Design and discovery of urease and Helicobacter pylori inhibitors based on benzofuran/benzothiophene-sulfonate and sulfamate scaffolds for the treatment of ureolytic bacterial infections.

A series of sulfonate and sulfamate derivatives bearing benzofuran or benzothiophene scaffold exhibited potent inhibitory effect on urease enzyme. Most of the derivatives exhibited significantly higher potency than thiourea, the standard inhibitor. Compound 1s was identified as the most potent urease inhibitor with an IC50 value of 0.42 ± 0.08 µM, which is 53-fold more potent than thiourea, positive control (IC50 = 22.3 ± 0.031 µM). The docking results further revealed the binding interactions towards the urease active site. Phenotypic screening revealed that compounds 1c, 1d, 1e, 1f, 1j, 1n, and 1t exhibit high potency against H. pylori with MIC values ranging from 0.00625 to 0.05 mM and IC50 values ranging from 0.0031 to 0.0095 mM, much more potent than the positive control, acetohydroxamic acid (MIC and IC50 values were 12.5 and 7.38 mM, respectively). Additional studies were performed to investigate the toxicity of these compounds against the gastric epithelial cell line (AGS) and their selectivity profile against E. coli, and five Lactobacillus species representative of the gut microflora. Permeability characteristics of the most promising derivatives were investigated in Caco-2 cell line. The results indicate that the compounds could be targeted in the GIT only without systemic side effects.

Structure-based drug design of DNA minor groove binders and evaluation of their antibacterial and anticancer properties.

Antimicrobial and chemotherapy resistance are escalating medical problem of paramount importance. Yet, research for novel antimicrobial and anticancer agents remains lagging behind. With their reported medical applications, DNA minor groove binders (MGBs) are worthy of exploration. In this study, the approach of structure-based drug design was implemented to generate 11 MGB compounds including a novel class of bioactive alkyne-linked MGBs. The NCI screening protocol was utilized to evaluate the antitumor activity of the target MGBs. Furthermore, a variety of bactericidal, cytopathogenicity, MIC90, and cytotoxicity assays were carried out using these MGBs against 6 medically relevant bacteria: Salmonella enterica, Escherichia coli, Serratia marcescens, Bacillus cereus, Streptococcus pneumoniae and Streptococcus pyogenes. Moreover, molecular docking, molecular dynamic simulations, DNA melting, and isothermal titration calorimetry (ITC) analyses were utilized to explore the binding mode and interactions between the most potent MGBs and the DNA duplex d(CGACTAGTCG)2. NCI results showed that alkyne-linked MGBs (26 & 28) displayed the most significant growth inhibition among the NCI-60 panel. In addition, compounds MGB3, MGB4, MGB28, and MGB32 showed significant bactericidal effects, inhibited B. cereus and S. enterica-mediated cytopathogenicity, and exhibited low cytotoxicity. MGB28 and MGB32 demonstrated significant inhibition of S. pyogenes, whereas MGB28 notably inhibited S. marcescens and all four minor groove binders significantly inhibited B. cereus. The ability of these compounds to bind with DNA and distort its groove dimensions provides the molecular basis for the allosteric perturbation of proteins-DNA interactions by MGBs. This study shed light on the mechanism of action of MGBs and revealed the important structural features for their antitumor and antibacterial activities, which are important to guide future development of MGB derivatives as novel antibacterial and anticancer agents.

Synthesis and Biological Activity of Sulfamate-Adamantane Derivatives as Glucosinolate Sulfatase Inhibitors.

The glucosinolate-myrosinase system, exclusively found in the Brassicaceae family, is a main defense strategy against insect resistance. The efficient detoxification activity of glucosinolate sulfatases (GSSs) has successfully supported the feeding of Plutella xylostella on cruciferous plants. With the activity of GSSs hampered in P. xylostella, the toxic isothiocyanates produced from glucosinolates severely impair larval growth and adult reproduction. Therefore, inhibitors of GSSs have been suggested as an alternative approach to controlling P. xylostella. Herein, we synthesized eight adamantyl-possessing sulfamate derivatives as novel inhibitors of GSSs. Adam-20-S exhibited the most potent GSS inhibitory activity, with an IC50 value of 9.04 mg/L. The suppression of GSSs by Adam-20-S impaired glucosinolate metabolism to produce more toxic isothiocyanates in P. xylostella. Consequently, the growth and development of P. xylostella were significantly hindered when feeding on the host plant. Our study may help facilitate the development of a comprehensive pest management strategy that combines insect detoxification enzyme inhibitors with plant chemical defenses.

The latest perspectives of small molecules FMS kinase inhibitors.

FMS kinase is a type III tyrosine kinase receptor that plays a central role in the pathophysiology and management of several diseases, including a range of cancer types, inflammatory disorders, neurodegenerative disorders, and bone disorders among others. In this review, the pathophysiological pathways of FMS kinase in different diseases and the recent developments of its monoclonal antibodies and inhibitors during the last five years are discussed. The biological and biochemical features of these inhibitors, including binding interactions, structure-activity relationships (SAR), selectivity, and potencies are discussed. The focus of this article is on the compounds that are promising leads and undergoing advanced clinical investigations, as well as on those that received FDA approval. In this article, we attempt to classify the reviewed FMS inhibitors according to their core chemical structure including pyridine, pyrrolopyridine, pyrazolopyridine, quinoline, and pyrimidine derivatives.

Complexity-to-Diversity and Pseudo-Natural Product Strategies as Powerful Platforms for Deciphering Next-Generation Therapeutics.

Stereochemical and skeletal complexity are particularly important vis-à-vis the cross-talks between a small molecule and a complementary active site of a biological target. This intricate harmony is known to increase selectivity, reduce toxicity, and increase the success rate in clinical trials. Therefore, the development of novel strategies for establishing underrepresented chemical space that is rich in stereochemical and skeletal diversity is an important milestone in a drug discovery campaign. In this review, we discuss the evolution of interdisciplinary synthetic methodologies utilized in chemical biology and drug discovery that has revolutionized the discovery of first-in-class molecules over the last decade with an emphasis on complexity-to-diversity and pseudo-natural product strategies as a remarkable toolbox for deciphering next-generation therapeutics. We also report how these approaches dramatically revolutionized the discovery of novel chemical probes that target underrepresented biological space. We also highlight selected applications and discuss key opportunities offered by these tools and important synthetic strategies used for the construction of chemical spaces that are rich in skeletal and stereochemical diversity. We also provide insight on how the integration of these protocols has the promise of changing the drug discovery landscape.

Divergent Protocol for the Synthesis of Isoquinolino[1,2-b]quinazolinone and Isoquinolino[2,1-a]quinazolinone Derivatives.

The development of robust and step-economic strategies to access structurally diverse drug-like compound collections remains a challenge. A distinct structural option that constitutes the core scaffold of many biologically significant molecules is the quinazolinone ring system. Several members of this family of privileged substructures have gained attention due to their diverse biological activities. In this context, the development of an efficient strategy for their access is needed. Herein, we report a divergent metal-free operation to access a diverse collection of C6-substituted pyrrolo[4',3',2':4,5]isoquinolino[1,2-b]quinazolin-8(6H)-one and pyrrolo[4',3',2':4,5]isoquinolino[2,1-a]quinazolin-12(6H)-one architectures. The described cascade unites Friedel-Crafts and aza-Michael addition reactions. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the cascade features a promising approach for the design of unique compound libraries for drug design and discovery programs.

Stereodivergent Desymmetrization of Phenols En Route to Modular Access to Densely Functionalized Quinazoline and Oxazine Scaffolds.

The de novo assembly of stereochemically and skeletally diverse scaffolds is a powerful tool for the discovery of novel chemotypes. Hence, the development of modular, step- and atom-economic synthetic methods to access stereochemically and skeletally diverse compound collection is particularly important. Herein, we show a metal-free, stereodivergent build/couple/pair strategy that allows access to a unique collection of benzo[5,6][1,4]oxazino[4,3-a]quinazoline, quinolino[1,2-a]quinazoline and benzo[b]benzo [4,5]imidazo[1,2-d][1,4]oxazine scaffolds with complete diastereocontrol and wide distribution of molecular architectures. This metal-free process proceeds via desymmetrization of phenol derivatives. The cascade unites Mannich with aza-Michael addition reactions, providing expeditious entries to diverse classes of molecular shapes in a single operation.

Blue Light-Driven [4+2]-Cycloaddition: Diastereoselective Synthesis of Chromeno[4,3-b]quinoline and Chromeno[4,3-b][1,8]naphthyridine Scaffolds.

A one-pot, metal-free, light-driven [4+2]-cycloaddition reaction is described by accessing a diverse collection of chromeno[4,3-b]quinoline and chromeno[4,3-b][1,8]naphthyridine scaffolds in a diastereoselective manner. This process delivered stereoisomers, which were challenging to produce by an inverse-demand Diels-Alder reaction. The tetracyclic products were provided in good yields, promoted by rose bengal and blue light in a single operation. The developed protocol proceeded efficiently without the need for expensive photosensitizers such as Ir or Ru complexes. The cascade is modular and step-economic, and the substrate scope is wide. Polycyclic architectures can be assembled from readily available aniline, aminoazine, indole, and salicylaldehyde derivatives.

Molecular Receptors for Recognition and Sensing of Nucleotides.

Nucleotides are constituents of nucleic acids and they have a variety of functions in cellular metabolism. Synthetic receptors and sensors are required to reveal the role of nucleotides in living organisms and mechanisms of signal transduction events. In recent years, a large number of nucleotide-selective synthetic receptors have been devised, which utilize different molecular designs and sensing mechanisms. This Minireview presents recent progress in the design of synthetic molecular receptors for selective recognition of nucleotides in aqueous solution. The binding properties of receptors and the origins of their selectivity for a particular nucleotide are discussed.

Cation Molecular Exchanger Based on a Conformational Hinge.

A cation molecular exchanger has been developed that consists of the bipyridine and crown ether receptor subunits. It has been shown that binding of the zinc(II) cation to the bipyridine subunit induces the conformational switching of the crown ether subunits, which results in a release of the potassium cation. Two conformational states of the cation exchanger have been supported by the results from solution- and solid-state studies. It has been demonstrated that the cation exchanger is able to communicate with a cation sensor induced by a chemical stimulus.

Finding a receptor design for selective recognition of perrhenate and pertechnetate: hydrogen vs. halogen bonding.

Receptors bearing hydrogen and halogen bond donors for recognition of perrhenate and pertechnetate were designed and studied. Acyclic hosts with N-H and C-H binding sites showed the best selectivity for TcO4- and ReO4- over spherical and more basic tetrahedral anions.

Synthesis of crinane utilizing an allylic sulfoxide for the construction of a hydroindole ring via vinylogous C-N bond formation.

The synthesis of crinane is disclosed via intramolecular C-N bond formation by the displacement of an allylic sulfoxonium salt. The allylic sulfide precursor was synthesized by a ring-closing metathesis reaction. The quaternary carbon stereocenter was created by alkylation of a benzylic cyanide. The allyl sulfide 14 was prepared by adding vinylmagnesium bromide to an α-chlorosulfide.