Publications by authors named "Shutao Ma"

79 Publications

Design, synthesis and structure-activity relationships of novel N11-, C12- and C13-substituted 15-membered homo-aza-clarithromycin derivatives against various resistant bacteria.

Bioorg Chem 2021 Aug 18;113:104992. Epub 2021 May 18.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, PR China. Electronic address:

Bacterial infections are still the main significant problem of public health in the world, and their elimination will greatly rely on the discovery of antibacterial drugs. In the processes of our searching for novel macrolide derivatives with excellent activity against sensitive and resistant bacteria, three series of novel N11-, C12- and C13-substituted 15-membered homo-aza-clarithromycin derivatives were designed and synthesized as Series A, B and C by creatively opening the lactone ring of clarithromycin (CAM), introducing various 4-substituted phenyl-1H-1,2,3-triazole side chains at the N11, C12 or C13 position of CAM and macrolactonization. The results from their in vitro antibacterial activity demonstrated that compounds 20c, 20d and 20f displayed not only the most potent activity against S. aureus ATCC25923 with the MIC values of 0.5, 0.5 and 0.5 µg/mL, but also greatly improved activity against B. subtilis ATCC9372 with the MIC values of less than or equal to 0.25, 0.25 and 0.25 µg/mL, respectively. In particular, compound 11g exhibited the strongest antibacterial effectiveness against all the tested resistant bacterial strains and had well balanced activity with the MIC values of 4-8 µg/mL. Further study on minimum bactericidal concentration and kinetics confirmed that compound 11g possessed a bacteriostatic effect on bacterial proliferation. Moreover, the results of molecular docking revealed an potential additional binding force between compound 11g and U790 in addition to the normal binding force of macrolide skeleton, which may explain why this compound performed the most potent activity against resistant bacteria. The results of cytotoxic assay indicated that compounds 20c, 20d and 20f were non-toxic to human breast cancer MCF-7 cells at its effective antibacterial concentration.
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http://dx.doi.org/10.1016/j.bioorg.2021.104992DOI Listing
August 2021

Design, synthesis and antibacterial evaluation of novel C-11, C-9 or C-2'-substituted 3-O-descladinosyl-3-ketoclarithromycin derivatives.

Bioorg Med Chem Lett 2021 Jul 13;43:128110. Epub 2021 May 13.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China. Electronic address:

A novel series of 3-O-descladinosyl-3-keto-clarithromycin derivatives, including 11-O-carbamoyl-3-O-descladinosyl-3-keto-clarithromycin derivatives and 2',9(S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial activity. Among them, some derivatives were found to have activity against resistant bacteria strains. In particular, compound 9b showed not only the most significantly improved activity (16 µg/mL) against S. aureus ATCC43300 and S. aureus ATCC31007, which was >16-fold more active than that of CAM and AZM, but also the best activity against S. pneumoniae B1 and S. pyogenes R1, with MIC values of 32 and 32 µg/mL. In addition, compounds 9a, 9c, 9d and 9g exhibited the most effective activity against S. pneumoniae AB11 with MIC values of 32 or 64 µg/mL as well. Unfortunately, 2',9(S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin derivatives failed to exhibit better antibacterial activity than references. It can be seen that the combined modification of the C-3 and C-11 positions of clarithromycin is beneficial to improve activity against resistant bacteria, while the single modification of the C-2'' position is very detrimental to antibacterial activity.
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http://dx.doi.org/10.1016/j.bmcl.2021.128110DOI Listing
July 2021

Design, synthesis and evaluation of novel 9-arylalkyl-10-methylacridinium derivatives as highly potent FtsZ-targeting antibacterial agents.

Eur J Med Chem 2021 Oct 28;221:113480. Epub 2021 Apr 28.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, 250012, China. Electronic address:

With the increasing incidence of antibiotic resistance, new antibacterial agents having novel mechanisms of action hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Four novel series of substituted 9-arylalkyl-10-methylacridinium derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activities against various Gram-positive and Gram-negative bacteria. The results demonstrated that they exhibited broad-spectrum activities with substantial efficacy against MRSA and VRE, which were superior or comparable to the berberine, sanguinarine, linezolid, ciprofloxacin and vancomycin. In particular, the most promising compound 15f showed rapid bactericidal properties, which avoid the emergence of drug resistance. However, 15f showed no inhibitory effect on Gram-negative bacteria but biofilm formation study gave possible answers. Further target identification and mechanistic studies revealed that 15f functioned as an effective FtsZ inhibitor to alter the dynamics of FtsZ self-polymerization, which resulted in termination of the cell division and caused cell death. Further cytotoxicity and animal studies demonstrated that 15f not only displayed efficacy in a murine model of bacteremia in vivo, but also no significant hemolysis to mammalian cells. Overall, this compound with novel skeleton could serve as an antibacterial lead of FtsZ inhibitor for further evaluation of drug-likeness.
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http://dx.doi.org/10.1016/j.ejmech.2021.113480DOI Listing
October 2021

Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ.

Antibiotics (Basel) 2020 Dec 5;9(12). Epub 2020 Dec 5.

Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide 5000, South Australia, Australia.

The bacterial cell division protein, FtsZ, has been identified as a target for antimicrobial development. Derivatives of 3-methoxybenzamide have shown promising activities as FtsZ inhibitors in Gram-positive bacteria. We sought to characterise the activity of five difluorobenzamide derivatives with non-heterocyclic substituents attached through the 3-oxygen. These compounds exhibited antimicrobial activity against methicillin resistant (MRSA), with an isopentyloxy-substituted compound showing modest activity against vancomycin resistant (VRE). The compounds were able to reverse resistance to oxacillin in highly resistant clinical MRSA strains at concentrations far below their MICs. Three of the compounds inhibited an strain lacking the AcrAB components of a drug efflux pump, which suggests the lack of Gram-negative activity can partly be attributed to efflux. The compounds inhibited cell division by targeting FtsZ, producing a dose-dependent increase in GTPase rate which increased the rate of FtsZ polymerization and stabilized the FtsZ polymers. These compounds did not affect the polymerization of mammalian tubulin and did not display haemolytic activity or cytotoxicity. These derivatives are therefore promising compounds for further development as antimicrobial agents or as resistance breakers to re-sensitive MRSA to beta-lactam antibiotics.
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http://dx.doi.org/10.3390/antibiotics9120873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762090PMC
December 2020

Design and structural optimization of novel 2H-benzo[h]chromene derivatives that target AcrB and reverse bacterial multidrug resistance.

Eur J Med Chem 2021 Mar 27;213:113049. Epub 2020 Nov 27.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, 250012, China. Electronic address:

Drug efflux pumps have emerged as a new drug targets for the treatment of bacterial infections in view of its critical role in promoting multidrug resistance. Herein, novel chromanone and 2H-benzo[h]chromene derivatives were designed by means of integrated molecular design and structure-based pharmacophore modeling in an attempt to identify improved efflux pump inhibitors that target Escherichia coli AcrB. The compounds were tested for their efflux inhibitory activity, ability to inhibit efflux, and the effect on bacterial outer and inner membranes. Twenty-three novel structures were identified that synergized with antibacterials tested, inhibited Nile Red efflux, and acted specifically on the AcrB. Among them, WK2, WL7 and WL10 exhibiting broad-spectrum and high-efficiency efflux inhibitory activity were identified as potential ideal AcrB inhibitors. Molecular modeling further revealed that the strong π-π stacking interactions and hydrogen bond networks were the major contributors to tight binding of AcrB.
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http://dx.doi.org/10.1016/j.ejmech.2020.113049DOI Listing
March 2021

Recent Advances in the Discovery of Multitargeted Tyrosine Kinase Inhibitors as Anticancer Agents.

Authors:
Ting Guo Shutao Ma

ChemMedChem 2021 Feb 24;16(4):600-620. Epub 2020 Nov 24.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, West Wenhua Road 44, Jinan, 250012, P. R. China.

The treatment of cancer has been one of the most significant challenges for the medical field. Further research on the signal transduction pathway of tumor cells is driving the rapid development of antitumor agents targeting tyrosine kinases. However, most of the currently approved tyrosine kinase inhibitors based on the "single target/single drug" design are becoming less and less effective in the treatment of complex, heterogeneous, and multigenic cancers; this also results in resistance to chemotherapy. In contrast, multitargeted tyrosine kinase inhibitors (MT-TKIs) can effectively block multiple pathways of intracellular signal transduction. Therefore, they have therapeutic advantages over single-targeted inhibitors and have become a hotspot in antitumor drug research in recent years. This minireview summarizes recent advances in the discovery of MT-TKIs based on their chemical structures. In particular, we describe the kinase inhibitory and antitumor activity of promising compounds, as well as their structure - activity relationships (SARs).
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http://dx.doi.org/10.1002/cmdc.202000658DOI Listing
February 2021

Design and synthesis of novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB to reverse the bacterial multidrug resistance.

Bioorg Chem 2020 12 21;105:104394. Epub 2020 Oct 21.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China. Electronic address:

Novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB were designed, synthesized and evaluated for their biological activity as AcrB inhibitors. In particular, the ability of the compounds to potentiate the activity of antibiotics, to inhibit Nile Red efflux and to target AcrB was investigated. In this study, 19 compounds were identified to reduce the MIC values of at least one tested antibacterial by 2- to 16-fold at a lower concentration. Identified modulating compounds also possessed considerable inhibition on Nile red efflux at concentrations as low as 50 µM and did not display off-target effects on the outer membrane. Among the above compounds with characteristics of ideal AcrB inhibitors, the most outstanding ones are A15 and B5-B7. In particular, A15 and B7 exhibited not only the most prominent performance in the synergistic effect, but also completely abolished Nile Red efflux at concentrations of 50 and 100 μM, respectively. In docking simulations, A15 was observed to have the most favorable docking score and was predicted to bind in the hydrophobic trap as has been noted with other inhibitors such as MBX2319. It is worth noting that the 4-morpholinoquinazoline-2-carboxamide core appears to be a promising chemical skeleton to be further optimized for the discovery of more potent AcrB inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2020.104394DOI Listing
December 2020

Design and synthesis of aryl-substituted pyrrolidone derivatives as quorum sensing inhibitors.

Bioorg Chem 2020 12 13;105:104376. Epub 2020 Oct 13.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, PR China. Electronic address:

Quorum sensing, a common cell-to-cell communication system, is considered to have promising application in antibacterial therapy since they are expected to induce lower bacterial resistance than conventional antibiotics. However, most of present quorum sensing inhibitors have potent cell toxicity, which limits their application. In this study we evaluated the diverse quorum sensing inhibition activities of different biaromatic furanones and brominated pyrrolones. On this basis, we further designed and synthesized a new series of aryl-substituted pyrrolones 12a-12f. In the quorum sensing inhibition assay, compound 12a showed improved characteristics and low toxicity against human hepatocellular carcinoma cell. In particular, it can inhibit the pyocyanin production and protease activity of Pseudomonas aeruginosa by 80.6 and 78.5%, respectively. Besides, in this series, some compounds exerted moderate biofilm inhibition activity. To sum up, all the findings indicate that aryl-substituted pyrrolidone derivatives are worth further investigation as quorum sensing inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2020.104376DOI Listing
December 2020

Design, synthesis of novel 4,5-dihydroisoxazole-containing benzamide derivatives as highly potent FtsZ inhibitors capable of killing a variety of MDR Staphylococcus aureus.

Bioorg Med Chem 2020 11 27;28(21):115729. Epub 2020 Aug 27.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China. Electronic address:

Antibiotic resistance among clinically significant bacterial pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. As a part of continuing effort to develop antibacterial agents, we rationally designed and synthesized two series of 4,5-dihydroisoxazol-5-yl and 4,5-dihydroisoxazol-3-yl-containing benzamide derivatives that targeted the bacterial cell division protein FtsZ. Evaluation of their activity against a panel of Gram-positive and -negative pathogens revealed that compound A16 possessing the 4,5-dihydroisoxazol-5-yl group showed outstanding antibacterial activity (MIC, ≤0.125-0.5 μg/mL) against various testing strains, including methicillin-resistant, penicillin-resistant and clinical isolated S. aureus strains. Besides, further mouse infection model revealed that A16 could be effective in vivo and non-toxic to Hela cells. Finally, a detailed discussion of structure-activity relationships was conducted, referring to the docking results. It is worth noting that substituting a 4,5-dihydroisoxazole ring for the isoxazole ring not only broadened the antibacterial spectrum but also resulted in a significant increase in antibacterial activity against S. aureus strains. Taken together, these results suggest a promising chemotype for the development of new FtsZ-targeting bactericidal agents.
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http://dx.doi.org/10.1016/j.bmc.2020.115729DOI Listing
November 2020

Total Synthesis of Semaglutide Based on a Soluble Hydrophobic-Support-Assisted Liquid-Phase Synthetic Method.

ACS Comb Sci 2020 12 15;22(12):821-825. Epub 2020 Oct 15.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China.

Considering the high cost of the production of semaglutide, which is currently the most promising antidiabetic drug especially for the treatment of type 2 diabetes mellitus, a new synthetic route of semaglutide production that possesses excellent yield and high purity is of vital importance. Herein, we reported a newly developed synthetic route of semaglutide that is simple and efficient, based on a soluble hydrophobic-support-assisted liquid-phase synthetic method by applying Alloc-chemistry to the synthesis of the main chain peptide and side chain peptide of semaglutide. With careful optimization of the reaction conditions and innovative strategy of post-synthetic treatments, the total yield and purity of the crude semaglutide was improved satisfactorily.
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http://dx.doi.org/10.1021/acscombsci.0c00134DOI Listing
December 2020

Recent Development of Pyrimidine-Containing Antimicrobial Agents.

ChemMedChem 2020 Oct 11;15(20):1875-1886. Epub 2020 Sep 11.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, West Wenhua Road, 44, Jinan, 250012, P.R. China.

Multidrug-resistant bacterial infections have become an important cause of clinical death in the twenty-first century. Much effort has been made to overcome this challenge. The discovery of novel antimicrobial compounds, as well as the rational use of antibacterial drugs with different structure types and mechanisms, is helping to deal with bacterial resistance. Currently, pyrimidine-containing agents are the major areas of new antibacterial drug discovery. Given their good activities and diverse mechanisms of action, many pyrimidine-containing heterocyclic compounds have become the focus of interest for many scientists. In addition, pyrimidine structure is an important part of many endogenous substances, which is an advantage that allows pyrimidine derivatives to interact with genetic materials, enzymes and other biopolymeric substances in the cell. Scientists have focused on the discovery and structural optimization of pyrimidine derivatives, which has resulted in the discovery of many novel pyrimidine derivatives with intriguing profiles. Herein we summarize the therapeutic potentials of pyrimidine compounds that are promising for antimicrobial applications over the last decade. In particular, the relationships between the structures of modified pyrimidines and their antimicrobial activity are systematically discussed.
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http://dx.doi.org/10.1002/cmdc.202000378DOI Listing
October 2020

Childhood Maltreatment and Mobile Phone Addiction Among Chinese Adolescents: Loneliness as a Mediator and Self-Control as a Moderator.

Front Psychol 2020 12;11:813. Epub 2020 May 12.

School of Education, Guangzhou University, Guangzhou, China.

Previous studies have found that childhood maltreatment is an important risk predictor of adolescent mobile phone addiction (MPA). However, little is known about the mediating and moderating mechanisms underlying this association. Grounded in the Basic Psychological Needs Theory and the organism-environment interaction model, this study examined the mediating effect of loneliness and the moderating effect of self-control in the relationship between childhood maltreatment and adolescent MPA. A total of 981 Chinese adolescents (Mage = 13.68 years, = 0.92) completed measures regarding childhood maltreatment, MPA, loneliness, and self-control. After controlling for participants' demographic variables, loneliness partially mediated the relation between childhood maltreatment and adolescent MPA and this indirect path was moderated by self-control. Specifically, the effect of loneliness on MPA was stronger for adolescents with lower self-control than for those with higher self-control. Our research provides additional evidence for the negative association between childhood maltreatment and MPA.
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http://dx.doi.org/10.3389/fpsyg.2020.00813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235189PMC
May 2020

Research Progress of 70 kDa Ribosomal Protein S6 Kinase (P70S6K) Inhibitors as Effective Therapeutic Tools for Obesity, Type II Diabetes and Cancer.

Authors:
Na Zhang Shutao Ma

Curr Med Chem 2020 ;27(28):4699-4719

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education) School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China.

At present, diseases such as obesity, type Ⅱ diabetes and cancer have brought serious health problems, which are closely related to mTOR pathway. 70 kDa ribosomal protein S6 kinase (p70S6K), as a significant downstream effector of mTOR, mediates protein synthesis, RNA processing, glucose homeostasis, cell growth and apoptosis. Inhibiting the function of p70S6K can reduce the risk of obesity which helps to treat dyslipidemia, enhance insulin sensitivity, and extend the life span of mammals. Therefore, p70S6K has become a potential target for the treatment of these diseases. So far, except for the first p70S6K specific inhibitor PF-4708671 developed by Pfizer and LY2584702 developed by Lilai, all of them are in preclinical research. This paper briefly introduces the general situation of p70S6K and reviews their inhibitors in recent years, which are mainly classified into two categories: natural compounds and synthetic compounds. In particular, their inhibitory activities, structure-activity relationships (SARs) and mechanisms are highlighted.
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http://dx.doi.org/10.2174/0929867327666200114113139DOI Listing
September 2020

Recent Advances in the Development of Macrolide Antibiotics as Antimicrobial Agents.

Mini Rev Med Chem 2020 ;20(7):601-625

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China.

The chemical modification of natural products has been a major method in the discovery and synthesis of new macrolide antibiotics (MA) to treat a variety of infectious diseases. However, a lot of MA obtained in the above methods are no longer effective, because the bacteria quickly develop their resistance to these new macrolides, which has become a great threat to successful treatment of infectious diseases, such as infections of the respiratory system and urinary system. In this paper, total synthetic methods for MA that include erythromycin A (ERY), azithromycin (AZM), the clinical candidate solithromycin (CEM-101), as well as 14-membered and 15-membered azaketolides have been systematically reviewed on the basis of the literature reported previously. The total synthetic methods we describe here helps to accelerate the discovery of newer MA to deal with the serious problem of bacterial resistance.
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http://dx.doi.org/10.2174/1389557520666191223160942DOI Listing
December 2020

A novel series of 11-O-carbamoyl-3-O-descladinosyl clarithromycin derivatives bearing 1,2,3-triazole group: Design, synthesis and antibacterial evaluation.

Bioorg Med Chem Lett 2020 01 3;30(2):126850. Epub 2019 Dec 3.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address:

A series of novel 11-O-carbamoyl-3-O-descladinosyl clarithromycin derivatives bearing the 1,2,3-triazole group were designed, synthesized, and evaluated for their in vitro antibacterial activity. The antibacterial results indicated that most of the target compounds not only increased their activity against resistant bacterial strains, but also partially retained the activity against sensitive bacterial strains compared with clarithromycin. Among them, 13d had the best antibacterial activity against resistant strains, including Streptococcus pneumoniae B1 expressing the ermB gene (16 µg/mL), Streptococcus pneumoniae AB11 expressing the mefA and ermB genes (16 µg/mL) and Streptococcus pyogenes R1 (16 µg/mL), showing >16, 8 and 16-fold higher activity than that of CAM, respectively. Moreover, 13d and 13g exhibited the best antibacterial activity against sensitive bacterial strains, including Staphylococcus aureus ATCC25923 (4 µg/mL) and Bacillus Subtilis ATCC9372 (1 µg/mL). The MBC results showed that the most promising compounds 13d and 13g exhibited antibacterial activity through bacteriostatic mechanism, while the time-kill kinetic experiment revealed bactericidal kinetics of 13g from microscopic point of view. In vitro antibacterial experiments and molecular docking results further confirmed that it was feasible to our initial design strategy by modifying the C-3 and C-11 positions of clarithromycin to increase the activity against resistant bacteria.
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http://dx.doi.org/10.1016/j.bmcl.2019.126850DOI Listing
January 2020

Structural optimization of natural product nordihydroguaretic acid to discover novel analogues as AcrB inhibitors.

Eur J Med Chem 2020 Jan 26;186:111910. Epub 2019 Nov 26.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China. Electronic address:

Drug efflux pumps confer multidrug resistance to dangerous bacterial pathogens which makes these proteins promising drug targets. Herein, we present initial chemical optimization and structure-activity relationship (SAR) data around a previously described efflux pump inhibitor, nordihydroguaretic acid (NDGA). Four series of novel NDGA analogues that target Escherichia coli AcrB were designed, synthesized and evaluated for their ability to potentiate the activity of antibiotics, to inhibit AcrB-mediated substrate efflux and reduce off-target activity. Nine novel structures were identified that increased the efficacy of a panel of antibiotics, inhibited drug efflux and reduced permeabilization of the bacterial outer and inner membranes. Among them, WA7, WB11 and WD6 possessing broad-spectrum antimicrobial sensitization activity were identified as NDGA analogues with favorable properties as potential AcrB inhibitors, demonstrating moderate improvement in potency as compared to NDGA. In particular, WD6 was the most broadly active analogue improving the activity of all four classes of antibacterials tested.
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http://dx.doi.org/10.1016/j.ejmech.2019.111910DOI Listing
January 2020

Recent development of membrane-active molecules as antibacterial agents.

Authors:
Nan Zhang Shutao Ma

Eur J Med Chem 2019 Dec 27;184:111743. Epub 2019 Sep 27.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China. Electronic address:

The continuous emergence of drug-resistant bacteria has become a severe threat to the public health. Therefore, the discovery of novel antibacterial mechanisms to combat this jeopardized problem is urgently needed. In the past decades, plenty of new antibacterial modes of action have been discovered continuously, based on which many promising scaffolds have been designed and synthesized. In particular, cationic amphiphilic small-molecules open a door to the new mode of action of bactericidal agents by depolarizing and disturbing the bacteria membrane. The cationic amphiphilic are characterized by high efficacy, resistant-proof, wide-spectrum, and high selectivity toward bacteria. In this review, we summarized recent advances in the discovery of membrane-active small-molecules and their structure-activity relationships (SARs), hoping to provide an evidence for future research and development of new antibacterial agents with new mechanism.
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http://dx.doi.org/10.1016/j.ejmech.2019.111743DOI Listing
December 2019

Recent development of leucyl-tRNA synthetase inhibitors as antimicrobial agents.

Medchemcomm 2019 Aug 27;10(8):1329-1341. Epub 2019 May 27.

Department of Medicinal Chemistry , Key Laboratory of Chemical Biology , Ministry of Education , School of Pharmaceutical Sciences , Shandong University , 44, West Culture Road , Jinan 250012 , P. R. China . Email: E mail:

Aminoacyl-tRNA synthetases (aaRSs) widely exist in organisms and mediate protein synthesis. Inhibiting these synthetases can lead to the termination of protein synthesis and subsequently achieve antibacterial and antiparasitic purposes. Moreover, the structures of aaRSs found in eukaryotes have considerable structural differences compared to those in prokaryotes, based on which it is possible to develop highly selective inhibitors. Leucyl-tRNA synthetase (LeuRS) with unique synthesis and editing sites is one of 20 kinds of aaRSs. Many inhibitors targeting LeuRS have been designed and synthesized, some of which have entered clinical use. For example, the benzoxaborole compound AN2690 has been approved by the FDA for the treatment of onychomycosis. AN3365 is suspended in the phase II clinical trial due to the rapid development of AN3365 resistance, but it may be used in combination with other antibiotics. The aaRSs, especially LeuRS, are being considered as targets of new potential anti-infective drugs for the treatment of not only bacterial or fungal infections but also infections by trypanosomes and malaria parasites. This review mainly describes the development of LeuRS inhibitors, focusing on their mechanisms of action, structure-activity relationships (SARs), and and activities.
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http://dx.doi.org/10.1039/c9md00139eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727470PMC
August 2019

Design, synthesis and antibacterial evaluation of novel 15-membered 11a-azahomoclarithromycin derivatives with the 1, 2, 3-triazole side chain.

Eur J Med Chem 2019 Oct 11;180:321-339. Epub 2019 Jul 11.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China. Electronic address:

Macrolides are widely prescribed in clinic to treat various respiratory tract infections. However, due to their inappropriate use, the prevalence of macrolide-resistant strains among clinical isolates has become a concern for public health. Therefore, novel macrolides skeleton structures against resistant pathogens are badly needed. Thus, three series of novel 15-membered 11a-azahomoclarithromycin derivatives (series A-C) with the 1, 2, 3-triazole side chain were designed and synthesized through creatively opening the ring of clarithromycin (CAM), expanding the ring properly and introducing a suitable side chain of 1, 2, 3-triazole at the C12 and C13 positions, and evaluated for their antibacterial activity. The antibacterial results indicated that compounds 38b, 38l and 38v possessed strong antibacterial activity against Staphylococcus aureus ATCC25923 (0.25 μg/mL) and Bacillus subtilis ATCC9372 (0.25 μg/mL). Furthermore, compounds 9e and 38g were found to exhibit promising potent activity (8 μg/mL) against Streptococcus pneumonia AB11 expressing the ermB and mefA genes. In addition, the determination of minimum bactericidal concentration (MBC) indicated that the most promising compounds 38b, 38l, 38v, 9e and 38g were excellent bacteriostatic agents. The bactericidal curve showed that 9e exhibited antibacterial activity through bacteriostatic mechanism. Finally, 38b, 38l and 38v were confirmed to be non-toxic to MCF-7 breast cancer cells up to a concentration of 32 μg/mL in preliminary cytotoxicity assay. In summary, 38b, 38l, 38v, 9e and 38g can be served as lead compounds to provide a new perspective for further structural optimization.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.022DOI Listing
October 2019

Discovery of 1,3,4-oxadiazol-2-one-containing benzamide derivatives targeting FtsZ as highly potent agents of killing a variety of MDR bacteria strains.

Bioorg Med Chem 2019 07 7;27(14):3179-3193. Epub 2019 Jun 7.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address:

The spread of infections caused by multidrug-resistant (MDR) pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), has created a need for new antibiotics with novel mechanisms of action. The bacterial division protein FtsZ has been identified as a novel drug target that can be exploited clinically. As part of an ongoing effort to develop FtsZ-targeting antibacterial agents, we describe herein the design, synthesis and bioactivity of six series of novel 1,3,4-oxadiazol-2-one-containing, 1,2,4-triazol-3-one-containing and pyrazolin-5-one-containing benzamide derivatives. Among them, compound A14 was found to be the most potent antibacterial agent, much better than clinical drugs such as ciprofloxacin, linezolid and erythromycin against all the tested gram-positive strains, particularly methicillin-resistant, penicillin-resistant and clinical isolated S. aureus. Subsequent studies on biological activities and docking analyses proved that A14 functioned as an effective compound targeting FtsZ. Preliminary SAR indicated a general direction for further optimization of these novel analogues. Taken together, this research provides a promising chemotype for developing newer FtsZ-targeting bactericidal agents.
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http://dx.doi.org/10.1016/j.bmc.2019.06.010DOI Listing
July 2019

Design, synthesis and evaluation of a series of 5-methoxy-2,3-naphthalimide derivatives as AcrB inhibitors for the reversal of bacterial resistance.

Bioorg Med Chem Lett 2019 04 4;29(7):882-889. Epub 2019 Feb 4.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address:

A series of novel 5-methoxy-2,3-naphthalimide derivatives were designed, synthesized and evaluated for their biological activities. In particular, the ability of the compounds to synergize with antimicrobials, to inhibit Nile Red efflux, and to target AcrB was assayed. The results showed that the most of the tested compounds more sensitized the Escherichia coli BW25113 to the antibiotics than the parent compounds 7c and 15, which were able to inhibit Nile Red efflux. Significantly, compound A5 possessed the most potent antibacterial synergizing activity in combination with levofloxacin by 4 times and 16 times at the concentration of 8 and 16 µg/mL, respectively, whilst A5 could effectively abolish Nile Red efflux at 100 μM. Additionally, target effect of A5 was confirmed in the outer- or inner membrane permeabilization assays. Therefore, A5 is an excellent lead compound for further structural optimization.
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http://dx.doi.org/10.1016/j.bmcl.2019.02.003DOI Listing
April 2019

Design, synthesis and structure-based optimization of novel isoxazole-containing benzamide derivatives as FtsZ modulators.

Eur J Med Chem 2018 Nov 22;159:90-103. Epub 2018 Sep 22.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China. Electronic address:

Antibiotic resistance among clinically significant bacterial pathogens is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. Utilizing computational docking method and structure-based optimization strategy, we rationally designed and synthesized two series of isoxazol-3-yl- and isoxazol-5-yl-containing benzamide derivatives that targeted the bacterial cell division protein FtsZ. Evaluation of their activity against a panel of Gram-positive and -negative pathogens revealed that compounds B14 and B16 that possessed the isoxazol-5-yl group showed strong antibacterial activity against various testing strains, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. aureus. Further molecular biological studies and docking analyses proved that the compound functioned as an effective inhibitor to alter the dynamics of FtsZ self-polymerization via a stimulatory mechanism, which finally terminated the cell division and caused cell death. Taken together, these results could suggest a promising chemotype for development of new FtsZ-targeting bactericidal agent.
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http://dx.doi.org/10.1016/j.ejmech.2018.09.053DOI Listing
November 2018

Synthesis and antibacterial activity of novel 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives.

Bioorg Med Chem Lett 2018 11 10;28(20):3324-3328. Epub 2018 Sep 10.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address:

A novel series of 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial activity. These derivatives were found to have strong activity against susceptible and resistant bacteria strains. Among them, compounds 7a and 7q showed the most potent activity (0.125 µg/mL) against erythromycin-resistant S. pneumoniae expressing the mefA gene. Moreover, compounds 7f, 7i, 7p and 7z displayed remarkably improved activity (4 µg/mL) against penicillin-resistant S. aureus ATCC31007, and compounds 7a, 7b, 7f, 7p and 7z showed improved activity (8 µg/mL) against erythromycin-resistant S. pyogenes. In particular, compound 7z exhibited potent and balanced activity against the tested drug-susceptible and -resistant bacterial strains.
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http://dx.doi.org/10.1016/j.bmcl.2018.09.012DOI Listing
November 2018

Recent development of lipoxygenase inhibitors as anti-inflammatory agents.

Authors:
Chaoyu Hu Shutao Ma

Medchemcomm 2018 Feb 29;9(2):212-225. Epub 2017 Nov 29.

Department of Medicinal Chemistry , Key Laboratory of Chemical Biology (Ministry of Education) , School of Pharmaceutical Sciences , Shandong University , 44, West Culture Road , Jinan 250012 , P.R. China . Email:

Inflammation is favorable in most cases, because it is a kind of body defensive response to external stimuli; sometimes, inflammation is also harmful, such as attacks on the body's own tissues. It could be that inflammation is a unified process of injury and resistance to injury. Inflammation brings extreme pain to patients, showing symptoms of rubor, swelling, fever, pain and dysfunction. As the specific mechanism is not clear yet, the current anti-inflammatory agents are given priority for relieving suffering of patients. Thus it is emergent to find new anti-inflammatory agents with rapid effect. Lipoxygenase (LOX) is a kind of rate-limiting enzyme in the process of arachidonic acid metabolism into leukotriene (LT) which mediates the occurrence of inflammation. The inhibition of LOX can reduce LT, thereby producing an anti-inflammatory effect. In this review, the LOX inhibitors reported in recent years are summarized, and, in particular, their activities, structure-activity relationships and molecular docking studies are emphasized, which will provide new ideas to design novel LOX inhibitors.
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http://dx.doi.org/10.1039/c7md00390kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083793PMC
February 2018

Recent Advances in the Discovery of Novel Peptide Inhibitors Targeting 26S Proteasome.

Authors:
Xinjie Gu Shutao Ma

Anticancer Agents Med Chem 2018 ;18(12):1656-1673

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, Jinan 250012, China.

Background: The 26S proteasome is a proteolytic complex of multimeric protease, which operates at the executive end of the Ubiquitin-Proteasome System (UPS) and degrades the polyubiquitylated proteins.

Methods: After a brief introduction of 26S proteasome and Ubiquitin-Proteasome System (UPS), this review focuses on the structure and function of the 26S proteasome in intracellular protein level regulation. Then, physiological regulation mechanisms and processes are elaborated. In addition, the advantages and defects of approved 26S proteasome inhibitors were discussed. Finally, we summarized the novel peptide 26S proteasome inhibitors according to their structural classifications, highlighting their design strategies, inhibitory activity and Structure-Activity Relationships (SARs).

Results: Cellular function maintenance relies on the proteasome metabolizing intracellular proteins to control intracellular protein levels, which is especially important for cancer cells to survive and proliferate. In primary tumors, proteasomes had a higher level and more potent activity. Currently, the approved small peptide inhibitors have proved their specific 26S proteasome inhibitory effects and considerable antitumor activities, but with obvious defects. Increasingly, novel peptide inhibitors are emerging and possess promising values in cancer therapy.

Conclusion: Overall, the 26S proteasome is an efficient therapeutic target and novel 26S proteasome inhibitors hold potency for cancer therapy.
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http://dx.doi.org/10.2174/1871520618666180813120012DOI Listing
July 2019

Synthesis and antibacterial evaluation of novel 11-O-aralkylcarbamoyl-3-O-descladinosylclarithromycin derivatives.

Bioorg Med Chem Lett 2018 08 2;28(14):2471-2476. Epub 2018 Jun 2.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (Ministry of Education) School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address:

A series of novel 11-O-aralkylcarbamoyl-3-O-descladinosylclarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed potent activity against erythromycin-susceptible S. pyogenes, erythromycin-resistant S. pneumoniae A22072 expressing the mef gene and S. pneumoniae AB11 expressing the mef and erm genes. Besides, most of the target compounds exhibited moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372. In particular, compounds 11a, 11b, 11c, 11e, 11f and 11h were found to exert favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.015-0.125 μg/mL. Furthermore, compounds 10e, 11a, 11b and 11c showed superior activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.25-0.5 μg/mL. Additionally, compound 11c was the most effective against all the erythromycin-resistant S. pneumoniae strains (A22072, B1 and AB11), exhibiting 8-, 8- and 32-fold more potent activity than clarithromycin, respectively.
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http://dx.doi.org/10.1016/j.bmcl.2018.06.006DOI Listing
August 2018

Novel 5-methyl-2-phenylphenanthridium derivatives as FtsZ-targeting antibacterial agents from structural simplification of natural product sanguinarine.

Bioorg Med Chem Lett 2018 06 7;28(10):1825-1831. Epub 2018 Apr 7.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address:

A novel series of 5-methyl-2-phenylphenanthridium derivatives were displayed outstanding activity against a panel of antibiotic-sensitive and -resistant bacteria strains compared with their precursor sanguinarine, ciprofloxacin and oxacillin sodium. Compounds 7 l, 7m and 7n were found to display the most effective activity against five sensitive strains (0.06-2 μg/mL) and three resistant strains (0.25-4 μg/mL). The kinetic profiles indicated that compound 7l possessed the strongest bactericidal effect on S. aureus ATCC25923, with the MBC value of 16 μg/mL. The cell morphology and the FtsZ polymerization assays indicated that these compounds inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. The SARs showed that all the 4-methyl-substituted 5-methyl-2-phenylphenanthridium subseries could be further investigated as the FtsZ-targeting antibacterial agents.
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http://dx.doi.org/10.1016/j.bmcl.2018.04.015DOI Listing
June 2018

Substitution of terminal amide with 1H-1,2,3-triazole: Identification of unexpected class of potent antibacterial agents.

Bioorg Med Chem Lett 2018 03 2;28(5):884-891. Epub 2018 Feb 2.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address:

3-Methoxybenzamide (3-MBA) derivatives have been identified as novel class of potent antibacterial agents targeting the bacterial cell division protein FtsZ. As one of isosteres for the amide group, 1,2,3-triazole can mimic the topological and electronic features of the amide, which has gained increasing attention in drug discovery. Based on these considerations, we prepared a series of 1H-1,2,3-triazole-containing 3-MBA analogues via isosteric replacement of the terminal amide with triazole, which had increased antibacterial activity. This study demonstrated the possibility of developing the 1H-1,2,3-triazole group as a terminal amide-mimetic element which was capable of both keeping and modulating amide-related bioactivity. Surprisingly, a different action mode of these new 1H-1,2,3-triazole-containing analogues was observed, which could open new opportunities for the development of antibacterial agents.
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http://dx.doi.org/10.1016/j.bmcl.2018.02.001DOI Listing
March 2018

Design, synthesis and biological activity evaluation of novel 4-subtituted 2-naphthamide derivatives as AcrB inhibitors.

Eur J Med Chem 2018 Jan 5;143:699-709. Epub 2017 Dec 5.

School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, SA 5000, Australia. Electronic address:

A novel series of 4-substituted 2-naphthamide derivatives were designed, synthesized and evaluated for their biological activity. In particular, the ability of the compounds to potentiate the action of antibiotics, to inhibit Nile Red efflux and to target AcrB specifically was investigated. The results indicated that most of the 4-substituted 2-naphthamide derivatives were able to synergize with the antibiotics tested, and inhibit Nile Red efflux by AcrB in the resistant phenotype. Subsequent exclusion of compounds with off target effects such as outer- or inner membrane permeabilization identified compounds 7c, 7g, 12c, 12i and 13g as efflux pump inhibitors (EPIs). Particularly, compounds 7c, 7g and 12i were found to be the most potent EPIs, which synergized with the two substrates tested at lower concentrations than that of parent A3, demonstrating an improvement in potency as compared to A3. Additionally, when the outer membrane of E. coli was permeabilized, compound 12c displayed a huge increase in efficacy and was able to synergize with erythromycin at a concentration that was 16 times lower than that of the parent A3. Hence we were able to design and synthesize compounds that displayed significant increase in efficacy as EPIs against AcrB.
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http://dx.doi.org/10.1016/j.ejmech.2017.11.102DOI Listing
January 2018

Disrupting Acetyl-lysine Interactions: Recent Advance in the Development of BET Inhibitors.

Authors:
Fa Zhang Shutao Ma

Curr Drug Targets 2018 ;19(10):1148-1165

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China.

Background: Histone acetylation is an essential approach of post-translational modification (PTM) and a significant component of epigenetic regulation that is mediated by Bromodomainscontaining protein (BRDs). In recent years, many researchers have found that a variety of malignancy, inflammatory and other diseases occurrences and developments are associated with BRD4 expression disorders or dysfunction. Meanwhile, many inhibitors of the extra-terminal (BET) family have been reported in many papers.

Objective: This review summarized those newly found BET inhibitors, their mechanism of action and bioactivity. Secondly, those compounds were mainly classified based on their structures and their structure-activity relationship information was discussed. Beyond that, every compound's design strategy was pointed out.

Results And Conclusion: Herein, the recent advances reported were reviewed for discovering more excellent small molecule inhibitors. Currently, in addition to compound 4, compounds 7, 22 and 90, have also been into the clinical trial stage. In the view of the outstanding performance of BET inhibitors in anti-tumor, anti-inflammatory and anti-drug resistance, we believe that more and more BET inhibitors will become the new epigenetic therapy for cancer, inflammation and autoimmune disease in clinical practice in the near future.
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http://dx.doi.org/10.2174/1389450119666171129165427DOI Listing
October 2019