Showing papers in "MedChemComm in 2016"
TL;DR: By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes, and an overview of these mechanisms is provided.
Abstract: Aminoglycoside (AG) antibiotics are used to treat many Gram-negative and some Gram-positive infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small molecules such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clinical prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clinical relevance.
329 citations
TL;DR: The efforts made in using ILs in drug solubility, API formulation and drug delivery, including topical, transdermal and oral delivery, are presented, with particular emphasis on recent developments.
Abstract: The pharmaceutical industries face a series of challenges in the delivery of many newly developed drug molecules because of their low solubility, bioavailability, stability and polymorphic conversion. These limitations are further exacerbated when drug molecules are insoluble or sparingly soluble in water and most pharmaceutically accepted organic solvents. To address these limitations, innovation is required in the pharmaceutical sciences for the formulation of drugs, solvents or systems for effective drug delivery. Fortunately, in the past few years, ionic liquids (ILs)—a novel class of environmentally benign and tailor-made solvents—have been increasingly exploited as solvents, co-solvents and/or materials in the fields of pharmaceutical drug delivery and active pharmaceutical ingredient (API) formulation because of their unique and tunable physicochemical and biological properties. The use of ILs can markedly improve the pharmacokinetic and pharmacodynamic properties of drugs. To highlight the potential of ILs as a drug delivery/formulation tool, this review gives an overview of the application of ILs to address critical pharmaceutical challenges, including the low solubility, polymorphism and bioavailability of drugs. This review is not intended to be comprehensive, but rather to present the efforts made in using ILs in drug solubility, API formulation and drug delivery, including topical, transdermal and oral delivery, with particular emphasis on recent developments.
196 citations
TL;DR: Several classes of NPs effective against a broad range of microbial biofilms, both in vivo and in vitro, are described and will help to fight resistant infections and will contribute in improving human health.
Abstract: Microbes form surface-adherent community structures called biofilms and these biofilms play a critical role in infection. Biofilms impart antibiotic resistance and sometimes become recalcitrant to the host immune system. It has been reported by the National Institutes of Health that more than 80% of bacterial infections are caused by biofilm formation. Such a kind of infection is also prevalent in biomedical devices which become a source of infection. The treatment of biofilm-mediated infections is a big challenge that requires more sensitive and effective antibiofilm strategies for their removal. Nanoparticles targeting antibiofilm therapy have gained tremendous impetus in the past decade due to their unique features. These nanoparticles are wonder particles having a wide spectrum of biological applications and among these applications their antibiofilm activity is significantly useful. These particles are reactive entities and can easily infiltrate into the matrix which acts as a barrier for many antibiotics. Biomedical surfaces are also nano-functionalized by coating, impregnation or embedding with nanomaterials to prevent biofilm formation. The study of interaction between nanoparticles and biofilms can provide us more insights into the mechanism of biofilm regulation. In this review article, several classes of NPs effective against a broad range of microbial biofilms, both in vivo and in vitro, are described. The application of nanoparticles against biofilms will help to fight resistant infections and will contribute in improving human health.
137 citations
TL;DR: An overview of the SLC transporters' structures and transport mechanisms is provided and computational techniques, such as homology modeling and virtual screening that are emerging as key tools to discover chemical probes for human SLC members are described.
Abstract: The human solute carrier (SLC) transporters are important targets for drug development. Structure-based drug discovery for SLC transporters requires the description of their structure, dynamics, and mechanism of interaction with small molecule ligands and ions. The recent determination of atomic structures of human SLC transporters and their homologs, combined with improved computational power and prediction methods, has led to an increased applicability of structure-based drug design methods for human SLC members. In this review, we provide an overview of the SLC transporters' structures and transport mechanisms. We then describe computational techniques, such as homology modeling and virtual screening that are emerging as key tools to discover chemical probes for human SLC members. We illustrate the utility of these methods by presenting case studies in which rational integration of computation and experiment was used to characterize SLC members that transport key nutrients and metabolites, including the amino acid transporters LAT-1 and ASCT2, the SLC13 family of citric acid cycle intermediates transporters, and the glucose transporter GLUT1. We conclude with a brief discussion about future directions in structure-based drug discovery for the human SLC superfamily, one of the most structurally and functionally diverse protein families in human.
125 citations
TL;DR: Significant progress has been made in discovering inhibitors and chemical probes of bromodomains, epigenetic readers of lysine acetylation, and their applications in medicine and materials science.
Abstract: In the last five years, the development of inhibitors of bromodomains has emerged as an area of intensive worldwide research. Emerging evidence has implicated a number of non-BET bromodomains in the onset and progression of diseases such as cancer, HIV infection and inflammation. The development and use of small molecule chemical probes has been fundamental to pre-clinical evaluation of bromodomains as targets. Recent efforts are described highlighting the development of potent, selective and cell active non-BET bromodomain inhibitors and their therapeutic potential. Over half of typical bromodomains now have reported ligands, but those with atypical binding site residues remain resistant to chemical probe discovery efforts.
118 citations
TL;DR: Bacterial membrane anionic lipids are highlighted as attractive targets in the design of antibacterial drugs which can be effective against both Gram-positive and Gram-negative resistant bacteria.
Abstract: Hereunder, we highlight bacterial membrane anionic lipids as attractive targets in the design of antibacterial drugs which can be effective against both Gram-positive and Gram-negative resistant bacteria. In this approach, first, molecular foundations and structure–activity relationships are laid out for membrane-targeting drugs and drug candidates from the structure and physicochemical properties of the main membrane targets, describing, as well, the corresponding identified resistances. Second, this approach is illustrated by the history of the emergence of antibacterial and antifungal amphiphilic aminoglycosides (AAGs) which are active against Gram-positive and Gram-negative resistant bacteria. AAGs have resulted from intensive medicinal chemistry development of a group of old antibiotic drugs known as aminoglycosides (AGs), which target ribosomal RNA. The aforementioned AAG's are being used towards discovering new antibiotics which are less toxic and less susceptible to resistance. The recent results in the field of AAGs are described and discussed in terms of structure–activity relationships and mechanism of action.
111 citations
TL;DR: Deep eutectic solvents (DESs) as mentioned in this paper are a new class of green solvants used to dissolve non-steroidal anti-inflammatory drugs (NSAIDs) for potential non-aqueous liquid administration applications.
Abstract: Deep eutectic solvents (DESs) are a new class of green solvents used to dissolve non-steroidal anti-inflammatory drugs (NSAIDs) for potential non-aqueous liquid administration applications. Several NSAIDs are readily soluble in various DESs to a high concentration. Aspirin, a hydrolabile NSAID, was 8.2-fold more stable against cleavage in DES than in water.
99 citations
TL;DR: Unique benefits of the GSK incubation include uptake of large numbers of building blocks and privileged scaffolds, guidance on library design, and opportunities to add value beyond lead discovery.
Abstract: DNA encoded library technology (ELT) provides access to broad chemical diversity through affinity selection. As an early adopter, GlaxoSmithKline enabled the development of ELT from proof of concept to full fledged contributor to the small molecule therapeutic pipeline. Unique benefits of the GSK incubation include uptake of large numbers of building blocks and privileged scaffolds, guidance on library design, and opportunities to add value beyond lead discovery. Soluble epoxide hydrolase and RIP1 kinase represent two case studies of ELT hits that have advanced into clinical studies. ELT also shows promise as a strategy to forecast target tractability. As an emerging technology, it benefits from incubation at the interface of industry and academia.
67 citations
TL;DR: Some of the most relevant GLUT inhibitors that have been recently developed as prospective anticancer agents are reviewed.
Abstract: The altered metabolism observed in cancer cells generally consists in increased glucose uptake and glycolytic activity. This is associated with an overexpression of glucose transporter proteins (GLUTs), which facilitate glucose uptake across the plasma membrane and play a crucial role in the survival of cancer cells. Therefore GLUTs are considered as suitable targets for the treatment of cancer. Herein we review some of the most relevant GLUT inhibitors that have been recently developed as prospective anticancer agents.
65 citations
TL;DR: The state of the art of membranolytic ACP research is summarized and the molecular features that have been related to the structure–activity relationships of alpha-helical ACPs are discussed.
Abstract: Membranolytic anticancer peptides (ACPs) potentially offer new perspectives for the development of anticancer drugs. Their receptor-independent mechanisms of action hold the promise to hinder the development of resistance, which is a hurdle of many present-day chemotherapeutics. Peptide selectivity for cancer cells is believed to be primarily due to a net charge difference between neoplastic and non-neoplastic cells at the membrane surface. However, their exact molecular mechanisms are not yet fully understood. In this review, we summarise the state of the art of membranolytic ACP research and discuss the molecular features that have been related to the structure–activity relationships of alpha-helical ACPs.
65 citations
TL;DR: How covalent tethering was developed, its current state, and its future are highlighted, as well as the risk of selecting the most reactive fragment rather than the best binder if the covalents fragments are screened in mixtures.
Abstract: Covalent probes and drugs have found widespread use as research tools and clinical agents. Covalent probes are useful because of their increased intracellular potency and because covalent labeling of cellular proteins can be tracked using click chemistry. Covalent drugs, on the other hand, can overcome drug resistance toward their reversible counterparts. The discovery of covalent probes and drugs usually follows two trajectories: covalent natural products and their analogues are used directly as covalent probes or drugs; or alternatively, a non-covalent probe is equipped with a reactive group and converted into a covalent probe. In both cases, there is a need to either have a natural product or a potent non-covalent scaffold. The alternative approach to discover covalent probes is to start with a drug-like fragment that already has an electrophile, and then grow the fragment into a potent lead compound. In this approach, the electrophilic fragment will react covalently with the target protein, and therefore the initial weak binding of the fragment can be amplified over time and detected using mass spectrometry. With this approach the surface of the protein can be interrogated with a library of covalent fragments to identify covalent drug binding sites. One challenge with this approach is the danger of non-specific covalent labeling of proteins with covalent fragments. The second challenge is the risk of selecting the most reactive fragment rather than the best binder if the covalent fragments are screened in mixtures. This review will highlight how covalent tethering was developed, its current state, and its future.
TL;DR: This study demonstrates the usability of DNA-encoded library technologies for identifying novel chemical matter with alternative binding modes to provide a good starting point for drug development.
Abstract: A highly specific and potent (7 nM cellular IC50) inhibitor of p38α kinase was identified directly from a 12.6 million membered DNA-encoded small molecule library. This was achieved using the high fidelity yoctoReactor technology (yR) for preparing the DNA-encoded library, and a homogeneous screening technique – the binder trap enrichment technology (BTE). Although structurally atypical to other kinase blockers, this inhibitor was found by X-ray crystallography to interact with the ATP binding site and provide strong distortion of the P-loop. Remarkably, it assumed an alternative binding mode as it lacks key features of known kinase inhibitors such as typical hinge binding motifs. Interestingly, the inhibitor bound assuming a canonical type-II (‘DFG-out’) binding mode by forming hinge hydrogen bonds with the backbone, showed excellent shape complementarity, and formed a number of specific polar interactions. Moreover, the crystal structure showed, that although buried in the p38α active site, the original DNA attachment point of the compound was accessible through a channel created by the distorted P-loop conformation. This study demonstrates the usability of DNA-encoded library technologies for identifying novel chemical matter with alternative binding modes to provide a good starting point for drug development.
TL;DR: This review, covering publications up to 2015, describes chemistry and antiplasmodial effects of p Skyrimidine-based antimalarials, including hybrids of pyrimidine with other partners.
Abstract: Pyrimidine-containing compounds have attracted great attention because of their biological effects, therapeutic potential and flexibility in structural modification by way of diversifying various positions as well as heterocyclic ring transformations. Emergence of the Plasmodium parasite's resistance against first-line antimalarial drugs has fuelled research interest in the direction of designing new scaffolds as well as strategies to counter drug resistance. One of these strategies that has gained prominence is the synthesis of molecular hybrids encompassing two covalently linked pharmacophores. This review, covering publications up to 2015, describes chemistry and antiplasmodial effects of pyrimidine-based antimalarials, including hybrids of pyrimidine with other partners.
TL;DR: These compounds acting as multitarget quinoidal systems could provide promising new leads for the development of trypanocidal and/or anticancer drugs.
Abstract: Quinonoid compounds based on 5-iodo-1,4-disubstituted-, 1,4- and 1,5-disubstituted-1,2,3-triazoles were synthesized using simple methodologies and evaluated against T. cruzi, the etiological agent of Chagas disease, and cancer cell lines PC3, HCT-116, HL-60, MDA-MB-435 and SF-295. The cytotoxic potential of the lapachones was also assayed against peripheral blood mononuclear cells (PBMC). Two compounds 6 and 12 were identified as potential hits against T. cruzi. β-Lapachone-based 1,5-disubstituted-1,2,3-triazole (12) displayed an IC50/24 h = 125.1 μM, similar to benznidazole, the standard drug. Compound 12 was also more active than the precursor β-lapachone against the cancer cell lines. These compounds acting as multitarget quinoidal systems could provide promising new leads for the development of trypanocidal and/or anticancer drugs.
TL;DR: Analysis of two DNA encoded library screens run against two protein targets employing mixtures of up to 16 different libraries finds physical properties of DEL-derived compounds correlate with average library properties when truncated sub-libraries are accounted for.
Abstract: DNA encoded library screens have gained recent interest as they allow for screening of millions of small molecules in a simple manner, with the goal of providing novel chemical starting points in target-based hit identification. Despite this interest, no publication describes the physical properties, novelty, or structural diversity of molecules derived from such screens, nor a comparison of productivity of different DNA encoded libraries. Here we address this gap by analysis of two DNA encoded library screens run against two protein targets employing mixtures of up to 16 different libraries. Fifty-seven exemplar small molecule compounds from 34 structurally distinct clusters were prioritized from the screening results, synthesized and tested for biochemical activity. Thirty-five of the 57 compounds possess significant biochemical activity (IC50 ≤ 10 μM). Seventeen of the 35 biochemically active compounds possess a molecular weight (MW) < 500 Dalton (Da) and clog P < 5, and 6 possess a MW < 400 Da and clog P < 4. None of the 57 DEL-derived compounds exist in the Roche corporate high throughput screening collection and public compound collections. Productivity per library was observed to be independent of library size. The most productive of the 16 investigated libraries was synthesized employing only simple chemistry. Physical properties of DEL-derived compounds correlate with average library properties when truncated sub-libraries are accounted for. Our analysis may help guide the design of future DNA encoded libraries.
TL;DR: The synthesis of two libraries containing Michael acceptors to identify cysteine reactive ligands is reported, developed a simple procedure to discriminate between covalent and high affinity non-covalent inhibitors using DNA display of the library in a microarray format.
Abstract: DNA-encoded chemical libraries are increasingly used to identify leads for drug discovery or chemical biology. Despite the resurging interest in covalent inhibitors, libraries are typically designed with synthon filtered out for reactive functionalities that can engage a target through covalent interactions. Herein, we report the synthesis of two libraries containing Michael acceptors to identify cysteine reactive ligands. We developed a simple procedure to discriminate between covalent and high affinity non-covalent inhibitors using DNA display of the library in a microarray format. The methodology was validated with known covalent and high affinity non-covalent kinase inhibitors. Screening of the library revealed novel covalent inhibitors for MEK2 and ERBB2.
TL;DR: This review describes recent progress in elucidating the various mechanisms of resistance to membrane-disrupting antibiotics and describes the mechanisms that thwart antimicrobial agents that target intracellular bacterial elements.
Abstract: Small-molecule-mediated disruption of bacterial membranes is an important component of the innate immune response in numerous organisms including humans. Although still under-represented in the clinically used repertoire of antibiotics, several antimicrobial agents that act by disrupting the structures and functions of bacterial membranes are used for treatment of topical and internal infections. Due to the relatively conserved structure compositions of bacterial membranes, antibiotics that disrupt bacterial membranes should be less likely to induce drug resistance than antibiotics that target other bacterial systems. However, drug resistance mechanisms that reduce the efficacy of membrane-disrupting antibiotics have evolved in a variety of bacterial pathogens. Similar to mechanisms that thwart antimicrobial agents that target intracellular bacterial elements, resistance to membrane-disrupting agents results from modifications to the target (in this case, lipids), the action of efflux pumps, expression of various drug deactivating agents, and proteolytic degradation. In this review, we describe recent progress in elucidating the various mechanisms of resistance to membrane-disrupting antibiotics.
TL;DR: In vivo studies using a mouse model failed to provide evidence these compounds were effective in blocking or attenuating fatty acid transport, but in vitro studies identified two compounds, 5'-bromo-5-phenyl-spiro[3H-1,3,4-thiadiazole-2,3'-indoline]-2'-one), now referred to as Lipofermata, and 2-benzyl-3-(4-chlorophenyl)-5-(4
Abstract: The fatty acid transport proteins (FATP) are classified as members of the Solute Carrier 27 (Slc27) family of proteins based on their ability to function in the transport of exogenous fatty acids. These proteins, when localized to the plasma membrane or at intracellular membrane junctions with the endoplasmic reticulum, function as a gate in the regulated transport of fatty acids and thus represent a therapeutic target to delimit the acquisition of fatty acids that contribute to disease as in the case of fatty acid overload. To date, FATP1, FATP2, and FATP4 have been used as targets in the selection of small molecule inhibitors with the goal of treating insulin resistance and attenuating dietary absorption of fatty acids. Several studies targeting FATP1 and FATP4 were based on the intrinsic acyl CoA synthetase activity of these proteins and not on transport directly. While several classes of compounds were identified as potential inhibitors of fatty acid transport, in vivo studies using a mouse model failed to provide evidence these compounds were effective in blocking or attenuating fatty acid transport. Studies targeting FATP2 employed a naturally occurring splice variant, FATP2b, which lacks intrinsic acyl CoA synthetase due to the deletion of exon 3, yet is fully functional in fatty acid transport. These studies identified two compounds, 5'-bromo-5-phenyl-spiro[3H-1,3,4-thiadiazole-2,3'-indoline]-2'-one), now referred to as Lipofermata, and 2-benzyl-3-(4-chlorophenyl)-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, now called Grassofermata, that are effective fatty acid transport inhibitors both in vitro using a series of model cell lines and in vivo using a mouse model.
TL;DR: A non-conventional approach is used to put forth this renaissance on AG development/application by summarizing all patents filed on AGs from 2011-2015 and highlighting some related publications on the most recent work done onAGs to overcome resistance and improving their therapeutic use while reducing ototoxicity and nephrotoxicity.
Abstract: Since the discovery of the first aminoglycoside (AG), streptomycin, in 1943, these broad-spectrum antibiotics have been extensively used for the treatment of Gram-negative and Gram-positive bacterial infections. The inherent toxicity (ototoxicity and nephrotoxicity) associated with their long-term use as well as the emergence of resistant bacterial strains have limited their usage. Structural modifications of AGs by AG-modifying enzymes, reduced target affinity caused by ribosomal modification, and decrease in their cellular concentration by efflux pumps have resulted in resistance towards AGs. However, the last decade has seen a renewed interest among the scientific community for AGs as exemplified by the recent influx of scientific articles and patents on their therapeutic use. In this review, we use a non-conventional approach to put forth this renaissance on AG development/application by summarizing all patents filed on AGs from 2011–2015 and highlighting some related publications on the most recent work done on AGs to overcome resistance and improving their therapeutic use while reducing ototoxicity and nephrotoxicity. We also present work towards developing amphiphilic AGs for use as fungicides as well as that towards repurposing existing AGs for potential newer applications.
TL;DR: An overview of the most commonly used antifungals in medicine and agriculture is provided and a summary of the recent progress in the discovery/development of new agents against fungal strains of medical/agricultural relevance is presented.
Abstract: Fungal infections directly affect millions of people each year. In addition to the invasive fungal infections of humans, the plants and animals that comprise our primary food source are also susceptible to diseases caused by these eukaryotic microbes. The need for antifungals, not only for our medical needs, but also for use in agriculture and livestock causes a high demand for novel antimycotics. Herein, we provide an overview of the most commonly used antifungals in medicine and agriculture. We also present a summary of the recent progress (from 2010–2016) in the discovery/development of new agents against fungal strains of medical/agricultural relevance, as well as information related to their biological activity, their mode(s) of action, and their mechanism(s) of resistance.
TL;DR: The kinetic study and molecular docking indicated that compound 5c is a promising drug candidate with balanced properties for the treatment of Alzheimer's disease.
Abstract: A novel family of donepezil–ferulic acid hybrids were designed, synthesized and biologically evaluated as multi-target-directed ligands against Alzheimer's disease by fusing a fragment of donepezil and ferulic acid. The in vitro assay indicated that some of these molecules exhibited potent cholinesterase inhibitory activities, outstanding radical scavenging activities and good neuroprotective effects on PC12 cells, and could penetrate into the central nervous system. Compound 5c especially showed moderate acetylcholinesterase inhibitory activity (IC50 values of 0.398 μM for electric eel acetylcholinesterase) and butyrylcholinesterase inhibitory activity (IC50 = 0.976 μM for equine serum butyrylcholinesterase). It also showed significant antioxidant activity (1.78 trolox equivalents by the ABTS method, IC50 values of 24.9 μM by the DPPH method). The kinetic study and molecular docking indicated that compound 5c interacted with both the peripheral anionic site and the catalytic binding site of acetylcholinesterase. Overall, these results indicated that compound 5c is a promising drug candidate with balanced properties for the treatment of Alzheimer's disease.
TL;DR: This work presents an approach for crosslinking DNA-linked ligands to target proteins using electrophilic or photoreactive groups and shows improved enrichment of both high and a low affinity ligands in comparison to a selection with a solid-phase immobilized protein.
Abstract: Achieving sufficient enrichment of ligands from DNA-encoded libraries for detection can be difficult, particularly for low affinity ligands within highly complex libraries. To address this challenge, we present an approach for crosslinking DNA-linked ligands to target proteins using electrophilic or photoreactive groups. The approach involves the tethering of a ssDNA oligonucleotide to a DNA-encoded molecule to enable attachment of a reactive group post-synthetically via DNA hybridization. Crosslinking traps ligand–protein complexes while in solution and allows for stringent washing conditions to be applied in the subsequent purification. Five reactive groups (tosyl, NHS ester, sulfonyl fluoride, phenyl azide, and diazirine) were tested for crosslinking efficiency and specificity with three DNA-linked ligands to their target proteins. In a model selection, crosslinking resulted in improved enrichment of both high and a low affinity ligands in comparison to a selection with a solid-phase immobilized protein.
TL;DR: A series of novel Schiff base-linked imidazole naphthalimides were developed and their antimicrobial behavior demonstrated that compound 9i could effectively inhibit the growth of some tested strains, especially for MRSA, which was superior to the reference drugs.
Abstract: A series of novel Schiff base-linked imidazole naphthalimides were developed and their antimicrobial behavior demonstrated that compound 9i could effectively inhibit the growth of some tested strains, especially for MRSA (MIC = 0.003 μmol mL−1), which was superior to the reference drugs. Bacterial membrane permeabilization, bacterial resistance and time-kill kinetic assays of compound 9i against MRSA manifested that it was able to permeate the cell membrane, rapidly kill the tested strains and stall the development of bacterial resistance. Preliminary research revealed that compound 9i could form a stable complex with calf thymus DNA by intercalation mode. These results suggested that compound 9i could serve as a promising anti-MRSA candidate.
TL;DR: The hERG cavity can trap very bulky compounds, without perturbing normal gate closure, by trapping them in the cavity of the hERG ring.
Abstract: Inhibition of hERG K+ channels by structurally diverse drugs prolongs the ventricular action potential and increases the risk of torsade de pointes arrhythmias and sudden cardiac death. The capture of drugs behind closed channel gates, so-called drug trapping, is suggested to harbor an increased pro-arrhythmic risk. In this study, the trapping mechanisms of a trapped hERG blocker propafenone and a bulky derivative (MW: 647.24 g mol−1) were studied by making use of electrophysiological measurements in combination with molecular dynamics simulations. Our study suggests that the hERG cavity is able to accommodate very bulky compounds without disturbing gate closure.
TL;DR: The practice of medicine was profoundly transformed by the introduction of the antibiotics and the antibacterials and a timeless biological activity for these compounds has been presumed.
Abstract: The practice of medicine was profoundly transformed by the introduction of the antibiotics (compounds isolated from Nature) and the antibacterials (compounds prepared by synthesis) for the control of bacterial infection. As a result of the extraordinary success of these compounds over decades of time, a timeless biological activity for these compounds has been presumed. This presumption is no longer. The inexorable acquisition of resistance mechanisms by bacteria is retransforming medical practice. Credible answers to this dilemma are far better recognized than they are being implemented. In this perspective we examine (and in key respects, reiterate) the chemical and biological strategies being used to address the challenge of bacterial resistance.
TL;DR: The mechanism studies revealed that compound 12k inhibited the proliferation of SK-N-SH cancer cells by inducing apoptosis and arresting the cell cycle at the G1 phase.
Abstract: A series of 1,2,3-triazole–chalcone hybrids were designed, synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (SK-N-SH, HepG-2 and MGC-803). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Particularly, compound 12k showed the most excellent antiproliferative activity with an IC50 value of 1.53 μM against SK-N-SH cancer cells. The mechanism studies revealed that compound 12k inhibited the proliferation of SK-N-SH cancer cells by inducing apoptosis and arresting the cell cycle at the G1 phase.
TL;DR: In this article, a series of electrophiles (acrylamides, nitriles, cyanamides, sulfones, and sulfonamides) using Nα-acetyl-L-lysine as a model amine-based nucleophile was compared with results using glutathione (GSH).
Abstract: Covalent drugs contain a reactive electrophilic moiety or covalent reactive group (CRG), which forms an irreversible bond between the drug and a biological target. Consequently, the intrinsic reactivity of the CRG is an important consideration in the design of irreversible inhibitors. Although reactivity assessments of CRGs with sulfur nucleophiles, such as glutathione and cysteine have been reported, reactivity of these moieties with amine-containing nucleophiles is not well described. In this study, intrinsic reactivities were determined for a series of electrophiles (acrylamides, nitriles, cyanamides, sulfones, and sulfonamides) using N-α-acetyl-L-lysine as a model amine-based nucleophile and compared with results using glutathione (GSH). Since the e-amine of N-α-acetyl-L-lysine is protonated at neutral pH, reactions were carried out at pH 10.2. In addition to reporting rate data for reactions of CRGs with N-α-acetyl-L-lysine, elements of selectivity relative to thiol-containing nucleophiles are also be discussed.
TL;DR: The drug discovery efforts against enzymes involved in the trehalose utilization pathways (TUPs) and their likelihood of becoming drug targets are discussed.
Abstract: Tuberculosis (TB) is an epidemic disease and the growing burden of multidrug-resistant (MDR) TB world wide underlines the need to discover new drugs to treat the disease. Mycobacterium tuberculosis (Mtb) is the etiological agent of most cases of TB. Mtb is difficult to treat, in part, due to the presence of a sturdy hydrophobic barrier that prevents penetration of drugs through the cell wall. Mtb can also survive in a non-replicative state for long periods of time avoiding the action of common antibiotics. Trehalose is an essential metabolite in mycobacteria since it plays key roles in cell wall synthesis, transport of cell wall glycolipids, and energy storage. It is also known for its stress protective roles such as: protection from desiccation, freezing, starvation and osmotic stress in bacteria. In this review we discuss the drug discovery efforts against enzymes involved in the trehalose utilization pathways (TUPs) and their likelihood of becoming drug targets.
TL;DR: It is demonstrated that rational halogen substitution on selected ligands would be greatly beneficial to achieve more promising metal-based antitumor agents and better cytotoxic selectivity of 2 than that of 1.
Abstract: Two platinum(II) complexes, [PtCl(Q)(DMSO)] (1) and [PtCl(IQ)(DMSO)] (2), bearing 8-hydroxyquinoline (H-Q) and 5,7-diiodo-8-hydroxyquinoline (H-IQ) as the bioactive ligand, respectively, were synthesized and structurally characterized. By MTT assay, complex 2 bearing the IQ ligand showed significantly higher growth inhibition than complex 1 against all the five typical tumor cell lines in the test, but showed no more cytotoxicity against the normal liver cell line HL-7702, suggesting the much better cytotoxic selectivity of 2 than that of 1. In addition, the HepG2 cell line was found to be the most sensitive towards both complexes. Aiming at the HepG2 cell line, both complexes arrested the cell cycle of HepG2 cells in the S phase, as examined by flow cytometry, in which complex 2 showed higher S-phase arrest than 1. This was supported by the down-regulation of cdc25 A, cyclin B, cyclin A, and CDK2 and the up-regulation of p53, p27 and p21 based on western blot assay. Complex 2 also acted as a more effective telomerase inhibitor than 1 by interacting with telomeric/c-myc G-quadruplexes and triggering cell senescence and cell apoptosis. Furthermore, both complexes caused mitochondrial dysfunction, suggesting a potential mitochondrion-mediated apoptotic pathway induced by each complex. From the platinum uptake assay, complex 2 exhibited obvious priority on the cell uptake effect than 1, which should be undoubtedly correlated with the key roles of the 5- and 7-iodo-substituted groups in the IQ ligand of 2. This may well explain the better cytotoxicity and the more significant antitumor mechanism of 2 throughout the study. This work further demonstrated that rational halogen substitution on selected ligands would be greatly beneficial to achieve more promising metal-based antitumor agents.
TL;DR: Two sets of triazole-linked glycoconjugates synthesized from indole/oxindole (29 compounds) were evaluated for their preliminary in vitro anticancer activity and confirmed that compounds 5f and E-9b act against the protein kinase B (Akt/PKB) pathway to inhibit the proliferation of cancer cells.
Abstract: In continuation of our venture towards the synthesis of novel bioactive agents, two sets of triazole-linked glycoconjugates were synthesized from indole/oxindole (29 compounds) and were further characterized by IR (infrared spectroscopy), 1H NMR (nuclear magnetic resonance), 13C NMR and mass spectral analysis. The newly synthesized target compounds were evaluated for their preliminary in vitro anticancer activity against DU145 (prostate cancer), HeLa (cervical cancer), A549 (lung cancer) and MCF-7 (breast cancer) cell lines. In the sulforhodamine B (SRB) assay, the results indicated that compounds 5f (indole derivative) and E-9b (oxindole derivative) displayed remarkable cytotoxic activity against DU145 cells. Moreover, the colony formation assay (soft agar assay) revealed that compounds 5f and E-9b can inhibit the growth and proliferation of DU145 cells. The impact of the most active cytotoxic compounds 5f and E-9b on the cell cycle distribution was assessed in DU145 cells, which displayed a cell cycle arrest at the sub-G1 phase. Next, compounds 5f and E-9b were tested for caspase activation in DU145 cells, and the results specified that these compounds have the capability to induce apoptosis in cells through an intrinsic pathway leading to subsequent cell death. Further studies also confirmed that compounds 5f and E-9b act against the protein kinase B (Akt/PKB) pathway to inhibit the proliferation of cancer cells. Thus, compounds 5f and E-9b could be novel potential anticancer leads as the normal cell line NIH/3T3 (fibroblast) studies showed no significant cytotoxicity.