasing evidences highlight the central role of ACLY, conferring a great therapeutic potential to this enzyme as a key target for the treatment of cancer. ACLY inhibitors, previously developed for metabolic disorders, have recently attracted interest as promising anti-cancer agents. After a brief introduction to the structure and the pathophysiological role of ACLY, this review article provides an overview of the main ACLY inhibitors reported in the literature. Graphical abstract Image 1 Highlights • ACLY is a key enzyme in cancer metabolism. • ACLY is involved in glucose and lipid metabolism. • Many ACLY inhibitors were developed as anti-cancer agents. [ABSTRACT FROM AUTHOR]

Abstract Even though many GyrB and ParE inhibitors have been reported in the literature, few possess activity against Gram-negative bacteria. This is primarily due to limited permeability across Gram-negative bacterial membrane as well as bacterial efflux mechanisms. Permeability of compounds across Gram-negative bacterial membranes depends on many factors including physicochemical properties of the inhibitors. Herein, we show the optimization of pyridylureas leading to compounds with potent activity against Gram-negative bacterial species such as P.aeruginosa, E.coli and A.baumannii. Graphical abstract Image 1 Highlights • Potent dual inhibitors of Gram-negative GyraseB and ParE enzymes has been identified. • Balancing the basicity and acidity of the groups lead to compounds with good permeability. • Compounds exhibit broad-spectrum activity and 2–8 μg/mL MIC 90 against P.aeruginosa and A.baumannii. [ABSTRACT FROM AUTHOR]

Abstract Indoleamine 2,3-dioxygenase 1 (IDO1) mediated kynurenine pathway of tryptophan degradation is identified as an appealing and novel target in immunotherapy for the treatment of cancer. In this study, a novel series of naphthoquinone derivatives were synthesized, characterized and evaluated for their inhibitory activities against IDO1, and their structure−activity relationship was investigated. Among them, compounds T16 , T44 , T47 , T49 , T53 and T54 displayed potent IDO1 inhibitory activities with IC 50 values ranging between 18 and 61 nM, which are more potent than INCB024360 undergoing clinical trial III evaluation. In addition, compounds T28 , T44 and T53 decreased the kynurenine levels in rat plasma by 30%–50%. Compounds exhibiting excellent IDO1 inhibitory activities were also evaluated for their inhibitory activities against tryptophan 2,3-dioxygenase (TDO). Of which, compound T28 (IDO1 IC 50 = 120 nM) showed promising TDO inhibition (IC 50 72 nM) and was identified as an IDO1/TDO dual inhibitor. Graphical abstract Image 1 Highlights • 60 naphthoquinone derivatives were synthesized and evaluated for IDO1/TDO inhibitory activity. • T47 , T53 , T44 were the most potent IDO1 inhibitors (IC 50 18, 18, 26 nM) with high selectivity against TDO. • T28 was identified as a potent dual IDO1/TDO inhibitor (IC 50 120/72 nM). • A single, oral dose of T44 decreased kynurenine levels in rat plasma by 50.1%. [ABSTRACT FROM AUTHOR]

Abstract Phosphatidylinositol 3-kinase α (PI3Kα) is the most frequently mutated kinase in human cancers, making it an attractive therapeutic target for cancer treatment. We identified a structurally novel PI3Kα H1047R mutant inhibitor Hit-01 (EC 50 = 76.0 μM) through a high-throughput screening campaign. Chemical optimizations enabled us to discover compound 7b , which strongly inhibited PI3Kα H1047R mutant with an EC 50 value of 0.137 μM, over 500-fold more potent than Hit-01. Western blotting analysis suggested that 7b could decrease the phosphorylation level of p -AKT, another proof that 7b inhibited PI3Kα H1047R function. Cell viability assay revealed that 7b inhibited HCT116 cancer cell growth with an IC 50 value of 11.23 μM. In addition, 7b was found to arrest cell cycle at G1 phase and induce cell apoptosis via up-regulation of caspase-3, caspase-8 and caspase-9 protein expressions. Collectively, all these data demonstrated that 7b could be a promising lead for the development of structurally novel PI3Kα inhibitors. Graphical abstract Image 1 Comp. EC 50 (μM) IC 50 (μM) Improved potency (Hit-01 to 7b) PI3Kα H1047R mutant PI3Kα WT HCT116 Hit-01 76.0 NT >100 76.0/0.137 > 500 (enzymatic level) 7b 0.137 0.093 11.2 100/11.2 > 9 (cellular level) Highlights • Compound 7b displayed a potent PI3Kα H1047R inhibitory activity. • Compound 7b strongly inhibited HCT116 cancer cell proliferation. • Compound 7b had little effect on other PI3K isoforms. [ABSTRACT FROM AUTHOR]

Abstract Purple acid phosphatases (PAPs) are metalloenzymes that catalyse the hydrolysis of phosphate esters under acidic conditions. Their active site contains a Fe(III)Fe(II) metal centre in mammals and a Fe(III)Zn(II) or Fe(III)Mn(II) metal centre in plants. In humans, elevated PAP levels in serum strongly correlate with the progression of osteoporosis and metabolic bone malignancies, which make PAP a target suitable for the development of chemotherapeutics to combat bone ailments. Due to difficulties in obtaining the human enzyme, the corresponding enzymes from red kidney bean and pig have been used previously to develop specific PAP inhibitors. Here, existing lead compounds were further elaborated to create a series of inhibitors with K i values as low as ∼30 μM. The inhibition constants of these compounds were of comparable magnitude for pig and red kidney bean PAPs, indicating that relevant binding interactions are conserved. The crystal structure of red kidney bean PAP in complex with the most potent inhibitor in this series, compound 4f , was solved to 2.40 Å resolution. This inhibitor coordinates directly to the binuclear metal centre in the active site as expected based on its competitive mode of inhibition. Docking simulations predict that this compound binds to human PAP in a similar mode. This study presents the first example of a PAP structure in complex with an inhibitor that is of relevance to the development of anti-osteoporotic chemotherapeutics. Graphical abstract Image 1 Highlights • A lead inhibitor against Purple acid phosphatase has been further developed. • Compounds are active against both pig and red kidney bean Purple acid phosphatases. • A crystal structure of an inhibitor in complex with the red kidney bean enzyme (2.40 Å) is reported. [ABSTRACT FROM AUTHOR]

Abstract This paper describes the rational development of a series of novel spiroindoline derivatives endowed with selective inhibitory activity on the HDAC6 isoform. A convenient multicomponent one-pot protocol was applied for the assembly of the desired N 1-substituted spiroindoline core which allowed a straightforward analoging. Computational studies and in vitro determination of inhibitory potency for the developed compounds against HDAC6 and HDAC1 isoforms were flanked by cell-based studies on histone H3 and α-tubulin acetylation. The effects on cancer cell cycle and apoptosis of the best performing derivatives were assessed on cancer cell lines highlighting a promising antitumor potential. In view of cell-based data and calculated drug-like properties, the selective HDAC6 inhibitor 5b , with a spiroindoline-based hydroxamate bearing a tert -butyl carbamate functionality, was selected to be further investigated for its potential in inhibiting tumor cells migration. It was able to potently inhibit cell migration in SH-SY5Y neuroblastoma cells and did not display toxicity in NIH3T3 mouse fibroblasts. Taken together, these data foster further investigation and optimization for this class of compounds as novel anticancer agents. Graphical abstract Image 1 Highlights • Rational design of novel spiroindoline as HDAC6 inhibitors. • Biological studies showed a strong antitumor potential for the synthesized compounds. • Compound 5b was able to potently inhibit cell migration in a SH-SY5Y cell culture. • Compound 5b did not display toxicity in NIH3T3 mouse fibroblasts. [ABSTRACT FROM AUTHOR]

Abstract The identification of novel Topoisomerase II (Topo II) inhibitors is one of the most attractive directions in the field of bactericide research and development. In our ongoing efforts to pursue the class of inhibitors, six series of 70 novel coumarin-pyrazole carboxamide derivatives were designed and synthesized. As a result of the evaluation against four destructive bacteria, including Staphylococcus aureus , Listeria monocytogenes , Escherichia coli and Salmonella. Compound 8III-k (MIC = 0.25 mg/L) showed considerable inhibitory activity than ciprofloxacin (MIC = 0.5 mg/L) against Escherichia coli and 8V-c (MIC = 0.05 mg/L) exhibited excellent antibacterial activity than ciprofloxacin (MIC = 0.25 mg/L) against Salmonella. The selected compounds (8III-k , 8V-c and 8V-k) exhibit potent inhibition against Topo II and Topo IV with IC 50 values (9.4–25 mg/L). Molecular docking model showed that the compounds 8V-c and 8V-k can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial Topo II inhibiting bactericides. Graphical abstract Image 1 Highlights • Structure-based design and synthesis of novel coumarin-pyrazole carboxamide derivatives are reported. • Molecular simulation was carried out to verify the rationality the reliability of the activity data of the compounds. • In vitro and in vivo studies reveal that some of the reported compounds possessed good antibacterial activities. [ABSTRACT FROM AUTHOR]

PI3Kδ, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3Kδ inhibitors. Among them compound 15i (CHMFL-PI3KD-317) displays an IC 50 of 6 nM against PI3Kδ in the ADP-Glo biochemical assays. It also exhibits over 10–1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3Kδ mediated phosphorylation of Akt T308 but not PI3Kα, β, γ mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 μM. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3Kδ armory. [ABSTRACT FROM AUTHOR]

Twenty pyrazole-containing diarylureas and diarylamides were designed and synthesized. They were tested for in vitro antiproliferative activity over a 58-cancer cell line panel at the NCI, USA. The diarylurea derivatives 1b-e and 1g exerted the strongest antiproliferative activity. Among them, compound 1e possessing 3,5-bis(trifluoromethyl)phenyl terminal ring and 3`-methoxy-5`-chlorophenyl ring attached to the central pyrazole ring was the most potent. Its IC 50 values were in sub-micromolar range against most of the tested cell lines. It showed superior potency than sorafenib, a reference diarylurea drug, over all the tested cell lines. It was also extremely selective towards cancer cells than non-cancerous cells (IC 50 against RAW 264.7 macrophages was higher than 100 μM). At molecular level, compound 1e selectively inhibited V600E mutated B-RAF kinase (IC 50  = 0.39 μM). It also stimulated caspase 3/7 enzymes in RPMI-8226 leukemia cells (2.79 fold increase at 10 μM concentration, EC 50  = 1.52 μM). So compound 1e may kill cancer cells through induction of apoptosis. This promising candidate can be considered further for development of new efficient anticancer agents. [ABSTRACT FROM AUTHOR]

Plants produce a diverse range of peptides and proteins that inhibit the activity of different serine proteases. The value of these inhibitors not only stems from their native role(s) in planta , but they are also regarded as promising templates for inhibitor engineering. Interest in this field has grown rapidly in recent years, particularly for therapeutic applications. The serine protease mesotrypsin has been implicated in several cancers, but is a challenging target for inhibitor engineering as a number of serine protease inhibitors that typically display broad-range activity show limited activity against mesotrypsin. In this study, we use a cyclic peptide isolated from sunflower seeds, sunflower trypsin inhibitor-1 (SFTI-1), as a scaffold for engineering potent mesotrypsin inhibitors. SFTI-1 comprises 14-amino acids and is a potent inhibitor of human cationic trypsin ( K i  = 30 ± 0.8 pM) but shows 165,000-fold weaker activity against mesotrypsin ( K i  = 4.96 ± 0.2 μM). Using an inhibitor library based on SFTI-1, we show that the inhibitor's P2′ residue (Ile) is a key contributor to SFTI-1's limited activity against mesotrypsin. Substituting P2′ Ile with chemically diverse amino acids, including non-canonical aromatic residues, produced new inhibitor variants that maintained a similar structure to SFTI-1 and showed marked improvements in activity (exceeding 100-fold). An assessment of the activity of the new inhibitors against closely-related trypsin paralogs revealed that the improved activity against mesotrypsin was accompanied by a loss in activity against off-target proteases, such that several engineered variants showed comparable activity against mesotrypsin and human cationic trypsin. Together, these findings identify potent mesotrypsin inhibitors that are suitable for further optimisation studies and demonstrate the potential gains in activity and selectivity that can be achieved by optimising the P2′ residue, particularly for engineered SFTI-based inhibitors. [ABSTRACT FROM AUTHOR]

Butyrylcholinesterase (BuChE) inhibitors have become interesting target for treatment of Alzheimer's disease (AD). A series of dual binding site BuChE inhibitors were designed and synthesized based on 2,3,4,9-tetrahydro-1H-carbazole attached benzyl pyridine moieties. In-vitro assay revealed that all of the designed compounds were selective and potent BuChE inhibitors. The most potent BuChE inhibitor was compound 6i (IC 50  = 0.088 ± 0.0009 μM) with the mixed-type inhibition. Docking study revealed that 6i is a dual binding site BuChE inhibitor. Also, Pharmacokinetic properties for 6i were accurate to Lipinski's rule. In addition, compound 6i demonstrated neuroprotective and β-secretase (BACE1) inhibition activities. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation at concentration of 100 μM and 10 μM respectively. Generally, the results are presented as new potent selective BuChE inhibitors with a therapeutic potential for the treatment of AD. [ABSTRACT FROM AUTHOR]

Inflammation comprises the reaction of the body to injury, in which a series of changes of the terminal vascular bed, blood, and connective tissue tends to eliminate the injurious agent and to repair the damaged tissue. It is a complex process, which involves the release of diverse regulatory mediators. The current anti-inflammatory agents are challenged by multiple side effects and thus, new effective therapies are highly needed. The aim of this review is to summarize the described microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors or transcriptional suppressors from medicinal plants, which could be an ideal approach in the management of inflammatory disorders, but need further clinical trials in order to be ultimately validated. [ABSTRACT FROM AUTHOR]

Two series of 2-benzylpiperazines have been prepared and tested for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1). The new compounds carry on one nitrogen atom of the piperazine ring a sulfamoylbenzamide group as zinc-binding moiety, and different alkyl/acyl/sulfonyl groups on the other nitrogen. Regio- and stero-isomers are described. The majority of these compounds showed Ki values in the low-medium nanomolar range against hCA I, II and IV, but not IX. In many instances interaction with the enzyme was enantioselective. The binding mode has been studied by means of X-ray crystallography and molecular modelling. Two compounds, evaluated in rabbit models of glaucoma, were able to significantly reduce intraocular pressure, making them interesting candidates for further studies. [ABSTRACT FROM AUTHOR]