Small organometallic compounds as antibacterial agents

The emergence of bacterial resistance to commercial antibiotics is an issue of global importance. During the last two decades, the number of antibacterial agents that have been discovered and introduced into the market has steadily declined and failed to meet the challenges posed by rapidly increasing resistance of the pathogens against common antibacterial drugs. The development of new classes of compounds to control the virulence of the pathogens is therefore urgently required. This perspective describes the historical development in brief and recent advances on the preparation of small organometallic compounds as new classes of antibacterial agents with potential for clinical development.     

Anionic amphiphilic dendrimers as antibacterial agents

An anionic amphiphilic dendrimer is reported that possesses increased cytotoxicological potency against prokaryotic cells compared to eukaryotic cells. The half-maximal effective concentration (EC50) for the dendrimer against Bacillus subtilis, a Gram-positive bacterial strain, was measured to be 4.1 x 10(-5) M, while that against human umbilical vein endothelial cells (HUVEC) was more than 36x greater at a value of 1.5 x 10(-3) M. EC50 ratios for two commercial amphiphiles, sodium dodecyl sulfate (SDS) and Triton X-100, in addition to a similar synthesized dendritic structure were at most only 3.8x greater. Furthermore, the observed EC50 values appear to be correlated to the critical aggregation constant (CAC) in solution suggesting a mechanism of action for these anionic amphiphilic dendrimers related to their supramolecular structures.     

Quinoline-3-carboxylates as potential antibacterial agents

The ethyl-2-chloroquinoline-3-carboxylates, 4, were achieved from o-aminobenzophenones in two steps. i.e. initially, the ethyl-2-oxoquinoline-3-carboxylates, 3, were obtained by base-catalyzed Friedlander condensations of o-aminobenzophenones, 1, and diethylmalonate, 2. The 2-chloroquinoline-3-carboxylates, 4, were then obtained by the reaction with POCl₃ in good yields. The chemical structures were confirmed by FTIR, mass and ¹H-NMR spectroscopic techniques. All the synthesized compounds were tested for their in vitro antibacterial activity against Bacillus subtilis and Vibrio cholera and found to possess moderate activity.     

[4.3.0] pyrazolidinones as potential antibacterial agents

The synthesis of [4.3.0] fused pyrazolidinones is described. The compounds were prepared with substituents identical to those of the known antibacterial agents in the [3.3.0] pyrazolidinone series. Their preparation involved a six-membered ring annulation to a known pyrazolidinone monocycle. Appropriate deblocking and functionalization of the nuclei provided compounds suitable for biological evaluation. In contrast to their lower homologues, the [4.3.0] pyrazolidinones did not exhibit significant antibacterial activity.     

Inulin as a carrier for contrast agents in magnetic resonance imaging

Magnetic resonance angiography (MRA) has put forth an impetus for the development of macromolecular GdIII complexes that have a prolonged lifetime in the vascular system. Herein, we report the synthesis and GdIII complexation of a new sugar conjugate based on inulin and the DO3A ligand (DO3A = 1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid). Two API-DO3ASQ conjugates (API = O-(aminopropyl)inulin, SQ = squaric acid = 3,4-dihydroxy-3-cyclobutene-1,2-dione) with different degrees of substitution (ds = 0.7 and ds = 1.5) were prepared from API by using the diethyl ester of squaric acid as a linking agent for the DO3A chelate. The efficacies of the resulting GdIII compounds were evaluated by investigation of their water 1H longitudinal-relaxation-rate enhancements at variable field (NMRD). A dramatic increase in relaxivity was observed in the more highly substituted conjugate (ds = 1.5); this prompted us to do a variable-temperature (17)O study in order to further characterize the relaxation parameters involved in this system. [Gd(API-DO3ASQ)] shows promising properties for application as a contrast agent for MRI.     

Synthesis of novel steroidal oxazolo quinoxaline as antibacterial agents

Steroidal[oxazolo(4,5-b)quinoxaline-2-yl-hydrazone] derivative (7a–9a) (7b–9b) were prepared by the multi-step reactions of steroid. It is prepared via the reaction of steroidal semicarbazones with 2,3-dichloroquinoxaline at 80 °C in ethanol. The structures of the compounds were evident by IR, ¹H NMR and mass spectrometry and their purities were confirmed by elemental analyses. The antibacterial activity of these compounds was evaluated by the disk diffusion assay against two Gram-positive and two Gram-negative bacteria and then the minimum inhibitory concentration (MIC) of compounds was determined. The results showed that compounds (7a, 7b, 8a, 8b) are better antibacterial agent as compared with the standard drug amoxicillin.     

Polymers as advanced antibacterial and antibiofilm agents for direct and combination therapies

The growing prevalence of antimicrobial drug resistance in pathogenic bacteria is a critical threat to global health. Conventional antibiotics still play a crucial role in treating bacterial infections, but the emergence and spread of antibiotic-resistant micro-organisms are rapidly eroding their usefulness. Cationic polymers, which target bacterial membranes, are thought to be the last frontier in antibacterial development. This class of molecules possesses several advantages including a low propensity for emergence of resistance and rapid bactericidal effect. This review surveys the structure–activity of advanced antimicrobial cationic polymers, including poly(α-amino acids), β-peptides, polycarbonates, star polymers and main-chain cationic polymers, with low toxicity and high selectivity to potentially become useful for real applications. Their uses as potentiating adjuvants to overcome bacterial membrane-related resistance mechanisms and as antibiofilm agents are also covered. The review is intended to provide valuable information for design and development of cationic polymers as antimicrobial and antibiofilm agents for translational applications.

This review surveys the structure–activity of advanced antimicrobial cationic polymers with low toxicity and high selectivity. Their uses as potentiating adjuvants and as antibiofilm agents are also covered.     

Novel 1,2,3-triazolo phosphonate derivatives as potential antibacterial agents

We describe the synthesis, characterization, and in vitro antibacterial evaluation of a library of novel compounds based on 1,2,3-triazolo phosphonate framework along with the evaluation of DNA gyrase inhibitory potential of a promising molecule in silico. Preparation of these compounds was carried out via a multistep sequence comprising of the Abramov reaction followed by the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) as the key steps. Various α-hydroxyphosphonate derivatives containing either a secondary or tertiary alcohol at the α position were prepared. When screened for their antibacterial activities in vitro using a Gram-positive (Staphylococcus aureus) and three Gram-negative (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa) strains, majority of these derivatives exhibited reasonable to good effects with the analogue 5k being active against all the strains. The SAR analysis indicated that the activity was influenced by the position of the α-hydroxyphosphonate moiety as well as the substituent present on the benzene ring attached to the 1,2,3-triazole ring. Moreover, the compound 5k showed strong interactions with the DNA active site when docked into the DNA gyrase in silico. Thus, the 1,2,3-triazolo phosphonate derivative 5k appeared to be a novel and promising hit molecule that deserves further study as a potential antibacterial agent.     

Synthesis of benzimidazo-substituted 3-quinolinecarboxylic acids as antibacterial agents

The 6- and 7-(1-ethylbenzimidazolyl)-substituted 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were synthesized. Antibacterial activity was tested in vitro. Only one of the new compounds prepared showed slight antibacterial activity against one of the strains tested. So, they are of no interest as antibacterial agents.     

Polycations. III. Synthesis of polyphosphonium salts for use as antibacterial agents

Several series of polyphosphonium salts have been prepared. These include those in which the cationic sites are located at regular intervals along a linear chain of defined length (“strings”) and those in which the cationic sites are in linkages arrayed in branching arms about a central focus unit (“balloons”). Similarly, polyphosphonium balloon arrays have been attached to a polystyrene backbone providing a material that can serve as an anionic exchange resin. Several of the resultant materials have demonstrated antibacterial activity, in systems analogous to those previously reported for simple functionalized polystyrene species, and continue to be investigated. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9:495–502, 1998     

Synthesis of novel N-sulfonyl monocyclic beta-lactams as potential antibacterial agents

New cis monocyclic beta-lactams were synthesized by [2+2] Staudinger cycloaddition reactions of the imine (3,4-dimethoxybenzylidene)-(4-methoxyphenyl)-amine and ketenes derived from different acyl chlorides and Et3N. These monocyclic beta-lactams were then cleaved by ceric ammonium nitrate (CAN) to give NH-monocyclic beta-lactams, which in turn were converted to N-sulfonyl monocyclic beta-lactams by treatment with four different sulfonyl chlorides in the presence of Et3N and 4,4-dimethyl-aminopyridine (DMAP).     

Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial agents

A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains(including multidrug-resistant clinical isolates) and Gramnegative bacterial strains, with minimum inhibitory concentrations(MICs) in the range of 2.1–181.2 mmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Grampositive bacteria(e.g., Staphylococcus aureus 4220), Gram-negative bacteria(e.g., Escherichia coli 1924),and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1 mmol/L. Especially, compound 7a was the most potent, with an MIC of 2.1 mmol/L against four multidrug-resistant, Gram-positive bacterial strains.The cytotoxic activity of the compound 7a, 7c and 7f was assessed in HepG2 cells, and the results suggest that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting scaffolds for the development of novel antibacterial agents.     

G protein betagamma subunits as targets for small molecule therapeutic development

G proteins mediate the action of G protein coupled receptors (GPCRs), a major target of current pharmaceuticals and a major target of interest in future drug development. Most pharmaceutical interest has been in the development of selective GPCR agonists and antagonists that activate or inhibit specific GPCRs. Some recent thinking has focused on the idea that some pathologies are the result of the actions of an array of GPCRs suggesting that targeting single receptors may have limited efficacy. Thus, targeting pathways common to multiple GPCRs that control critical pathways involved in disease has potential therapeutic relevance. G protein betagamma subunits released from some GPCRs upon receptor activation regulate a variety of downstream pathways to control various aspects of mammalian physiology. There is evidence from cell- based and animal models that excess Gbetagamma signaling can be detrimental and blocking Gbetagamma signaling has salutary effects in a number of pathological models. Gbetagamma regulates downstream pathways through modulation of enzymes that produce cellular second messengers or through regulation of ion channels by direct protein-protein interactions. Thus, blocking Gbetagamma functions requires development of small molecule agents that disrupt Gbetagamma protein interactions with downstream partners. Here we discuss evidence that small molecule targeting Gbetagamma could be of therapeutic value. The concept of disruption of protein-protein interactions by targeting a "hot spot" on Gbetagamma is delineated and the biochemical and virtual screening strategies for identification of small molecules that selectively target Gbetagamma functions are outlined. Evaluation of the effectiveness of virtual screening indicates that computational screening enhanced identification of true Gbetagamma binding molecules. However, further refinement of the approach could significantly improve the yield of Gbetagamma binding molecules from this screen that could result in multiple candidate leads for future drug development.     

Self-enhanced photothermal-chemodynamic antibacterial agents for synergistic anti-infective therapy

Cu_2-xS nanostructures have been intensively studied as outstanding chemodynamic therapy (CDT) and good photothermal therapy (PTT) antibacterial agents due to their highly efficient Cu(Ⅰ)-initiated Fenton-like catalytic activity and good photothermal conversion property. However, they still suffer from shortage of Cu(Ⅰ) supply in the long-term and comparatively low inherent photothermal conversion efficiency. Herein, we constructed a self-enhanced synergistic PTT/CDT nanoplatform (Cu_1.94S@MPN) by coating Cu_1.94S nanoparticles with Fe(Ⅲ)/tannic acid based metal-polyphenol networks (MPN). Activated by the acidic bacterial infection microenvironment, Cu_1.94S@MPN could be decomposed to continuously release Cu(Ⅱ), Fe(Ⅲ) ions and tannic acid. As the result of tannic acid-involved Cu and Fe redox cycling, Cu(Ⅰ)/Fe(Ⅱ)-rich CDT could be achieved through the highly accelerated catalytic Fenton/Fenton-like reactions. More importantly, experimental results demonstrated that Cu_1.94S@MPN exhibited both excellent photothermal antibacterial and photothermal-enhanced CDT properties to eradicate bacteria in vitro and in vivo. Overall, this novel nanotherapeutics has great potential to become a clinic candidate for anti-infective therapy in future.     

Molecular basis for acyl carrier protein–ketoreductase interaction in trans-acyltransferase polyketide synthases

The biosynthesis of polyketides by type I modular polyketide synthases (PKS) relies on co-ordinated interactions between acyl carrier protein (ACP) domains and catalytic domains within the megasynthase. Despite the importance of these interactions, and their implications for biosynthetic engineering efforts, they remain poorly understood. Here, we report the molecular details of the interaction interface between an ACP domain and a ketoreductase (KR) domain from a trans-acyltransferase (trans-AT) PKS. Using a high-throughput mass spectrometry (MS)-based assay in combination with scanning alanine mutagenesis, residues contributing to the KR-binding epitope of the ACP domain were identified. Application of carbene footprinting revealed the ACP-binding site on the KR domain surface, and molecular docking simulations driven by experimental data allowed production of an accurate model of the complex. Interactions between ACP and KR domains from trans-AT PKSs were found to be specific for their cognate partner, indicating highly optimised interaction interfaces driven by evolutionary processes. Using detailed knowledge of the ACP:KR interaction epitope, an ACP domain was engineered to interact with a non-cognate KR domain partner. The results provide novel, high resolution insights into the ACP:KR interface and offer valuable rules for future engineering efforts of biosynthetic assembly lines.

The interaction epitope between a cognate KR–ACP domain pairing from a trans-AT polyketide synthase is elucidated in molecular detail, providing unique insights into recognition and specificity of the interface.     

3-Diethylaminopropyl-bearing glycol chitosan as a protein drug carrier

Polysaccharidic nanogels were fabricated with bovine serum albumin (BSA) and a glycol chitosan (GCS) grafted with functional 3-diethylaminopropyl (DEAP) groups. These nanogels were investigated to evaluate their cellular uptake in HeLa cells and in vivo fate in nude mice tumor model. Unlike free BSA, GCS-g-DEAP/BSA nanogels improved cellular uptake of BSA. Furthermore, this system led to an enhanced blood circulation and a high accumulation of BSA in the tumor site. Our collective results strongly support that GCS-g-DEAP/BSA nanogel is a potential carrier system for high molecular weight proteins.     

Synthesis and molecular docking study of pyrazole clubbed oxazole as antibacterial agents

Research on Chemical Intermediates - We have developed a simple synthetic protocol for the preparation of novel 3-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-arylisoxazoles. The structure of...     

Surface-modified protein nanospheres as potential antiviral agents

A novel application of surface-modified protein nanospheres as potential antiviral agents is illustrated. By using a single-step sonochemical process, bovine serum albumin nanospheres were generated, whose surface was covalently conjugated with mercaptoethane sulfonate to chemically and electrostatically mimic cellular heparan sulfate. The nanospheres effectively inhibited HSV-1 infection.