The synthesis and SAR study of phenylalanine-derived (Z)-5-arylmethylidene rhodanines as anti-methicillin-resistant Staphylococcus aureus (MRSA) compounds

A focused library of rhodanine compounds containing novel substituents at the C5-position was synthesized and tested in vitro against a panel of clinically relevant MRSA strains. The present SAR study was based on our lead compound 1 (MIC = 1.95 μg/mL), with a focus on identifying optimal C5-arylidene substituents. In order to obtain this objective, we condensed several unique aromatic aldehydes with phenylalanine-derived rhodanine intermediates to obtain C5-substituted target rhodanine compounds for evaluation as anti-MRSA compounds. These efforts produced three compounds with significant efficacy: 23, 32 and 44, with MIC values ranging from 0.98 to 1.95 μg/mL against all tested MRSA strains as compared to the reference antibiotics penicillin G (MIC = 15.60–250.0 μg/mL) and ciprofloxacin (MIC = 7.80–62.50 μg/mL) and comparable to that of vancomycin (MIC = 0.48 μg/mL). In addition, compounds 24, 28, 37, 41, 46 and 48 (MIC = 1.95–3.90 μg/mL) were efficacious against all MRSA strains. The majority of the synthesized compounds had bactericidal activity at concentrations only two to fourfold higher than their MIC. Overall, the results suggest that compounds 23, 32 and 44 may be of potential use in the treatment of MRSA infections.     

New class of methyl tetrazole based hybrid of (Z)-5-benzylidene-2-(piperazin-1-yl)thiazol-4(%H)-one as potent antitubercular agents

In search of potential therapeutics for tuberculosis, we describe here the synthesis and in vitro antitubercular activity of a novel series of thiazolone piperazine tetrazole derivatives. Among all the synthesized derivatives, four compounds (10, 14, 20 and 33) exhibited more potent activity (MIC = 3.08, 3.01, 2.62 and 2.51 μM) than ethambutol (MIC = 9.78 μM) and pyrazinamide (MIC = 101.53 μM) against Mycobacterium tuberculosis. Furthermore, they displayed no toxicity against Vero cells (C1008) and mouse bone marrow derived macrophages (MBMDMϕ). These investigated analogues have emerged as possible lead molecule to enlarge the scope of the study.     

The green synthesis and molecular docking of novel N-substituted rhodanines as effective inhibitors for carbonic anhydrase and acetylcholinesterase enzymes

Recently, inhibition effects of enzymes such as acetylcholinesterase (AChE) and carbonic anhydrase (CA) has appeared as a promising approach for pharmacological intervention in a variety of disorders such as epilepsy, Alzheimer’s disease and obesity. For this purpose, novel N-substituted rhodanine derivatives (RhAs) were synthesized by a green synthetic approach over one-pot reaction. Following synthesis the novel compounds, RhAs derivatives were tested against AChE and cytosolic carbonic anhydrase I, and II (hCAs I, and II) isoforms. As a result of this study, inhibition constant (Ki) were found in the range of 66.35 ± 8.35 to 141.92 ± 12.63 nM for AChE, 43.55 ± 14.20 to 89.44 ± 24.77 nM for hCA I, and 16.97 ± 1.42 to 64.57 ± 13.27 nM for hCA II, respectively. Binding energies were calculated with docking studies as −5.969, −5.981, and −9.121 kcal/mol for hCA I, hCA II, and AChE, respectively.     

Synthesis and biological evaluation of rhodanine derivatives bearing a quinoline moiety as potent antimicrobial agents

Three series of rhodanine derivatives bearing a quinoline moiety (6a–h, 7a–g, and 8a–e) have been synthesized, characterized, and evaluated as antibacterial agents. The majority of these compounds showed potent antibacterial activities against several different strains of Gram-positive bacteria, including multidrug-resistant clinical isolates. Of the compounds tested, 6g and 8c were identified as the most effective with minimum inhibitory concentration (MIC) values of 1 μg/mL against multidrug-resistant Gram-positive organisms, including methicillin-resistant and quinolone-resistant Staphylococcus aureus (MRSA and QRSA, respectively). None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 at 64 μg/mL. The cytotoxic activity assay showed that compounds 6g, 7g and 8e exhibited in vitro antibacterial activity at non-cytotoxic concentrations. Thus, these studies suggest that rhodanine derivatives bearing a quinoline moiety are interesting scaffolds for the development of novel Gram-positive antibacterial agents.     

Rhodanine-based PRL-3 inhibitors blocked the migration and invasion of metastatic cancer cells

PRL-3, phosphatase of regenerating liver-3, plays a role in cancer progression through its involvement in invasion, migration, metastasis, and angiogenesis. We synthesized rhodanine derivatives, CG-707 and BR-1, which inhibited PRL-3 enzymatic activity with IC₅₀ values of 0.8 μM and 1.1 μM, respectively. CG-707 and BR-1 strongly inhibited the migration and invasion of PRL-3 overexpressing colon cancer cells without exhibiting cytotoxicity. The specificity of the inhibitors on PRL-3 phosphatase activity was confirmed by the phosphorylation recovery of known PRL-3 substrates such as ezrin and cytokeratin 8. The compounds selectively inhibited PRL-3 in comparison with other phosphatases, and CG-707 regulated epithelial-to-mesenchymal transition (EMT) marker proteins. The results of the present study reveal that rhodanine is a specific PRL-3 inhibitor and a good lead molecule for obtaining a selective PRL-3 inhibitor.     

New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds

We present a new class of inhibitors of pancreatic cholesterol esterase (CEase) based on ‘priviledged’ 5-benzylidenerhodanine and 5-benzylidene-2,4-thiazolidinedione structural scaffolds. The lead structures (5-benzylidenerhodanine 4a and 5-benzylidene-2,4-thiazolidinedione 4b) were identified in an in-house screening and these inhibited CEase with some selectivity over another serine hydrolase, acetylcholinesterase (AChE) (4a, CEase IC₅₀ = 1.76 μM vs AChE IC₅₀ = 5.14 μM and 4b, CEase IC₅₀ = 5.89 μM vs AChE IC₅₀ >100 μM). A small library of analogs (5a–10a) containing a core amino acid in place of the glycerol group of the lead structures, was prepared to explore other potential binding interaction with CEase. These analogs inhibited CEase with IC₅₀ values ranging from 1.44 to 85 μM, with the majority exhibiting some selectivity for CEase versus AChE. The most potent compound of the library (10a) had 17-fold selectivity over AChE. We also report molecular docking (with CEase) and detailed kinetic analysis on the amino acid analogs to further understand the associated structure–activity relationships.     

Discovery and development of novel rhodanine derivatives targeting enoyl-acyl carrier protein reductase

A series of rhodanine derivatives RB1–RB23 were synthesized through a two-round screening. Their Mycobacterial tuberculosis (Mtb) InhA inhibitory activity and Mtb growth blocking capability were evaluated. The most potent hit compound RB23 indicated comparable InhA inhibiton (IC₅₀?=?2.55?μM) with the positive control Triclosan (IC₅₀?=?6.14?μM) and Isoniazid (IC₅₀?=?8.29?μM). Its improved growth-blocking effect on Mtb and low toxicity were attractive for further development. The docking simulation revealed the possible binding pattern of this series and picked the key interacted residues as Ser20, Phe149, Lys165 and Thr196. The 3D-QSAR model visualized the SAR discussion and hinted new information. Modifying the surroundings near rhodanine moiety might be promising attempts in later investigations.     

Design and synthesis of l- and d-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase

Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC₅₀ = 7.7 μM) and 2 (IC₅₀ = 10.6 μM) as represented by hybrid compound 27 (IC₅₀ = 6.7 μM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC₅₀ of 2.6 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the d-isomers 41 (IC₅₀ = 19.3 μM) and 45 (IC₅₀ = 5.4 μM) as enantiomers of the l-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition.     

Insight into coordination of dilead unit by molecules of 4-thiazolidinone-2-thione: Structural and computational studies

The reaction of Pb²⁺ ions with 4-thiazolidinone-2-thione (Hrd) yields to coordination of the uncommon dilead unit (Pb₂²⁺) by the N-deprotonated molecule of the ligand. The powder structure determination of the complex reveals an almost planar dimeric structure with the {N,S} coordination mode. The intermolecular distance of the Pb-Pb moiety (3.51(4) Å) is lower than the van der Waals parameter suggesting the formation of a bond. The structure in the solid state and DFT calculations of molecular orbitals and the presence of a bond critical point between the lead atoms clearly demonstrate the existence of a single bond within the Pb-Pb unit formed by the 6p orbital electrons. The lone pairs of the 6s orbitals do not participate in bonding with the ligand atoms and are likely bisdirected. FT-IR and FT-Raman spectra confirm the molecular structure since all the modes of the NH group disappear in the spectra of the complex, while the stretching mode of the CS bond shifts to lower values, as would be expected for this coordination fashion.     

Computer-aided identification of novel 3,5-substituted rhodanine derivatives with activity against Staphylococcus aureus DNA gyrase

Methicillin resistant Staphylococcus aureus (MRSA) is among the major drug resistant bacteria that persist in both the community and clinical settings due to resistance to commonly used antimicrobials. This continues to fuel the need for novel compounds that are active against this organism. For this purpose we have targeted the type IIA bacterial topoisomerase, DNA gyrase, an essential enzyme involved in bacterial replication, through the ATP-dependent supercoiling of DNA. The virtual screening tool Shape Signatures was applied to screen a large database for agents with shape similar to Novobiocin, a known gyrase B inhibitor. The binding energetics of the top hits from this initial screen were further validated by molecular docking. Compounds with the highest score on available crystal structure of homologous DNA gyrase from Thermus thermophilus were selected. From this initial set of compounds, several rhodanine-substituted derivatives had the highest antimicrobial activity against S. aureus, as determined by minimal inhibitory concentration assays, with Novobiocin as the positive control. Further activity validation of the rhodanine compounds through biochemical assays confirmed their inhibition of both the supercoiling and the ATPase activity of DNA gyrase. Subsequent docking and molecular dynamics on the crystal structure of DNA gyrase from S. aureus when it became available, provides further rationalization of the observed biochemical activity and understanding of the receptor–ligand interactions. A regression model for MIC prediction against S. aureus is generated based on the current molecules studied as well as other rhodanines derivatives found in the literature.