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.

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.

Homologous human milk supplement for very low birth weight preterm infant feeding / Aditivo homólogo para a alimentação do recém-nascido pré-termo de muito baixo peso

OBJECTIVE: To develop a homologous human milk supplement for very low-birth weight infant feeding, using an original and simplified methodology, to know the nutritional composition of human milk fortified with this supplement and to evaluate its suitability for feeding these infants. METHODS: For the production and analysis of human milk with the homologous additive, 25 human milk samples of 45mL underwent a lactose removal process, lyophilization and then were diluted in 50mL of human milk. Measurements of lactose, proteins, lipids, energy, sodium, potassium, calcium, phosphorus and osmolality were performed. RESULTS: The composition of the supplemented milk was: lactose 9.22±1.00g/dL; proteins 2.20±0.36g/dL; lipids 2.91±0.57g/dL; calories 71.93±8.69kcal/dL; osmolality 389.6±32.4mOsmol/kgH2O; sodium 2.04±0.45mEq/dL; potassium 1.42±0.15mEq/dL; calcium 43.44±2.98mg/dL; and phosphorus 23.69±1.24mg/dL. CONCLUSIONS: According to the nutritional contents analyzed, except for calcium and phosphorus, human milk with the proposed supplement can meet the nutritional needs of the very low-birth weight preterm infant. .

OBJETIVO: Elaborar com metodologia original e simplificada um aditivo homólogo do leite humano para a alimentação do recém-nascido de muito baixo peso, conhecer a composição nutricional do leite humano fortificado com esse aditivo e avaliar sua adequação para a alimentação desses recém-nascidos. MÉTODOS: Para a produção e análise do leite humano com o aditivo homólogo, 25 amostras de 45 mL de leite humano passaram por processos de retirada de lactose, liofilização e foram diluídas em 50 mL de leite humano. Foram feitas dosagens de lactose, proteínas, lipídios, energia, sódio, potássio, cálcio, fósforo e osmolalidade. RESULTADOS: A composição do leite aditivado foi lactose 9,22 ± 1 g/dL; proteínas 2,20 ± 0,36 g/dL; lípides 2,91 ± 0,57 g/dL; calorias 71,93 ± 8,69 kcal/dL; osmolalidade 389,6 ± 32,4mOsmol/kgH2O; sódio 2,04 ± 0,45mEq/dL; potássio 1,42 ± 0,15mEq/dL; cálcio 43,44 ± 2,98 mg/dL; e fósforo 23,69 ± 1,24 mg/dL. CONCLUSÕES: De acordo com os teores nutricionais analisados, com exceção do cálcio e do fósforo, o leite humano com o aditivo proposto pode atender às necessidades nutricionais do recém-nascido pré-termo de muito baixo peso. .

Toward the discovery of novel anti-HIV drugs. Second-generation inhibitors of the cellular ATPase DDX3 with improved anti-HIV activity: synthesis, structure-activity relationship analysis, cytotoxicity studies, and target validation.

A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.

Polyrhodanine modified anodic aluminum oxide membrane for heavy metal ions removal.

Polyrhodanine was immobilized onto the inner surface of anodic aluminum oxide (AAO) membrane via vapor deposition polymerization method. The polyrhodanine modified membrane was applied to remove heavy metal ions from aqueous solution because polyrhodanine could be coordinated with specific metal ions. Several parameters such as initial metal concentration, contact time and metal species were evaluated systematically for uptake efficiencies of the fabricated membrane under continuous flow condition. Adsorption isotherms of Hg(II) ion on the AAO-polyrhodanine membrane were analyzed with Langmuir and Freundlich isotherm models. The adsorption rate of Hg(II) ion on the membrane was obeyed by a pseudo-second order equation, indicating the chemical adsorption. The maximum removal capacity of Hg(II) ion onto the fabricated membrane was measured to be 4.2 mmol/g polymer. The AAO-polyrhodanine membrane had also remarkable uptake performance toward Ag(I) and Pb(II) ions. Furthermore, the polyrhodanine modified membrane could be recycled after recovery process. These results demonstrated that the polyrhodanine modified AAO membrane provided potential applications for removing the hazardous heavy metal ions from wastewater.

Identification of (beta-carboxyethyl)-rhodanine derivatives exhibiting peroxisome proliferator-activated receptor gamma activity.

We applied an improved virtual screening scheme combining ligand-centric and receptor-centric methods for the identification of a new series of PPARgamma agonists known as (beta-carboxyethyl)-rhodanine derivatives which include a thiazolidin-based core structure, 2-thioxo-thiazolidine-4-one. An in vitro assay confirmed the nanomolar binding affinity in one of the (beta-carboxyethyl)-rhodanine derivatives, SP1818. It showed a PPARgamma agonistic activity similar to that of a known PPARgamma drug, pioglitazone, in a cell-based transactivation assay. Furthermore, the structure-activity relationships of the rhodanine derivatives were investigated through comparative molecular field analysis. We also characterized the inconsistency between the in vitro binding affinity and cell-based transactivation ability by using a set of property-based molecular descriptors. The binding mode analysis provided new insight concerning their agonistic effect on PPARgamma.

Rhodanine as a privileged scaffold in drug discovery.

Rhodanines, thiazolidine-2,4-diones and pseudothiohydantoins have become a very interesting class of heterocyclic compounds since the introduction of various glitazones and epalrestat into clinical use for the treatment of type II diabetes mellitus and diabetic complications, respectively. Chemical modifications of these heterocycles constantly result in compounds with a wide spectrum of pharmacological activities. 5-Arylidenerhodanines are frequently identified as potent hits in high throughput screening against various prokaryotic and eukaryotic targets. Synthesis of substituted rhodanines, based on high throughput screening hits, often leads to potent and selective modulators of targeted enzymes or receptors, which exert their pharmacological activities through different mechanisms of action. Due to various possibilities of chemical derivatization of the rhodanine ring, rhodanine-based compounds will probably remain a privileged scaffold in drug discovery. We have therefore reviewed their biological activities, mechanism of action, structure activity relationship and selectivity against other targets.

Beta-diketo acid pharmacophore hypothesis. 1. Discovery of a novel class of HIV-1 integrase inhibitors.

HIV-1 Integrase (IN) is an essential enzyme for viral replication. The discovery of beta-diketo acids was crucial in the validation of IN as a legitimate target in drug discovery against HIV infection. In this study, we discovered a novel class of IN inhibitors using a 3D pharmacophore guided database search. We used S-1360 (1), the first IN inhibitor to undergo clinical trials, and three other analogues to develop a common feature pharmacophore hypothesis. Testing this four-featured pharmacophore against a multiconformational database of 150,000 structurally diverse small molecules yielded 1,700 compounds that satisfied the 3D query. Subsequently, all 1,700 compounds were docked into the active site of IN. On the basis of docking scores, Lipinski's rule-of-five, and structural novelty, 110 compounds were selected for biological screening. We found that compounds that contain both salicylic acid and a 2-thioxo-4-thiazolidinone (rhodanine) group (e.g. 5-13) showed significant inhibitory potency against IN, while the presence of either salicylic acid or a rhodanine group alone did not. Although some of the compounds containing only a salicylic acid showed inhibitory potency against IN, none of the compounds containing only rhodanine exhibited considerable potency. Of the 52 compounds reported in this study, 11 compounds (5, 6, 8, 10-13, 32-33, 51, and 53) inhibited 3'-processing or strand transfer activities of IN with IC(50) < or = 25 microM. This is the first reported use of S-1360 and its analogues as leads in developing a pharmacophore hypothesis for IN inhibition and for identification of new compounds with potent inhibition of this enzyme.

The synthesis and SAR of rhodanines as novel class C beta-lactamase inhibitors.

Beta-lactam antibiotics such as the cephalosporins and penicillins have diminished clinical effectiveness due to the hydrolytic activity of diverse beta-lactamases, especially those in molecular classes A and C. A structure activity relationship (SAR) study of a high-throughput screening lead resulted in the discovery of a potent and selective non-beta-lactam inhibitor of class C beta-lactamases.