Rhodanine Scaffold Research Articles

First fragment-based screening identifies new chemotypes inhibiting ERAP1-metalloprotease

Inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) by small-molecules is being eagerly investigated for the treatment of various autoimmune diseases and in the field of immuno-oncology after its active involvement in antigen presentation and processing. Currently, ERAP1 inhibitors are at different stages of clinical development, which highlights its significance as a promising drug target. In the present work, we describe the first-ever successful identification of several ERAP1 inhibitors derived from a fragment-based screening approach. We applied an enzymatic activity assay to a large library of ∼3000 fragment entries in order to retrieve 32 hits. After a multi-faceted selection process, we prioritized 3 chemotypes for SAR optimization and strategic modifications provided 2 series (2-thienylacetic acid and rhodanine scaffolds) with improved analogues at the low micromolar range of ERAP1 inhibition. We report also evidence of selectivity against homologous aminopeptidase IRAP, combined with complementary in silico docking studies to predict the binding mode and site of inhibition. Our compounds can be the starting point for future fragment growing and rational drug development, incorporating new chemical modalities.

Rhodanine‐Incorporated Indole Derivatives as Pharmacologically Vital Hybrids

AbstractNowadays, some life‐threatening diseases keep individuals living in fear of death and experiencing health losses that were before unexpected. Therefore, there is an urgent need for the development of active pharmacological agents to minimize the injurious effect of such diseases. For that, numerous heterocyclic compounds and their hybrids have been designed, developed, and synthesized. They are also considered to be more effective against microorganisms that have developed multi‐drug resistance. 2‐Thioxo‐4‐thiazolidinone (rhodanine) and indole are regarded as advantageous heterocycles in medicinal chemistry. The pharmacological properties of rhodanine scaffolds can be improved by incorporating indole moieties. The present review expresses the pharmacological advances of rhodanine‐incorporated indole derivatives along with their structure‐activity relationships (SAR). To find novel drugs and combat serious diseases, we have observed that such hybrid structures are more effective pharmacophores than single motifs.

Design, dynamic docking, synthesis, and in vitro validation of a novel DNA gyrase B inhibitor

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate-resistant Staphylococcus aureus (VRSA) are among the WHO's high priority pathogens. Among these two, MRSA is the most globally documented pathogen that necessitates the pressing demand for new classes of anti-MRSA drugs. Bacterial gyrase targeted therapeutics are unique strategies to overcome cross-resistance as they are present only in bacteria and absent in higher eukaryotes. The GyrB subunit is essential for the catalytic functions of the bacterial enzyme DNA Gyrase, thereby constituting a promising druggable target. The current study performed a structure-based virtual screening to designing GyrB target-specific candidate molecules. The de novo ligand design of novel hit molecules was performed using a rhodanine scaffold. Through a systematic in silico screening process, the hit molecules were screened for their synthetic accessibility, drug-likeness and pharmacokinetics properties in addition to its target specific interactions. Of the 374 hit molecules obtained through de novo ligand design, qsl-304 emerged as the most promising ligand. The molecular dynamic simulation studies confirmed the stable interaction between the key residues and qsl-304. qsl-304 was synthesized through a one-step chemical synthesis procedure, and the in vitro activity was proven, with an IC50 of 31.23 µg/mL against the novobiocin resistant clinical isolate, Staphylococcus aureus sa-P2003. Further studies on time-kill kinetics showed the bacteriostatic nature with the diminished recurrence of resistance. The on-target gyrB inhibition further proved the efficacy of qsl-304. Communicated by Ramaswamy H. Sarma

Synthesis, molecular modeling, selective aldose reductase inhibition and hypoglycemic activity of novel meglitinides

In the present study, a novel generation of selective aldose reductase ALR2 inhibitors with significant hypoglycemic activities was designed and modulated based on rhodanine scaffold joined to an acetamide linker in between two lipophilic moieties. The synthesis of the novel compounds was accomplished throughout simple chemical pathways. Molecular docking was performed on B-cell membrane protein SUR1, aldehyde reductase ALR1 and aldose reductase ALR2 active sites. Compounds 10B, 11B, 12B, 15C, 16C, 26F and 27F displayed the highest hypoglycemic activities with 80.7, 85.2, 87, 82.3, 83.5, 81.4 and 85.3% reduction in blood glucose levels, respectively. They were more potent than the standard hypoglycemic agent repaglinide with 65.4% reduction in blood glucose level. Compounds 12B and 15C with IC50 0.29 and 0.35 µM were more potent than the standard ALR2 inhibitor epalrestat with IC50 0.40 µM. They were selective towards ALR2 over ALR1 134 and 116 folds, respectively. Molecular docking studies matched with the in-vitro and in-vivo results to elucidate the dual activities of both compounds 12B and 15C as potent antagonists for ALR2 over ALR1 and good agonists for the SUR1 protein.

The Importance of Rhodanine Scaffold in Medicinal Chemistry: A Comprehensive Overview.

After the clinical use of epalrestat that contains a rhodanine ring, in type II diabetes mellitus and diabetic complications, rhodanin-based compounds have become an important class of heterocyclic in the field of medicinal chemistry. Various modifications to the rhodanine ring have led to a broad spectrum of biological activity of these compounds. Synthesis of rhodanine derivatives, depended on advenced throughput scanning hits, frequently causes potent and selective modulators of targeted enzymes or receptors, which apply their pharmacological activities through different mechanisms of action. Rhodanine-based compounds will likely stay a privileged scaffold in drug discovery because of different probability of chemical modifications of the rhodanine ring. We have, therefore reviewed their biological activities and structure activity relationship.

A naked-eye colorimetric sensor for methanol and ‘turn-on’ fluorescence detection of Al3+

A multifunctional Schiff base compound, NRSB, having a rhodanine scaffold was fabricated by a simple and cost-effective protocol.

Structural and energetic quantum chemical investigations into how the bioactive thiazolidinedione and rhodanine scaffolds interact with cytosine to form part of DNA

The interaction within biologically active complex configurations composed of thiazolidinedione-cytosine (TC) and rhodanine-cytosine (RC) have been fully investigated using B3LYP and M062X methods in conjunction with various basis sets, including 6-311++G(d,p), 6-311++G(2d,2p), 6-311++G(df,pd) and AUG-cc-pVDZ. Dispersion corrections to interaction energies using M06-2X-GD3 and double hybrid density functionals (B2PLYP-GD2, B2PLYP-GD3 and mPW2PLYP-GD2) have also been taken into account. The results showed that the interaction energies, including long range dispersion corrections obtained using double hybrid density functionals, are about 1–2.5 kcal/mol higher than uncorrected ones. Various combinations of all possible sites around the monomers which could lead to formation of stable complex configurations were considered, and then six double hydrogen bonded interactions which are formed in a cyclic pattern were further investigated for both complex configurations between cytosine-thiazolidinedione and cytosine-rhodanine. The intermolecular hydrogen bonds which are involved in forming of cyclic interaction patterns are of NH⋯O(N) and CH⋯O(N) types.The TCS′2S1 and RCS′2S1 complex configurations were found to have the largest interaction energies within all the complex configurations studied for cytosine-thiazolidinedione and cytosine-rhodanine respectively at all computational levels used for the calculation of interaction energies. These two most stable complex configurations formed between the S1 site of the cytosine monomer and the S′2 site of the thiazolidinedione or rhodanine.The BSSE-corrected interaction energy for six cyclic double hydrogen bonded complex configurations, calculated at M062X/6-311++G(df,pd) level range from −11.26 to −16.22 kcal/mol for TC complexes and −11.04 to −15.59 kcal/mol for RC complexes.The stability order within thiazolidinedione-cytosine (TC) complexes is TCS′2S1 > TCS′1S1 > TCS′2S2 > TCS′1S2 > TCS′3S2 > TCS′3S1 in all levels studied. The same trend was observed for the stability order of rhodanine-cytosine (RC) complexes.The NBO results reveal that the charge transfer occurred from cytosine to thiazolidinedione or rhodanine within complex configurations which are formed at S′1S1, S′1S2, S′2S1 and S′2S2 sites, whereas in the case of complex configurations of cytosine with thiazolidinedione or rhodanine at S′3S1 and S′3S2 sites this order was reversed.The atom in molecule theory (AIM) and natural bond orbital analysis (NBO) were used to understand the nature of the interactions within the complex configurations studied. This showed good consistency with the interaction energies. In addition, good correlations between geometrical parameters, interaction energies, topological AIM data and NBO results were obtained. Based on AIM and NBO results, it is concluded that the H-bond interactions are electrostatic and partially covalent. Finally, the relationship between interaction energies and vibrational frequency changes at involved H-bonds was analyzed.

Diversity-oriented catalyst-free synthesis of pseudopeptides containing rhodanine scaffolds via a one-pot sequential isocyanide-based six-component reactions in water using ultrasound irradiation

A planning strategy for diversity‐oriented catalyst-free synthesis of pseudopeptides containing rhodanine scaffolds has been developed via a novel one-pot sequential six-component reaction in water. This approach is an efficient, environmentally friendly and expeditious procedure for direct access to wide ranges of pharmacologically significant and structurally interesting compounds based on the union of multicomponent reactions approach via tandem Michael/domino cycloaddition/Ugi reactions sequence from readily available starting materials. The syntheses were achieved by reaction of various primary amines, carbon disulfide, maleic anhydride or itaconic anhydride, aromatic aldehydes, anilines and isocyanides under ultrasound irradiation at room temperature in good yields. Providing of pseudopeptides containing rhodanines with the tandem formation of one new heterocyclic ring as well as creating the seven new bonds such as carbon-carbon, carbon-nitrogen, carbon-oxygen and carbon-sulfur with great efficiency and high atom/bond-forming/structure economy are outstanding features of this designed synthetic route.

Optimization of rhodanine scaffold for the development of protein–protein interaction inhibitors

Searching for novel protein–protein interactions inhibitors (PPIs) herein we describe the identification of a new series of rhodanine derivatives. The selection was performed by means virtual-screening, docking studies, Molecular Dynamic (MD) simulations and synthetic approaches. All the new obtained compounds were tested in order to evaluate their ability to inhibit the interaction between the HIV-1 integrase (IN) enzyme and the nuclear protein lens epithelium growth factor LEDGF/p75.

Application of the β-cyclodextrin supramolecules as a green accelerator hosts in one-step preparation of highly functionalised rhodanine scaffolds

β-Cyclodextrin (β-CD) supramolecule was found to be a convenient, green and economical tool in one-pot synthesis of rhodanine scaffolds as a highly efficient mediating agent in aqueous media in which the reaction accelerated to complete in 15 min and room temperature. In this work, amines reacted with equimolar ratio of CS2 (not excess ratio of CS2) and then with activated acetylenes in the presence of β-CD in aqueous media.

Expanding the Scope of Human DNA Polymerase λ and β Inhibitors

The exact biological functions of individual DNA polymerases still await clarification, and therefore appropriate reagents to probe their respective functions are required. In the present study, we report the development of a highly potent series of human DNA polymerase λ and β (pol λ and β) inhibitors based on the rhodanine scaffold. Both enzymes are involved in DNA repair and are thus considered as future drug targets. We expanded the chemical diversity of the small-molecule inhibitors arising from a high content screening and designed and synthesized 30 novel analogues. By biochemical evaluation, we discovered 23 highly active compounds against pol λ. Importantly, 10 of these small-molecules selectively inhibited pol λ and not the homologous pol β. We discovered 14 small-molecules that target pol β and found out that they are more potent than known inhibitors. We also investigated whether the discovered compounds sensitize cancer cells toward DNA-damaging reagents. Thus, we cotreated human colorectal cancer cells (Caco-2) with the small-molecule inhibitors and hydrogen peroxide or the approved drug temozolomide. Interestingly, the tested compounds sensitized Caco-2 cells to both genotoxic agents in a DNA repair pathway-dependent manner.

Discovery of a new class of dithiocarbamates and rhodanine scaffolds as potent antifungal agents: synthesis, biology and molecular docking

Drug resistance to established antifungals such as azole derivatives (fluconazole and ketoconazole) is driving the rise in global mortality due to fungal infection. Identification of new molecular entities structurally unrelated to these may represent a valid strategy to overcome resistance to currently available drugs. In an effort to develop highly potent antifungal agents, we report herein a series of 27 compounds of dithiocarbamate and the rhodanine molecules containing pyridine moiety and their antifungal activity. Among the synthesized compounds, several analogues have shown potent antifungal activity. The potent compounds against Candida albicans strain were further tested for in vitro anticandidal activity and amphotericin B-resistant strain of Candida albicans. Several derivatives 4a–f, 6, and 7k–n were found to be more effective (MIC = 0.39 – 3.12 μg mL−1) against Candida albicans MTCC183 and further these compounds, except 4e, 4f, and 7m, showed significant activity against amphotericin B-resistant strain of Candida albicans than that of fluconazole. Moreover, these analogues did not exhibit any toxicity up to MIC 3.12 μg mL−1 against mammalian cell line L929. A molecular docking study was undertaken to understand the mode of action of the active compounds towards prospective target lanosterol 14α-demethylase (CYP-51).

Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase

Hepatitis C virus (HCV) NS5B polymerase is a key target for the development of therapeutic agents aimed at the treatment of HCV infections. Here we report on the identification of novel allosteric inhibitors of HCV NS5B through a combination of structure-based virtual screening, synthesis and structure–activity relationship (SAR) optimization approach. Virtual screening of 260,000 compounds from the ChemBridge database against the tetracyclic indole inhibitor binding pocket of NS5B (allosteric pocket-1, AP-1), sequentially down-sized the library by 4 orders of magnitude to yield 23 candidates. In vitro evaluation of the NS5B inhibitory activity of the in-silico selected compounds resulted in 17% hit rate, identifying two novel chemotypes. Of these, compound 3, bearing the rhodanine scaffold, proved amenable for productive SAR exploration and synthetic modification. As a result, 25 derivatives that exhibited IC 50 values ranging from 7.7 to 68.0 μM were developed. Docking analysis of lead compound 28 within the tetracyclic indole- and benzylidene-binding allosteric pockets (AP-1 and AP-3, respectively) of NS5B revealed topological similarities between these two pockets. Compound 28, a novel rhodanine analog with NS5B inhibitory potency in the low micromolar level range may be a promising lead for future development of more potent NS5B inhibitors.

De Novo Discovery of Serotonin N-Acetyltransferase Inhibitors

Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) is a member of the GCN5 N-acetyltransferase (GNAT) superfamily and catalyzes the penultimate step in the biosynthesis of melatonin; a large daily rhythm in AANAT activity drives the daily rhythm in circulating melatonin. We have used a structure-based computational approach to identify the first druglike and selective inhibitors of AANAT. Approximately 1.2 million compounds were virtually screened by 3D high-throughput docking into the active site of X-ray structures for AANAT, and in total 241 compounds were tested as inhibitors. One compound class, containing a rhodanine scaffold, exhibited low micromolar competitive inhibition against acetyl-CoA (AcCoA) and proved to be effective in blocking melatonin production in pineal cells. Compounds from this class are predicted to bind as bisubstrate inhibitors through interactions with the AcCoA and serotonin binding sites. Overall, this study demonstrates the feasibility of using virtual screening to identify small molecules that are selective inhibitors of AANAT.