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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 1. H-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 1. H-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 1. H-1,2,3-triazole-containing analogues was observed, which could open new opportunities for the development of antibacterial agents. Refereed/Peer-reviewed

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.

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. Refereed/Peer-reviewed

A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed improved activity compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18, 19 and 22 showed the most potent activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.5μg/mL. Furthermore, compounds 11, 18, 19, 24 and 29 were also found to exhibit favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.125-1μg/mL, and moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372.

Three novel structural series of 4″- O -(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs were designed, synthesized and evaluated for their in vitro antibacterial activity. All the target compounds exhibited excellent activity against erythromycin-susceptible Streptococcus pyogenes , and significantly improved activity against three phenotypes of erythromycin-resistant Streptococcus pneumoniae compared with clarithromycin and azithromycin. Among the three series of azithromycin analogs, the novel series of 11,4″-disubstituted azithromycin analogs 9a – k exhibited the most effective and balanced activity against susceptible and resistant bacteria. Among them, compound 9j showed the most potent activity against Staphylococcus aureus ATCC25923 (0.008 µg/mL) and Streptococcus pyogenes R2 (1 µg/mL). Besides, all the 11,4″-disubstituted azithromycin analogs 9a – k except 9f shared the identical activity with the MIC value Streptococcus pyogenes S2. Furthermore, compounds 9g , 9h , 9j and 9k displayed significantly improved activity compared with the references against all the three phenotypes of resistant S. pneumoniae . Particularly, compound 9k was the most effective (0.06, 0.03 and 0.125 µg/mL) against all the erythromycin-resistant S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, exhibiting 2133, 133 and 2048-fold more potent activity than azithromycin, respectively.

5-Methylphenanthridium derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cell division inhibitory activity against various Gram-positive and -negative bacteria. Among them, compounds 5A2, 5B1, 5B2, 5B3, 5C1 and 5C2 displayed the best on-target antibacterial activity with an MIC value of 4 µg/mL against B. subtilis ATCC9372 and S. pyogenes PS, showing over 2-fold better activity than sanguinarine. The SARs showed that the 5-methylphenanthridium derivatives with the alkyl side chains at the 2-postion, especially the straight alkyl side chains exerted better on-target antibacterial activity. Refereed/Peer-reviewed

Drug efflux pumps confer multidrug resistance to dangerous pathogens which makes these pumps important drug targets. We have synthesised a novel series of compounds based on a 2-naphthamide pharmacore aimed at inhibiting the efflux pumps from Gram-negative bacteria. The archeatypical transporter AcrB from Escherichia coli was used as model efflux pump as AcrB is widely conserved throughout Gram-negative organisms. The compounds were tested for their antibacterial action, ability to potentiate the action of antibiotics and for their ability to inhibit Nile Red efflux by AcrB. None of the compounds were antimicrobial against E. coli wild type cells. Most of the compounds were able to inhibit Nile Red efflux indicating that they are substrates of the AcrB efflux pump. Three compounds were able to synergise with antibiotics and reverse resistance in the resistant phenotype. Compound A3, 4-(isopentyloxy)-2-naphthamide, reduced the MICs of erythromycin and chloramphenicol to the MIC levels of the drug sensitive strain that lacks an efflux pump. A3 had no effect on the MIC of the non-substrate rifampicin indicating that this compound acts specifically through the AcrB efflux pump. A3 also does not act through non-specific mechanisms such as outer membrane or inner membrane permeabilisation and is not cytotoxic against mammalian cell lines. Therefore, we have designed and synthesised a novel chemical compound with great potential to further optimisation as inhibitor of drug efflux pumps. Refereed/Peer-reviewed

Novel series of 3-substituted 2,6-difluorobenzamide derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their in vitro antibacterial activity against various phenotype of Gram-positive and Gram-negative bacteria, and their cell division inhibitory activity against three representative strains. As a result, 3-chloroalkoxy derivative 7, 3-bromoalkoxy derivative 12 and 3-alkyloxy derivative 17 were found to exhibit the best antibacterial activity against Bacillus subtilis with MICs of 0.25–1 μg/mL, and good activity (MIC < 10 μg/mL) against both susceptible and resistant Staphylococcus aureus. Additionally, all the three compounds displayed potent cell division inhibitory activity with MIC values of below 1 μg/mL against Bacillus subtilis and Staphylococcus aureus. Refereed/Peer-reviewed

The overuse of antibiotics which exerts the selective pressure for bacterial pathogens has facilitated the spread of antibiotics' resistance. Metallo-β-lactamases (MβLs) are zinc enzymes produced by an increasing number of bacterial pathogens. They can readily cleave carbapenems and most other β-lactams that are mainstays of therapy for bacterial infections. MβL-conferred resistance to antibiotics is most worrisome due to MβLs exhibiting very broad-spectrum resistance. Therefore, the bacteria carrying MβLs have recently become a significant clinical threat. No clinically useful MβLs inhibitor has been discovered yet. To address the serious threat to public health posed by the MβL-conferred resistance to antibiotics, novel effective MβL inhibitors are urgently needed. This review mainly describes various MβL inhibitors, giving special attention to their antibacterial activity, mechanisms of action, structure-activity relationships and synergetic effect with clinically available antibiotics.

A series of novel 11,4″-disubstituted azithromycin analogs were synthesized and evaluated for their antibacterial activity. All the 11,4″-disubstituted analogs exhibited excellent activity (0.03–0.12 μg/ml) against erythromycin-susceptible Streptococcus pneumoniae , and significantly improved activity against three phenotypes of erythromycin-resistant S. pneumoniae compared with erythromycin A, clarithromycin or azithromycin. Among them, compounds 26 – 28 showed the most potent activity (0.25, 0.03 and 2 μg/ml) against S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, respectively. In addition, compound 28 was the most effective (0.03 and 0.12 μg/ml) against erythromycin-susceptible S. pneumoniae and Staphylococcus aureus as well. It is noteworthy that the most active compounds described above possess the same terminal 3,5-dinitrophenyl groups on their C-4″ bisamide side chains.

Novel series of novel 3- O -arylalkylcarbamoyl descladinosylazithromycin derivatives with the 2′- O -acetyl and 11,12-cyclic carbonate groups, the 11,12-cyclic carbonate group and the 11- O -arylalkylcarbamoyl side chain, and 2′- O -arylalkylcarbamoyl descladinosylazithromycin with the 11,12-cyclic carbonate group were designed, synthesized and evaluated for their antibacterial activity using broth microdilution method. The results showed that the majority of the target compounds showed moderate to favorable activity against six kinds of susceptible strains and almost all of them displayed significantly improved activity compared with references against three erythromycin-resistant strains of S. pneumoniae B1 expressing the erm B gene, S. pneumoniae AB11 expressing the erm B and mef A genes, and S. pyogenes R1. In particular, compound 6h exhibited the most potent activity against susceptible B. subtilis ATCC9372 (0.5 μg/mL), penicillin-resistant S. epidermidis (0.125 μg/mL), and erythromycin-resistant S. pneumoniae B1 (1 μg/mL) and S. pneumoniae AB11 (1 μg/mL), which were 2-, 2-, 256-, 256-fold better activity than azithromycin, respectively. Additionally, compounds 6f (0.5 μg/mL) and 6g (0.25 μg/mL) were the most active against S. pneumoniae A22072, which were 8- and 16-fold better activity than azithromycin (4 μg/mL). As for erythromycin-resistant S. pyogenes R1, compound 5a presented the most excellent activity (8 μg/mL), showing 32- and 32-fold higher activity than azithromycin (256 μg/mL) and clarithromycin (256 μg/mL).

With the serious problem of multiple drug resistance to antibiotics among pathogenic bacteria spreading across the world over the past 30 years, it is crucial to search for novel inhibitors with distinct modes of action from diverse chemical classes. NAD+-dependent DNA ligases (LigAs) are essential enzymes in bacteria, vital for DNA replication and repair. Additionally, LigAs exclusively exist in eubacteria and some viruses and are not found in humans. Those enzymes have therefore been identified as attractive antibacterial drug targets. In this review we explore the discovered inhibitors of LigA through high-throughput screening or virtual screening respectively and their further structure optimization.

Non-Small Cell Lung Cancer (NSCLC) is an especially aggressive cancer, the optimal drugs for which are still being developed. The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. EML4-ALK fusion gene initially identified in patients with NSCLC in 2007 is defined as a new molecular subset, which is highly sensitive to ALK inhibition. Since the first ALK inhibitor, crizotinib, was approved by the US Food and Drug Administration (FDA) for the treatment of NSCLC patients in 2011, ALK has been identified as a promising target for NSCLC therapy. However, crizotinib is not effective for various point mutations in ALK and central nervous system (CNS) metastasis. To date, there are only eight of second-and third-generation ALK inhibitors in clinical investigation and others are in preclinical research. This review summarizes recent advances of ALK inhibitors, with a focus on their biological activity, selectivity and structure-activity relationship (SAR) information. We hope this review could help medicinal chemists to discover newer ALK-inhibitors to overcome exist issues in the process of drug discovery, such as potency, selectivity and secondary mutations.

Infections caused by pathogenic bacteria are a major health concern throughout the world. There is a great need to develop novel antibacterial agents with new mechanisms of action. Lipopolysaccharides (LPS) are the main component of the outer membrane of Gram-negative bacteria, serving as a permeability barrier, which protects the bacteria from many antibiotics. The UDP-3-O-(R-3- hydroxyacyl)-N-acetylglucosamine deacetylase (LpxC), a Zn2+-dependent enzyme, catalyzes the first irreversible step of the biosynthesis of lipid A, the hydrophobic membrane anchor of LPS being essential for cell viability. Additionally, it shares no sequence or structural homology with any mammalian proteins. Therefore, it may become a novel target for the new drugs against Gram-negative bacteria. Thus, research on LpxC inhibitors as new antibacterial agents has become an attractive field in the development of the novel antibiotic therapy of Gram-negative bacteria. In this review, we will summarize the recent progress in the structure and catalytic mechanism of LpxC and the research and development of LpxC inhibitors.

Clinically significant antibiotic resistance is one of the greatest challenges of the twenty-first century. However, new antibacterial agents are currently being developed at a much slower pace than our growing need for such drugs. Given their diverse biological activities and clinical applications, many bioactive heterocyclic compounds containing a benzimidazole nucleus have been the focus of interest for many researchers. The benzimidazole nucleus is a structural isostere of naturally occurring nucleotides. This advantage allows benzimidazoles to readily interact with the various biopolymers found in living systems. In view of this situation, much attention has been given to the exploration of benzimidazole-based antibacterial agents, leading to the discovery of many new chemical entities with intriguing profiles. In this minireview we summarize novel benzimidazole derivatives active against various bacterial strains. In particular, we outline the relationship between the structures of variously modified benzimidazoles and their antibacterial activity.

The continuing emergence of bacterial resistance has provided an incentive for recent intensified research on macrolide antibiotics. Belonging to the macrolide family, 16-membered macrolides also experience a renewed interest in further exploration. The medicinal potential of 16-membered macrolides in search for new antibacterials stems from some advantages over 14-membered macrolides, such as gastrointestinal tolerability, structural flexibility, and lack of inducible resistance. Thus, compared with abundant articles on various 14-membered macrolide derivatives in the literature, this review will highlight some representative 16-membered macrolide antibiotics and their recently discovered analogs. Furthermore, the action and resistance mechanisms of 16-membered macrolide antibiotics will be elucidated as well to assist the drug design.

Novel 4″-O-benzimidazolyl clarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. These benzimidazolyl derivatives exhibited excellent activity against erythromycin-susceptible strains better than the references, and some of them showed greatly improved activity against erythromycin-resistant strains. Compounds 16 and 17, which have the terminal 2-(4-methylphenyl)benzimidazolyl and 2-(2-methoxyphenyl)benzimidazolyl groups on the C-4″ bishydrazide side chains, were the most active against erythromycin-resistant Staphylococcus pneumoniae expressing the erm gene and the mef gene. In addition, compound 17 exhibited the highest activity against erythromycin-susceptible S. pneumoniae ATCC49619 and Staphylococcus aureus ATCC25923 as well. It is worth noting that the 4″-O-(2-aryl)benzimidazolyl derivatives show higher activity against erythromycin-susceptible and erythromycin-resistant strains than the 4″-O-(2-alkyl)benzimidazolyl derivatives.

Novel clarithromycin derivatives with C-4″ elongated arylalkyl groups were designed, synthesized and evaluated to probe the effect of different lengths of their C-4″ side chains on the activity against resistant bacterial strains. These derivatives had excellent activity against erythromycin-susceptible Streptococcus pneumoniae, Streptococcus aureus or Streptococcus pyogenes and some of them exhibited greatly improved activity against erythromycin-resistant strains. Compounds 18 and 16, which had the C-4″ elongated arylalkyl groups with eight atoms from the 4″-oxygen atom to the terminal benzene ring, were the most effective against S. pneumoniae expressing the erm gene and the erm and mef genes. In contrast, the most potent compounds 3, 5, 9, 17 and 18 against S. pneumoniae expressing the mef gene had C-4″ elongated arylalkyl groups with three to eight atoms between the 4″-oxygen atom and the terminal aromatic ring.

The rapid emergence of drug resistance intensified the search for new antimicrobial agents, leading to lots of novel derivatives obtained from 14- and 15-membered macrolides by chemical modifications. Many of them exhibited enhanced antibacterial activity and expanded antibacterial spectrum. Especially some of them were found to be potent for the treatment of multi-drug-resistant bacterial infections. Besides, the other biological effects of macrolide derivatives were also found. In this article, we reviewed the recent advance in the novel macrolide derivatives designed by different structural modifications on erythronolide skeleton, cladinose and desosamine in the structures.

A series of novel 4″- O -carbamoyl analogs of clarithromycin were synthesized and evaluated for their in vitro antibacterial activity. All of the desired compounds showed excellent activity against erythromycin-susceptible S. pneumoniae . Particularly, 4-fluorobenzyl carbamate 7a demonstrated potent activity against erythromycin-resistant S. pneumoniae encoded by the mef gene, and remarkably improved activity against erythromycin-resistant S. pneumoniae encoded by the erm gene, and the erm and mef genes.

A series of novel dimers of 15-membered macrolides was synthesized and evaluated. The dimers exhibited excellent activity against erythromycin-susceptible S. pneumonia, but did not show any improved activity against erythromycin-resistant S. pneumoniae encoded by erm gene.

Hepatitis C is a viral liver infection considered as the major cause of cirrhosis and hepatocellular carcinoma (HCC). The HCV NS5B polymerase, an RNA-dependent RNA polymerase, is essential for HCV replication, which is able to catalyze the synthesis of positive (genomic) and negative (template) strand HCV RNA, but has no functional equivalent in mammalian cells. Therefore, the NS5B polymerase has emerged as an attractive target for the development of specifically targeted antiviral therapy for HCV (DAA, for direct-acting antivirals). Recently, a growing number of compounds have been reported as the NS5B polymerase inhibitors, some of which especially have been licensed in clinical trials. This review describes recent advances on the synthesis of the NS5B polymerase inhibitors, focusing on the merits and demerits of their synthetic methods. In particular, inspiration from the synthesis and the future direction of the NS5B polymerase inhibitors are highlighted.

Novel 4″-O-(trans-β-arylacrylamido)carbamoyl azithromycin analogs were designed, synthesized and evaluated for their antibacterial activity against nine significant pathogens using broth microdilution method. A majority of these derivatives maintained the activity of azithromycin against susceptible Streptococcus pyogenes and all the compounds demonstrated remarkably improved activity compared with the references against all the three phenotypes of resistant Streptococcus pneumoniae. In particular, compound 24 exhibited the most potent activity against susceptible Staphylococcus aureus (MIC = 0.5 μg/mL), S. pneumoniae (MIC = 0.06 μg/mL) and S. pyogenes (MIC = 0.25 μg/mL). The most active compound 7 (MIC = 0.015 μg/mL) against resistant S. pneumoniae expressing the mefA gene, exhibited 512 and 256-fold more potent activity than erythromycin and azithromycin, respectively. Compounds 28 (MIC = 0.5 μg/mL), 29 (MIC = 0.25 μg/mL) and 30 (MIC = 0.5 μg/mL) demonstrated potent activity against resistant S. pneumoniae expressing the ermB gene, which were 256, 512 and 256-fold better than the references, respectively.

Currently, wide-spread antimicrobials resistance among bacterial pathogens continues being a dramatically increasing and serious threat to public health, and thus there is a pressing need to develop new antimicrobials to keep pace with the bacterial resistance. Filamentous temperature-sensitive protein Z (FtsZ), a prokaryotic cytoskeleton protein, plays an important role in bacterial cell division. It as a very new and promising target, garners special attention in the antibacterial research in the recent years. This review describes not only the function and dynamic behaviors of FtsZ, but also the known natural and synthetic inhibitors of FtsZ. In particular, the small molecules recently developed and the future directions of ideal candidates are highlighted.

Drug efflux protein complexes confer multidrug resistance on bacteria by transporting a wide spectrum of structurally diverse antibiotics. Moreover, organisms can only acquire resistance in the presence of an active efflux pump. The substrate range of drug efflux pumps is not limited to antibiotics, but it also includes toxins, dyes, detergents, lipids and molecules involved in quorum sensing; hence efflux pumps are also associated with virulence and biofilm formation. Inhibitors of efflux pumps are therefore attractive compounds to reverse multidrug resistance and to prevent the development of resistance in clinically relevant bacterial pathogens. Recent successes on the structure determination and functional analysis of the AcrB and MexB components of the AcrAB-TolC and MexAB-OprM drug efflux systems as well as the structure of the fully assembled, functional triparted AcrAB-TolC complex significantly contributed to our understanding of the mechanism of substrate transport and the options for inhibition of efflux. These data, combined with the well-developed methodologies for measuring efflux pump inhibition, could allow the rational design and subsequent experimental verification of potential efflux pump inhibitors. In this review we will explore how the available biochemical and structural information can be translated into the discovery and development of new compounds that could reverse drug resistance in Gram-negative pathogens. The current literature on efflux pump inhibitors will also be analysed and the reasons why no compounds have yet progressed into clinical use will be explored.

The increasing multi-drug resistance has become a major threat to the public health. Overexpression of multidrug efflux pumps is one of the major mechanisms of drug resistance in bacteria. Since active efflux of antibacterial agents plays a significant role in mediating drug resistance in bacteria, the inhibition of efflux pumps appears to be a promising strategy to restore antibacterial potency. In recent years, in order to address this grave problem of multiple drug resistance mediated by efflux pump, a large number of efflux pump inhibitors have been discovered and tested, including natural products, antibiotics and synthetic molecules. This review mainly describes recent achievements in the search for new molecules that are able to inhibit efflux pumps in both Gram-positive and Gram-negative bacteria, in particular emphasis on natural and synthetic inhibitors of the NorA efflux pump in Staphylococcus aureus, MexAB-OprM efflux pump in Pseudomonas aeruginosa, and AcrAB-TolC efflux pump in Enterobacteriaceae, giving special attention to their mechanisms of action, structureactivity relationships and synergetic effect with clinically available antibiotics. Refereed/Peer-reviewed

Novel series of 3-O-arylalkylbenzamide and 3-O-arylalkyl-2,6-difluorobenzamide derivatives were synthesized and evaluated for their on-target activity and antibacterial activity. The results indicated that the 3-O-arylalkyl-2,6-difluorobenzamide derivatives possessed much better on-target activity and antibacterial activity than the 3-O-arylalkylbenzamide derivatives. Among them, 3-O-chlorobenzyl derivative 36 was the most effective in antibacterial activity (0.5, 4, and 8 μg/mL) against Bacillus subtilis ATCC9372, methicillin-resistant Staphylococcus aureus ATCC29213, and penicillin-resistant Staphylococcus aureus PR, while 3-O-methylbenzyl derivative 41 only exhibited the most potent activity (2 μg/mL) against Staphylococcus aureus ATCC25923. 3-O-Chlorobenzyl and 3-O-methylbenzyl derivatives 36 and 41 exhibited the most potent cell division inhibitory activity and antibacterial activity against four phenotypes of Gram-positive strains including MRSA. Refereed/Peer-reviewed

Cancer is a serious disease characterized by the uncontrolled growth division of cells, and nowadays it remains a significant challenge for the medical field. Malaria is an infectious disease in the similar situation to cancer. Almost 40% people in the world live in areas with malaria risk and each year there are about 2 to 3 million people dying from malaria. Farnesyltransferase (FTase) that belongs to isoprenyltransferase family can catalyze the initial step of Ras-processing and is identified as a promising target for the treatment of cancer and malaria. During the past decade years, a large number of FTase inhibitors with anticancer or antimalarial activity have been reported and some of them are undergoing clinical development. This review mainly introduces the FTase inhibitors as anticancer and antimalarial agents, with focus on their enzyme inhibitory activity, stability and enzyme selectivity, etc. In particular, the promising new FTase inhibitors among them will be discussed in detail and the inspirations for their design will be highlighted.

Currently, wide-spread antimicrobials resistance among bacterial pathogens continues being a dramatically increasing and serious threat to public health, and thus there is a pressing need to develop new antimicrobials to keep pace with the bacterial resistance. Filamentous temperature-sensitive protein Z (FtsZ), a prokaryotic cytoskeleton protein, plays an important role in bacterial cell division. It as a very new and promising target, garners special attention in the antibacterial research in the recent years. This review describes not only the function and dynamic behaviors of FtsZ, but also the known natural and synthetic inhibitors of FtsZ. In particular, the small molecules recently developed and the future directions of ideal candidates are highlighted.

New chiral bis-paracyclophane N -heterocyclic carbene (NHC) ligands 1 – 3 have been explored for ruthenium catalyzed asymmetric hydrosilylation of ketones using diphenylsilane to give enantioenriched alcohols. These ligands provide for efficient asymmetric reduction in the presence of silver(I) triflate (1 mol %) at room temperature with high reactivity and selectivity. Acetophenone 4 was reduced with 1 mol % catalyst in 96% isolated yield, 97% ee. Following removal of the silyl ether, various alcohols 5 were obtained from aromatic ketones in high yield and selectivity.

Review: [with particular focus on their activities, structure—activity relationships, and mechanisms; 74 refs.

A series of novel 4-bromo-1H-indazole derivatives as filamentous temperature-sensitive protein Z (FtsZ) inhibitors were designed, synthesized, and assayed for their in vitro antibacterial activity against various phenotypes of Gram-positive and Gram-negative bacteria and their cell division inhibitory activity. The results indicated that this series showed better antibacterial activity against Staphylococcus epidermidis and penicillin-susceptible Streptococcus pyogenes than the other tested strains. Among them, compounds 12 and 18 exhibited 256-fold and 256-fold more potent activity than 3-methoxybenzamide (3-MBA) against penicillin-resistant Staphylococcus aureus, and compound 18 showed 64-fold better activity than 3-MBA but 4-fold weaker activity than ciprofloxacin in the inhibition of S. aureus ATCC29213. Particularly, compound 9 presented the best activity (4 µg/mL) against S. pyogenes PS, being 32-fold, 32-fold, and 2-fold more active than 3-MBA, curcumin, and ciprofloxacin, respectively, but it was four times less active than oxacillin sodium. In addition, some synthesized compounds displayed moderate inhibition of cell division against S. aureus ATCC25923, Escherichia coli ATCC25922, and Pseudomonas aeruginosa ATCC27853, sharing a minimum cell division concentration of 128 µg/mL.

In an attempt to discover potential antibacterial agents against the increasing bacterial resistance, novel cinnamaldehyde derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activity against nine significant pathogens using broth microdilution method, and their cell division inhibitory activity against four representative strains. In the in vitro antibacterial activity, the newly synthesized compounds generally displayed better efficacy against Staphylococcus aureus ATCC25923 than the others. In particular, compounds 3, 8 and 10 exerted superior or comparable activity to all the reference drugs. In the cell division inhibitory activity, all the compounds showed the same trend as their in vitro antibacterial activity, exhibiting better activity against S. aureus ATCC25923 than the other strains. Additionally, compounds 3, 6, 7 and 8 displayed potent cell division inhibitory activity with an MIC value of below 1 μg/mL, over 256-fold better than all the reference drugs.

N-Myristoyltransferase (NMT) is a cytosolic monomeric enzyme present in eukaryotes such as fungi and protozoa, but is not found in prokaryotes. The attachment of a 14-carbon saturated fatty acid, myristate, from myristoyl-CoA (14:0 CoA) to the N-terminal glycine residue in a specific set of cellular proteins is commonly called protein N-myristoylation. The myristoylation reaction catalyzed by the enzyme myristoyl CoA:NMT is both necessary for the growth of various organisms and conclusive for cellular proliferation. Therefore, NMT has been identified as a novel and promising target for antifungal, antiparasitic, and anticancer agents, and a large number of potent NMT inhibitors with antifungal, antiparasitic, and anticancer activities have been reported. Herein we describe recent advances in the discovery of NMT inhibitors. We introduce not only the functions of NMT, but also some representative natural and synthetic inhibitors, with a focus on their biological activity, selectivity, and structure-activity relationship (SAR) information. In particular, inspiration from NMT inhibitor structures and the future direction of these compounds are highlighted.

In order to develop new antibiotics effective against resistant bacteria, a series of novel 15-membered macrolide derivatives were designed and synthesized by the modification of hydroxyl groups at C-11, C-12 and C-4″ positions. Their structures were confirmed by MS, IR, 1 H NMR or 13 C NMR.

Bacterial infections are a constant and serious threat to human health. With the increase of multidrug resistance of clinically pathogenic bacteria, common antibiotic therapies have been less effective. Fatty acid synthesis type II (FASII) system enzymes are essential for bacterial membrane lipid biosynthesis and represent increasingly promising targets for the discovery of antibacterial agents with new mechanisms of action. This review highlights recent advances in inhibitors of bacterial FASII as potential antibacterial agents, paying special attention to the activities, mechanisms, and structure-activity relationships of those inhibitors that mainly target β-ketoacyl-ACP synthase, β-ketoacyl-ACP reductase, β-hydroxyacyl-ACP dehydratase, and enoyl-ACP reductase. Although inhibitors with low nanomolar and selective activity against various bacterial FASII have entered clinical trials, further research is needed to expand upon both available and yet unknown scaffolds to identify new FASII inhibitors that may have antibacterial potential, particularly against resistant bacterial strains.

The overuse of antibiotics which exerts the selective pressure for bacterial pathogens has facilitated the spread of antibiotics' resistance. Metallo-β-lactamases (MβLs) are zinc enzymes produced by an increasing number of bacterial pathogens. They can readily cleave carbapenems and most other β-lactams that are mainstays of therapy for bacterial infections. MβL-conferred resistance to antibiotics is most worrisome due to MβLs exhibiting very broad-spectrum resistance. Therefore, the bacteria carrying MβLs have recently become a significant clinical threat. No clinically useful MβLs inhibitor has been discovered yet. To address the serious threat to public health posed by the MβL-conferred resistance to antibiotics, novel effective MβL inhibitors are urgently needed. This review mainly describes various MβL inhibitors, giving special attention to their antibacterial activity, mechanisms of action, structure-activity relationships and synergetic effect with clinically available antibiotics.

Bacterial infections are a constant and serious threat to human health. With the increase of multidrug resistance of clinically pathogenic bacteria, common antibiotic therapies have been less effective. Fatty acid synthesis type II (FASII) system enzymes are essential for bacterial membrane lipid biosynthesis and represent increasingly promising targets for the discovery of antibacterial agents with new mechanisms of action. This review highlights recent advances in inhibitors of bacterial FASII as potential antibacterial agents, paying special attention to the activities, mechanisms, and structure-activity relationships of those inhibitors that mainly target β-ketoacyl-ACP synthase, β-ketoacyl-ACP reductase, β-hydroxyacyl-ACP dehydratase, and enoyl-ACP reductase. Although inhibitors with low nanomolar and selective activity against various bacterial FASII have entered clinical trials, further research is needed to expand upon both available and yet unknown scaffolds to identify new FASII inhibitors that may have antibacterial potential, particularly against resistant bacterial strains.

Clinically significant antibiotic resistance is one of the greatest challenges of the twenty-first century. Yet new antibiotics are currently being developed at a much slower pace than our growing need for such drugs. Instead of focusing on conventional therapeutics that target in vitro bacterial viability, an alternative therapy is to target virulence factors and biofilms. Such anti-virulence strategies have attracted more and more attention recently, for it would add both supplement and diversity to our current antimicrobial library. This approach has several potential advantages including imposing less evolutionary pressure on the development of antibiotic resistance, increasing the antibacterial targets and preserving the host endogenous microbiome. Quorum sensing is an intercellular communication process in bacterial communities, which can regulate coordinated expression of virulence factors and biofilms. N-Acyl homoserine lactones (AHLs) are autoinducers generated by a variety of Gram-negative bacteria. These signals combining with their cognate LuxR-type receptors trigger the expression of virulence genes. In this critical review, we summarize various structural types of small molecules targeting AHL-based quorum sensing to attenuate bacteria virulence factors and biofilms.

Tuberculosis (TB) is a major health problem, with approximately one-third of the world's population infected with Mycobacterium tuberculosis, eight million people in the active disease state, and two million dying annually. Furthermore, the prevalence of TB/HIV co-infection, and the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have further aggravated the spread of this disease and thus mortality by it. There is an urgent need for novel antitubercular agents with improved properties, such as lower toxicity, shortened duration of therapy, rapid bactericidal action, and enhanced activity against MDR strains. Fortunately, a number of new potential antitubercular candidate drugs with heterocyclic rings, which are most likely to be effective against resistant strains, have entered clinical trials in recent years. This review highlights recent advances in the research of novel heterocyclic compounds, with particular focus on their antimycobacterial activity, mechanisms of action, toxicity, and structure-activity relationships (SARs).

Currently, schizophrenia, as a serious psychiatric disorder, continues affecting the quality of life in the psychotics. This disease is often debilitating and chronic, showing broad symptoms at one end by hallucinations, delusions, thought disorder and the other end by affective flattening, catatonia, social isolation. In order to combat this disease, many antipsychotic drugs have been developed and introduced into clinical practice in the past half century. However, only a small minority of them can treat effectively schizophrenia without side effects. In view of this situation, high attention has been given to the exploration of desired antipsychotic agents influential especially through the modulation of dopamine and serotonin receptors with substantial strides made in recent years, leading to the discovery of many novel chemical entities with intriguing profiles. In this review, we summarize novel structural antipsychotics in development and discuss the future direction of ideal antipsychotic drug candiates. In particular, the promising atypical antipsychotic profiles of new molecules and the inspirations for their design are highlighted.

Novel 3-elongated arylalkoxybenzamide derivatives were designed, synthesized and evaluated for their cell division inhibitory activity and antibacterial activity. Among them, the subseries of 3-alkyloxybenzamide derivatives exhibited greatly improved on-target activity against Bacillus subtilis and Staphylococcus aureus, and remarkably increased antibacterial activity against B. subtilis ATCC9372, penicillin-susceptible S. aureus ATCC25923, methicillin-resistant S. aureus ATCC29213 (MRSA) and penicillin-resistant S. aureus PR compared with 3-methoxybenzamide. In contrast, the subseries of 3-phenoxyaklyloxybenzamide, 3-heteroarylalkyloxybenzamide and 3-heteroarylthioalkyloxybenzamide derivatives only showed a significant improvement in on-target activity and antibacterial activity against B. subtilis ATCC9372.

Tuberculosis (TB) is a major health problem, with approximately one-third of the world's population infected with Mycobacterium tuberculosis, eight million people in the active disease state, and two million dying annually. Furthermore, the prevalence of TB/HIV co-infection, and the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have further aggravated the spread of this disease and thus mortality by it. There is an urgent need for novel antitubercular agents with improved properties, such as lower toxicity, shortened duration of therapy, rapid bactericidal action, and enhanced activity against MDR strains. Fortunately, a number of new potential antitubercular candidate drugs with heterocyclic rings, which are most likely to be effective against resistant strains, have entered clinical trials in recent years. This review highlights recent advances in the research of novel heterocyclic compounds, with particular focus on their antimycobacterial activity, mechanisms of action, toxicity, and structure-activity relationships (SARs).

The emergence and prevalence of bacterial resistance has resulted in a clear demand for novel antibacterial drugs. As a tubulin homologue, FtsZ is an essential cell-division protein in prokaryotic organisms and is showing increasing promise as a target for antibacterial drug discovery. This review describes the role of FtsZ in bacterial cytokinesis and various FtsZ inhibitors, with particular focus on their discovery, antibacterial activities, mechanisms of action, synthetic methods, and representative analogues.