Probing benzenesulfonamide-thiazolidinone hybrids as multitarget directed ligands for efficient control of type 2 diabetes mellitus through targeting the enzymes: α-glucosidase and carbonic anhydrase II.

Diabetes mellitus is a chronic metabolic disorder characterized by improper expression/function of a number of key enzymes that can be regarded as targets for anti-diabetic drug design. Herein, we report the design, synthesis, and biological assessment of two series of thiazolidinone-based sulfonamides 4a-l and 5a-c as multitarget directed ligands (MTDLs) with potential anti-diabetic activity through targeting the enzymes: α-glucosidase and human carbonic anhydrase (hCA) II. The synthesized sulfonamides were evaluated for their inhibitory activity against α-glucosidase where most of the compounds showed good to potent activities. Compounds 4d and 4e showed potent inhibitory activities (IC50 = 0.440 and 0.3456 µM), comparable with that of the positive control (acarbose; IC50 = 0.420 µM). All the synthesized derivatives were also tested for their inhibitory activities against hCA I, II, IX, and XII. They exhibited different levels of inhibition against these isoforms. Compound 4d outstood as the most potent one against hCA II with Ki equals to 7.0 nM, more potent than the reference standard (acetazolamide; Ki = 12.0 nM). In silico studies for the most active compounds within the active sites of α-glucosidase and hCA II revealed good binding modes that can explain their biological activities. MM-GBSA refinements and molecular dynamic simulations were performed on the top-ranking docking pose of the most potent compound 4d to confirm the formation of stable complex with both targets. Compound 4d was screened for its in vivo antihyperglycemic efficacy by using the oral glucose tolerance test. Compound 4d decreased blood glucose level to 217 mg/dl, better than the standard acarbose (234 mg/dl). Hence, this revealed its synergistic mode of action on post prandial hyperglycemia and hepatic gluconeogenesis. Thus, these benzenesulfonamide thiazolidinone hybrids could be considered as promising multi-target candidates for the treatment of type II diabetes mellitus.

One-Pot Synthesis of Novel 2-Imino-5-Arylidine-Thiazolidine Analogues and Evaluation of Their Anti-Proliferative Activity against MCF7 Breast Cancer Cell Line.

An efficient surface-mediated synthetic method to facilitate access to a novel class of thiazolidines is described. The rationale behind the design of the targeted thiazolidines was to prepare stable thiazolidine analogues and evaluate their anti-proliferative activity against a breast cancer cell line (MCF7). Most of the synthesized analogues exhibited increased potency ranging from 2-15-fold higher compared to the standard reference, cisplatin. The most active thiazolidines contain a halogenated or electron withdrawing group attached to the N-phenyl ring of exocyclic 2-imino group. However, combination of the two substituents did not enhance the activity. The anti-proliferative activity was measured in terms of IC50 values using an MTT assay.

Synthesis, Biological Evaluation and Molecular Docking Studies of 5-Indolylmethylen-4-oxo-2-thioxothiazolidine Derivatives.

BACKGROUND: Infectious diseases represent a significant global strain on public health security and impact on socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in the crucial need for the discovery and development of novel entities for the infectious treatment with different modes of action that could target both sensitive and resistant strains. METHODS: Compounds were synthesized using the classical organic chemistry methods. Prediction of biological activity spectra was carried out using PASS and PASS-based web applications. Pharmacophore modeling in LigandScout software was used for quantitative modeling of the antibacterial activity. Antimicrobial activity was evaluated using the microdilution method. AutoDock 4.2® software was used to elucidate probable bacterial and fungal molecular targets of the studied compounds. RESULTS: All compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Three compounds were tested against resistant strains MRSA, P. aeruginosa and E. coli and were found to be more potent than MRSA than reference drugs. All compounds demonstrated a higher degree of antifungal activity than the reference drugs bifonazole (6-17-fold) and ketoconazole (13-52-fold). Three of the most active compounds could be considered for further development of the new, more potent antimicrobial agents. CONCLUSION: Compounds 5b (Z)-3-(3-hydroxyphenyl)-5-((1-methyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one and 5g (Z)-3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid as well as 5h (Z)-3-(5-((5-methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid can be considered as lead compounds for further development of more potent and safe antibacterial and antifungal agents.

Novel 2-phenyl-3-(Pyridin-2-yl) thiazolidin-4-one derivatives as potent inhibitors for proliferation of osteosarcoma cells in vitro and in vivo.

Due to unknown pathogenesis and unidentified drug target, no drug for the treatment of osteosarcoma (OS) has been launched to the market. Herein, thiazolidinone 1a was discovered as a hit compound by phenotypic screening with an in-house patrimonial collection of structural diversity. The following SAR (Structure-Activity Relationship) study affords the final water-soluble lead compound (R)-8i as a potential inhibitor for the proliferation of OS cells by the modulation of solubility of the compounds with remarkable cellular potency (IC50 = 21.9 nM for MNNG/HOS cells) and in vivo efficacy (52.9% inhibition OS growth in mice), as well as pharmacokinetic properties. (R)-8i also significantly suppresses OS cell migration in vitro and showed to be well-tolerated. Our preliminary investigation shows that the effects of (R)-8i are not dependent on p53 and myoferlin (MYOF). These results suggest that (R)-8i might be a potential drug candidate for OS treatment.

2-Thioxothiazolidin-4-one Analogs as Pan-PIM Kinase Inhibitors.

Proviral integration site for Moloney murine leukemia virus (PIM) kinases are proto-oncogenic kinases involved in the regulation of several cellular processes. PIM kinases are promising targets for new drug development because they play a major role in many cancer-specific pathways, such as survival, apoptosis, proliferation, cell cycle regulation, and migration. Here, 2-thioxothiazolidin-4-one derivatives were synthesized and evaluated as potent pan-PIM kinase inhibitors. Optimized compounds showed single-digit nanomolar IC50 values against all three PIM kinases with high selectivity over 14 other kinases. Compound 17 inhibited the growth of Molm-16 cell lines (EC50 = 14 nM) and modulated the expression of pBAD and p4EBP1 in a dose-dependent manner.

Structure based designing of thiazolidinone-pyrimidine derivatives as ERK2 inhibitors: Synthesis and in vitro evaluation.

Breast cancer has been associated with an overexpression of various molecular targets; accordingly, various target-specific chemotherapeutic agents have been developed. Inhibition of ERK2, a member of MAPK pathway, is an important target involved in the treatment of both oestrogen receptor-positive and triple-negative breast cancer. Thus, in continuation of our previous work on the ERK2 target, we here report novel inhibitors of this kinase. Out of three lead molecules reported in our previous study, we selected the thiazolidinone-pyrimidine scaffold for further development of small molecule inhibitors of ERK2. Analogues of the lead molecule were docked in the target kinase, followed by molecular dynamic simulations and MM-GBSA calculations. Analogues maintaining key interactions with amino acid residues in the ATP-binding domain of ERK2 were selected and duly synthesized. In vitro biochemical evaluation of these molecules against ERK2 kinase disclosed that two molecules possess significant kinase inhibitory potential with IC50 values ≤ 0.5 µM.

Discovery of thiazolidin-4-one analogue as selective GSK-3ß inhibitor through structure based virtual screening.

GSK-3ß directly phosphorylate tubulin binding site of tau protein, indicating its importance in tau aggregation and, therefore, in Alzheimer's disease pathology. New GSK-3ß inhibitors were identified using a structure-based screening, ADMET analysis. These studies revealed that ZINC09036109, ZINC72371723, ZINC72371725, and ZINC01373165 approached optimal ADMET properties along with good MM-GBSA dG binding. Protein kinase assays of these compounds against eight disease-relevant kinases were performed. During disease-relevant kinase profiling, ZINC09036109 ((E)-2-((3,4-dimethylphenyl)imino)-5-(3-methoxy-4-(naphthalen-2-ylmethoxy)benzyl)thiazolidin-4-one) emerged as a selective GSK-3ß inhibitor with more than 10-fold selectivity over other disease-relevant kinases. Molecular dynamics study of ZINC09036109 molecule revealed interactions with Ile62, Phe67, Val135, Leu188, Asp200 amino acid residues of the binding site of GSK-3ß, which were highly comparable to the co-crystallized molecule and hence validating comparative better activity of this compound compared to overall screened molecules.

Novel thiazolidine derivatives as potent selective pro-apoptotic agents.

A series of 2-arylthiazolidine-4-carboxylic acid amide derivatives were synthesized and their cytotoxic activity against three cancer cell lines (PC-3, SKOV3 and MDA-MB231) was evaluated. Various structural modifications were tried including modifications of the length of the amide chain and modifications of the 2-aryl part using disubstituted phenyl and thiophene derivatives. The structure activity relationship was evaluated based on the in vitro biological evaluation against the above mentioned three cancer cell lines. The most selective compounds towards cancer cells were further evaluated against DLD-1, NCI-H520, Du145, MCF-7 and NCI-N87 cancer cells. The dodecyl amide having the 4-bromothienyl as the 2-aryl, compound 2e, exhibited the highest selectivity for cancer cells vs non-tumor cells. Mechanistic studies of the anticancer effect of compound 2e in prostate cancer PC-3 and colorectal cancer DLD-1 cells revealed that 2e could prevent the cell cycle in the G0/G1 phase by up-regulating the expression of p21 and reducing the expression of CDK2 and cyclin E. It increased the pro-apoptotic protein Bax and cleaved caspase 3, and down-regulated the expression of anti-apoptotic protein Bcl-2 to induce apoptosis. In addition, 2e also downregulated AKT, N-cadherin, and vimentin proteins expression giving indication that 2e inhibit the PI3K/AKT pathway to regulate cell cycle arrest and induce apoptosis, and can regulate the expression of epithelial-mesenchymal transition-related proteins.

Multicomponent reaction for the synthesis of new 1,3,4-thiadiazole-thiazolidine-4-one molecular hybrids as promising antidiabetic agents through α-glucosidase and α-amylase inhibition.

A simple and efficient protocol was developed to synthesize a new library of thiazolidine-4-one molecular hybrids (4a-n) via a one-pot multicomponent reaction involving 5-substituted phenyl-1,3,4-thiadiazol-2-amines, substituted benzaldehydes and 2-mercaptoacetic acid. The synthesized compounds were evaluated in vitro for their antidiabetic activities through α-glucosidase and α-amylase inhibition as well as their antioxidant and antimicrobial potentials. Compound 4e exhibited the most promising α-glucosidase and α-amylase inhibition with an IC50 value of 2.59 µM, which is ~1.5- and 14-fold superior as compared to the standard inhibitor acarbose. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the phenyl rings had a significant effect on the inhibitory potency.

Exploration of the Antimicrobial Effects of Benzothiazolylthiazolidin-4-One and In Silico Mechanistic Investigation.

BACKGROUND: Infectious diseases still affect large populations causing significant morbidity and mortality. Bacterial and fungal infections for centuries were the main factors of death and disability of millions of humans. Despite the progress in the control of infectious diseases, the appearance of resistance of microbes to existing drugs creates the need for the development of new effective antimicrobial agents. In an attempt to improve the antibacterial activity of previously synthesized compounds modifications to their structures were performed. METHODS: Nineteen thiazolidinone derivatives with 6-Cl, 4-OMe, 6-CN, 6-adamantan, 4-Me, 6-adamantan substituents at benzothiazole ring were synthesized and evaluated against panel of four bacterial strains S. aureus, L. monocytogenes, E. coli and S. typhimirium and three resistant strains MRSA, E. coli and P. aeruginosa in order to improve activity of previously evaluated 6-OCF3-benzothiazole-based thiazolidinones. The evaluation of minimum inhibitory and minimum bactericidal concentration was determined by microdilution method. As reference compounds ampicillin and streptomycin were used. RESULTS: All compounds showed antibacterial activity with MIC in range of 0.12-0.75 mg/mL and MBC at 0.25->1.00 mg/mL The most active compound among all tested appeared to be compound 18, with MIC at 0.10 mg/mL and MBC at 0.12 mg/mL against P. aeruginosa. as well as against resistant strain P. aeruginosa with MIC at 0.06 mg/mL and MBC at 0.12 mg/mL almost equipotent with streptomycin and better than ampicillin. Docking studies predicted that the inhibition of LD-carboxypeptidase is probably the possible mechanism of antibacterial activity of tested compounds. CONCLUSION: The best improvement of antibacterial activity after modifications was achieved by replacement of 6-OCF3 substituent in benzothiazole moiety by 6-Cl against S. aureus, MRSA and resistant strain of E. coli by 2.5 folds, while against L. monocytogenes and S. typhimirium from 4 to 5 folds.

Synthesis and analysis of 4-oxothiazolidines as potential dual inhibitors of deoxyribonuclease I and xanthine oxidase.

In this study, seven new 4-oxothiazolidine derivatives were synthesized and assayed, along 7 known derivatives, for inhibitory properties against deoxyribonuclease I (DNase I) and xanthine oxidase (XO) in vitro. Among tested compounds, (5Z)-Ethyl-2-(2-(cyanomethylene)-4-oxothiazolidin-5-yliden)acetate (6) exhibited inhibitory activity against both enzymes (DNase I IC50 = 67.94 ± 5.99 µM; XO IC50 = 98.98 ± 13.47 µM), therefore being the first reported dual inhibitor of DNase I and XO. Observed DNase I inhibition qualifies compound 6 as the most potent small organic DNase I inhibitor reported so far. Derivatives of 2-alkyliden-4-oxothiazolidinone (1) inhibited DNase I below 200 µM, while the other tested 4-oxothiazolidine derivatives remained inactive against both enzymes. The molecular docking and molecular dynamics simulations into the binding sites of DNase I and XO enzyme allowed us to clarify the binding modes of this 4-oxothiazolidine derivative, which might aid future development of dual DNase I and XO.

Structural design, synthesis and anti-Trypanosoma cruzi profile of the second generation of 4-thiazolidinones chlorine derivatives.

Chagas disease causes more deaths in the Americas than any other parasitic disease. Initially confined to the American continent, it is increasingly becoming a global health problem. In fact, it is considered to be an "exotic" disease in Europe, being virtually undiagnosed. Benznidazole, the only drug approved for treatment, effectively treats acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages remains uncertain. Previously, our research group demonstrated that 4-thiazolidinones presented anti-T. cruzi activity including in the in vivo assays in mice, making this fragment appealing for drug development. The present work reports the synthesis and anti-T. cruzi activities of a novel series of 4-thiazolidinones derivatives that resulted in an increased anti-T. cruzi activity in comparison to thiosemicarbazones intermediates. Compounds 2c, 2e, and 3a showed potent inhibition of the trypomastigote form of the parasite at low cytotoxicity concentrations in mouse splenocytes. Besides, all the 2c, 2e, and 3a tested concentrations showed no cytotoxic activity on macrophages cell viability. When macrophages were submitted to T. cruzi infection and treated with 2c and 3a, compounds reduced the release of trypomastigote forms. Results also showed that the increased trypanocidal activity induced by 2c and 3a is independent of nitric oxide release. Flow cytometry assay showed that compound 2e was able to induce necrosis and apoptosis in trypomastigotes. Parasites treated with the compounds 2e, 3a, and 3c presented flagellum shortening, retraction and curvature of the parasite body, and extravasation of the internal content. Together, these data revealed a novel series of 4-thiazolidinones fragment-based compounds with potential effects against T. cruzi and lead-like characteristics.

Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce tau levels.

The molecular chaperone, Heat Shock Protein 70 (Hsp70), is an emerging drug target for neurodegenerative diseases, because of its ability to promote degradation of microtubule-associated protein tau (MAPT/tau). Recently, we reported YM-08 as a brain penetrant, allosteric Hsp70 inhibitor, which reduces tau levels. However, the benzothiazole moiety of YM-08 is vulnerable to metabolism by CYP3A4, limiting its further application as a chemical probe. In this manuscript, we designed and synthesized seventeen YM-08 derivatives by systematically introducing halogen atoms to the benzothiazole ring and shifting the position of the heteroatom in a distal pyridine. In microsome assays, we found that compound JG-23 has 12-fold better metabolic stability and it retained the ability to reduce tau levels in two cell-based models. These chemical probes of Hsp70 are expected to be useful tools for studying tau homeostasis.

Synthesis, Characterization, Molecular Docking, In Vitro Biological Evaluation and In Vitro Cytotoxicity Study of Novel Thiazolidine-4-One Derivatives as Anti-Breast Cancer Agents.

BACKGROUND: Thiazolidine-4-one is a promising class of heterocyclic compounds with interesting pharmacological and biological activities, such as anticancer and antibacterial. Therefore, many researchers have synthesized thiazolidine-4-ones and evaluated their biological potential for developing new drugs. OBJECTIVE: In this study, two novel thiazolidine-4-one derivatives (T1 and T2) were synthesized and evaluated for their antibacterial activity toward Staphylococcus aureus, Escherichia coli, and Proteus mirabilis. Also, the cytotoxic activities of compounds T1 and T2 were estimated against MCF-7 (HER2+, ER+, and ER+) and MDAMB- 231 (triple-negative) human breast cancer cell lines. The chemical structures of the compounds T1 and T2 were proven using spectral techniques (FT-IR, 1HNMR, and 13CNMR) and CHN elemental analysis. METHODS: The synthesis of thiazolidine-4-one compounds was performed in two steps. The first step consisted of the formation of Schiff bases S1 and S2. In the second step, the synthesized Schiff bases were reacted with thioglycolic acid to prepare thiazolidine-4-one compounds. Hemolysis assay, molecular docking, cytotoxicity activity (MTT assay), and antibacterial activity (disc diffusion assay) were studied. RESULTS: The hemolysis study demonstrated that the hemolytic ratio of compounds T1 and T2 at (1, 2, and 3) mg/ml was less than 4%. MTT assay showed that 100 µg/ml of compounds T1 and T2 diminish the MCF-7 cell growth up to 80.05 ± 1.72 and 69.85 ± 3.26 respectively after 72hr., while the same concentration of compounds T1 and T2 reduces the MDA-MB-231 cell growth up 70.28 ± 2.31 and 57.15 ± 1.49, respectively. The inhibition zones of T1 and T2 were 12 mm at 50 mg/ml and 10 mm at 5 mg/ml in E. coli bacteria. Furthermore, a docking study was carried out to investigate the affinity and binding mode of compounds T1 and T2 towards the ERα, VEGF, and HER2 protein receptors in breast cancer cells. Data obtained from the docking study were exactly identical to that obtained from in vitro cytotoxicity assay. CONCLUSION: The results proved that T1 is an optimal anticancer agent toward breast cancer cells and the hemolysis study indicates the use of safety inside the body for compound T1. Synthesized compound T1 was most effective against MCF-7 cells compared to MDA-MB-231 cells and more effective than the reference drug tamoxifen in breast cell lines. The high cytotoxicity of T1 on the growth of MCF-7 cells because T1 binds with a high degree of affinity to the estrogen and HER2 receptors, which in turn inhibits cell proliferation and induces apoptosis.

Synthesis and biological evaluation of new 4-oxo-thiazolidin-2-ylidene derivatives as antimicrobial agents.

In this study, an efficient synthesis and the antimicrobial activity evaluation of some 4-oxo-thiazolidin-2-ylidene derivatives are presented. The structures of the target substances were confirmed by using 1 H and 13 C nuclear magnetic resonance spectroscopy, mass spectrometry, infrared spectroscopy, and elemental analysis. The synthesized compounds were evaluated for antimicrobial activity against five bacterial strains (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus) and two fungal strains (Candida albicans and Cryptococcus neoformans). It was shown that the compounds in this series possess antibacterial and antifungal activities.

Distinct Lugdunins from a New Efficient Synthesis and Broad Exploitation of Its MRSA-Antimicrobial Structure.

A new solid-phase peptide synthesis and bioprofiling of the antimicrobial activity of lugdunin, a fibupeptide, enable a comprehensive structure-activity relationship (SAR) study (MRSA Staphylococcus aureus). Distinct lugdunin analogues with variation of the three important amino acids Val2, Trp3, and Leu4 are readily available based on the established high-output synthesis. This efficient synthesis concept takes advantage of the presynthesized thiazolidine building block. To gain further knowledge of SAR, d-Val2, and d-Leu4 were replaced with aliphatic amino acids. For l-Trp3 derivatization, a set of non-natural aromatic amino acids with manifold substitution and annulation patterns precisely shows structural imperatives, starting from the exchange of d-Val6 → d-Trp6 with a 2-fold improved biological activity. d-Trp6-lugdunin analogues with additional variation of d-Val2 and d-Leu4 residues were designed and synthesized followed by antimicrobial profiling. For the first time, these SAR studies deliver valuable information on the tolerance of other amino acids to d-Val2, l-Trp3, and d-Leu4 in the sequence of lugdunin.

Ideality in Context: Motivations for Total Synthesis.

Total synthesis-the ultimate proving ground for the invention and field-testing of new methods, exploration of disruptive strategies, final structure confirmation, and empowerment of medicinal chemistry on natural products-is one of the oldest and most enduring subfields of organic chemistry. In the early days of this field, its sole emphasis focused on debunking the concept of vitalism, that living organisms could create forms of matter accessible only to them. Emphasis then turned to the use of synthesis to degrade and reconstitute natural products to establish structure and answer questions about biosynthesis. It then evolved to not only an intricate science but also a celebrated form of art. As the field progressed, a more orderly and logical approach emerged that served to standardize the process. These developments even opened up the possibility of computer-aided design using retrosynthetic analysis. Finally, the elevation of this field to even higher levels of sophistication showed that it was feasible to synthesize any natural product, regardless of complexity, in a laboratory. During this remarkable evolution, as has been reviewed elsewhere, many of the principles and methods of organic synthesis were refined and galvanized. In the modern era, students and practitioners are still magnetically attracted to this field due to the excitement of the journey, the exhilaration of creation, and the opportunity to invent solutions to challenges that still persist. Contemporary total synthesis is less concerned with demonstrating a proof of concept or a feasible approach but rather aims for increased efficiency, scalability, and even "ideality." In general, the molecules of Nature are created biosynthetically with levels of practicality that are still unimaginable using the tools of modern synthesis. Thus, as the community strives to do more with less (i.e., innovation), total synthesis is now focused on a pursuit for simplicity rather than a competition for maximal complexity. In doing so, the practitioner must devise outside-the-box strategies supplemented with forgotten or newly invented methods to reduce step count and increase the overall economy of the approach. The downstream applications of this pursuit not only empower students who often go on to apply these skills in the private sector but also lead to new discoveries that can impact numerous disciplines of societal importance. This account traces some select case studies from our laboratory over the past five years that vividly demonstrate our own motivation for dedicating so much effort to this classic field. In aiming for simplicity, we focus on the elusive goal of achieving ideality, a term that, when taken in the proper context, can serve as a guiding light to point the way to furthering progress in organic synthesis.

Structure-Activity Studies of Truncated Latrunculin Analogues with Antimalarial Activity.

Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics renders the parasites unable to effectively establish infection. Therefore, actin presents a potential target for malarial drug discovery, and naturally occurring actin inhibitors such as latrunculins are a promising starting point. However, the limited availability of the natural product and the laborious route for synthesis of latrunculins have hindered their potential development as drug candidates. In this regard, we recently described novel truncated latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core to summarize the SAR for inhibition of malaria motility. This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria.

Design, synthesis, and anticancer activity of novel 4-thiazolidinone-phenylaminopyrimidine hybrids.

4-Thiazolidinones and phenylaminopyrimidines are known as anticancer agents. Imatinib is the pioneer phenylaminopyrimidine derivative kinase inhibitor, which is used for the treatment of chronic myeloid leukemia. With a hybrid approach, a novel series of 5-benzylidene-2-arylimino-4-thiazolidinone derivatives containing phenylaminopyrimidine core were designed, synthesized, and tested for their anticancer activity on K562 (chronic myeloid leukemia), PC3 (prostat cancer), and SHSY-5Y (neuroblastoma) cells. Since superior anticancer activity was observed on K562 cells, further biological studies of selected compounds (8, 15, and 34) were performed on K562 cells. For the synthesis of designed compounds, thiourea compounds were converted to 2-imino-1,3-thiazolidin-4-ones with α-chloroacetic acid in the presence of sodium acetate. 5-Benzylidene-2-imino-1,3-thiazolidin-4-one derivatives were obtained by Knoevenagel condensation of 2-imino-1,3-thiazolidin-4-ones with related aldehydes. Compounds 8, 15, and 34 were evaluated for cell viability, apoptosis studies, cell cycle experiments, and DNA damage assays. IC50 values of compounds 8, 15, and 34 were found as 5.26 ± 1.03, 3.52 ± 0.91, and 8.16 ± 1.27 µM, respectively, in K562 cells. Preferably, these compounds showed less toxicity towards L929 cells compared to imatinib. Furthermore, compounds 8 and 15 significantly induced early and late apoptosis in a time-dependent manner. Compounds 15 and 34 induced cell cycle arrest at G0/G1 phase and compound 8 caused cell cycle arrest at G2/M phase. Based on DNA damage assay, compounds 8 and 15 were found to be more genotoxic than imatinib towards K562 cells. To put more molecular insight, possible Abl inhibition mechanisms of most active compounds were predicted by molecular docking studies. In conclusion, a novel series of 5-benzylidene-2-arylimino-4-thiazolidinone derivatives and their promising anticancer activities were reported herein.

QM/MM analysis, synthesis and biological evaluation of epalrestat based mutual-prodrugs for diabetic neuropathy and nephropathy.

Herein, a quantum mechanics/molecular mechanics (QM/MM) based biotransformation study was performed on synthetically feasible mutual-prodrugs of epalrestat which have been identified from an in-house database developed by us. These prodrugs were submitted to quantum polarized ligand docking (QPLD) with the CES1 enzyme followed by MM-GBSA calculation. Electronic aspects of transition state of these prodrugs were also considered to study the catalytic process through density functional theory (DFT). ADMET analysis of prodrugs was then carried out to assess the drug-likeness. On the basis of in-silico results, the best five prodrugs were synthesized and further evaluated for their neuroprotective and nephroprotective potential in high-fat diet-streptozotocin (HFD-STZ) induced diabetes in rat model. Clinically relevant molecular manifestations of diabetic complications (DC) including aldose reductase (ALR2) activity and oxidative stress markers such as reduced glutathione (GSH), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) were determined in blood plasma as well as tissues of the brain and kidneys. The histopathological examination of these organs was also carried out to see the improvement in structural deformities caused due to neuropathy and nephropathy. Finally, in-vivo pharmacokinetic study was performed for the best two prodrugs to assess the improvement in biopharmaceutical attributes of parent drugs. Overall, EP-G-MFA and EP-MFA have significantly reduced the hyperglycemia-induced ALR2 activity, levels of oxidative stress markers, and manifested about a two-fold increase in the biological half-life (T1/2) of parent drugs. The overall findings of this study suggest that methyl ferulate conjugated prodrugs of epalrestat may be considered as potential protective agents in diabetic neuropathy and nephropathy.