Oral empagliflozin-loaded tri-layer core-sheath fibers fabricated using tri-axial electrospinning: Enhanced in vitro and in vivo antidiabetic performance.

Empagliflozin (EM) was successfully loaded in polycaprolactone/poly (L-lactic acid)/polymethyl methacrylate (PCL/PLA/PMMA) fibers. In the rat ß-cell line (BRIN-BD11), the insulin expression ratio of pancreatic ß-cells was stimulated at high and low glucose by culturing with tri-layer EM-loaded fiber (EMF) for 48 h. The expression ratios of glucokinase and GLUT-2 proteins increased after EMF treatment. According to the in vitro drug release test, 97% of all drug contained in fibers was released in a controlled manner for 24 h. The pharmacokinetic test revealed that the bioavailability was improved ∼4.8-fold with EMF treatment compared to EM-powder and blood glucose level was effectively controlled for 24 h with EMF. Oral administration of EMF exhibited a better sustainable anti-diabetic activity even in the half-dosage than EM-powder in streptozotocin/nicotinamide-induced T2DM rats. The levels of GLP-1, PPAR-γ, and insulin were increased while the levels of SGLT-2 and TNF-α were decreased with EMF treatment. Also, EMF recovered the histopathological changes in the liver, pancreas, and kidney in T2DM rats and protected pancreatic ß-cells. Consequently, EMF is suggested as an unprecedented and promotive treatment approach for T2DM with a higher bioavailability and better antidiabetic effect compared to conventional dosage forms.

Novel 1,2,4-triazoles derived from Ibuprofen: synthesis and in vitro evaluation of their mPGES-1 inhibitory and antiproliferative activity.

Some novel triazole-bearing ketone and oxime derivatives were synthesized from Ibuprofen. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human cervix cancer HeLa, and human chronic myelogenous leukemia K562 cell lines) were evaluated by MTT assay. In addition, mouse embryonic fibroblast cells (NIH/3T3) were also evaluated to determine the selectivity. Compounds 18, 36, and 45 were found to be the most cytotoxic, and their IC50 values were in the range of 17.46-68.76 µM, against the tested cancer cells. According to the results, compounds 7 and 13 demonstrated good anti-inflammatory activity against the microsomal enzyme prostaglandin E2 synthase-1 (mPGES-1) enzyme at IC50 values of 13.6 and 4.95 µM. The low cytotoxicity and non-mutagenity of these compounds were found interesting. Also, these compounds significantly prevented tube formation in angiogenesis studies. In conclusion, the anti-inflammatory and angiogenesis inhibitory activities of these compounds without toxicity suggested that they may be promising agents in anti-inflammatory treatment and they may be supportive agents for the cancer treatment.

Synthesis and structure-activity relationship of L-methionine-coupled 1,3,4-thiadiazole derivatives with activity against influenza virus.

In previous investigations, we identified a class of 1,3,4-thiadiazole derivatives with antiviral activity. N-{3-(Methylsulfanyl)-1-[5-(phenylamino)-1,3,4-thiadiazole-2-yl]propyl}benzamide emerged as a relevant lead compound for designing novel influenza A virus inhibitors. In the present study, we elaborated on this initial lead by performing chemical synthesis and antiviral evaluation of a series of structural analogues. During this research, thirteen novel 1,3,4-thiadiazole derivatives were synthesized by the cyclization of the corresponding thiosemicarbazides as synthetic precursors. The structures and the purities of the synthesized compounds were confirmed through chromatographic and spectral data. Four L-methionine-based 1,3,4-thiadiazole derivatives displayed activity against influenza A virus, the two best compounds being 24 carrying a 5-(4-chlorophenylamino)-1,3,4-thiadiazole moiety and 30 possessing a 5-(benzoylamino)-1,3,4-thiadiazole structure [antiviral EC50 against influenza A/H3N2 virus: 4.8 and 7.4 µM, respectively]. The 1,3,4-thiadiazole derivatives were inactive against influenza B virus and a wide panel of unrelated DNA and RNA viruses. Compound 24 represents a new class of selective influenza A virus inhibitors acting during the virus entry process, as evidenced by our findings in a time-of-addition assay. Molecular descriptors and in silico prediction of ADMET properties of the active compounds were calculated. According to in silico ADMET and drug similarity studies, active compounds have been estimated to be good candidates for oral administration with no apparent toxicity considerations.

Small-Molecule Inhibitors Targeting Sterol 14α-Demethylase (CYP51): Synthesis, Molecular Modelling and Evaluation Against Candida albicans.

Fungal infections are a global issue affecting over 150 million people worldwide annually, with 750 000 of these caused by invasive Candida infections. Azole drugs are the frontline treatment against fungal infections; however, resistance to current azole antifungals in C. albicans poses a threat to public health. Two series of novel azole derivatives, short and extended derivatives, have been designed, synthesised and investigated for CYP51 inhibitory activity, binding affinity and minimum inhibitory concentration (MIC) against C. albicans strains. The short derivatives were more potent against the C. albicans strains (e. g., MIC 2-(4-chlorophenyl)-N-(2,4-dichlorobenzyl)-3-(1H-imidazol-1-yl)propanamide (5 f) <0.03 µg/mL, N-(4-((4-chlorophenyl)sulfonamido)benzyl)-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propanamide (12 c), 1 µg/mL, fluconazole 0.125 µg/mL) but both displayed comparable enzyme binding and inhibition (5 f Kd 62±17 nM, IC50 0.46 µM; 12 c Kd 43±18 nM, IC50 0.33 µM, fluconazole Kd 41±13 nM, IC50 0.31 µM, posaconazole Kd 43±11 nM, IC50 0.2 µM). The short series had poor selectivity for CaCYP51 over the human homologue, whereas the selectivity of the extended series, for example, compound 12 c, was higher (21.5-fold) than posaconazole (4.7-fold) based on Kd values, although posaconazole was more selective (615-fold) than 12 c (461-fold) based on IC50 values. Based on inhibitory activity and selectivity profile, the extended series are the better of the two series for further development.

Synthesis and antiproliferative evaluation of novel 2-(4H-1,2,4-triazole-3-ylthio)acetamide derivatives as inducers of apoptosis in cancer cells.

In this study, a series of thiosemicarbazide derivatives 12-14, 1,2,4-triazol-3-thione derivatives 15-17 and compounds bearing 2-(4H-1,2,4-triazole-3-ylthio)acetamide structure 18-32 have been synthesized starting from phenolic compounds such as 2-naphthol, paracetamol and thymol. Structures and purity of the target compounds were confirmed by the use of their chromatographic and spectral data besides microanalysis. All of the synthesized new compounds 12-32 were evaluated for their anti-HIV activity. Among these compounds, three representatives 18, 19 and 25 were selected and evaluated by the National Cancer Institute (NCI) against the full panel of 60 human cancer cell lines derived from nine different cancer types. Antiproliferative effects of the selected compounds were demonstrated in human tumor cell lines K-562, A549 and PC-3. These compounds inhibited cell growth assessed by MTT assay. Compound 18, 19 and 25 exhibited anti-cancer activity with IC50 values of 5.96 µM (PC-3 cells), 7.90 µM (A549/ATCC cells) and 7.71 µM (K-562 cells), respectively. After the cell viability assay, caspase activation and Bcl-2 activity of the selected compounds were measured and the loss of mitochondrial membrane potential (MMP) was detected. Compounds 18, 19 and 25 showed a significant increase in caspase-3 activity in a dose-dependent manner. This was not observed for caspase-8 activity with compound 18 and 25, while compound 19 was significantly elevated only at the dose of 50 µM. In addition, all three compounds significantly decreased the mitochondrial membrane potential and expression of Bcl-2.

Design, Synthesis, and Molecular Docking Studies of a Conjugated Thiadiazole-Thiourea Scaffold as Antituberculosis Agents.

In view of the emergence and frequency of multidrug-resistant and extensively drug-resistant tuberculosis and consequences of acquired resistance to clinically used drugs, we undertook the design and synthesis of novel prototypes that possess the advantage of the two pharmacophores of thiourea and 1,3,4-thiadiazole in a single molecular backbone. Three compounds from our series were distinguished from the others by their promising activity profiles against Mycobacterium tuberculosis strain H37Rv. Compounds 11 and 19 were the most active representatives with minimum inhibitory concentration (MIC) values of 10.96 and 11.48 µM, respectively. Compound 15 was shown to inhibit M. tuberculosis strain H37Rv with an MIC value of 17.81 µM. Cytotoxicity results in the Vero cell line showed that these three derivatives had selectivity indices between 1.8 and 8.7. In order to rationalize the biological results of our compounds, molecular docking studies with the enoyl acyl carrier protein reductase (InhA) of M. tuberculosis were performed and compounds 11, 15, and 19 were found to have good docking scores in the range of -7.12 to -7.83 kcal/mol.

Discovery of conjugated thiazolidinone-thiadiazole scaffold as anti-dengue virus polymerase inhibitors.

Dengue virus (DENV) infection is a significant health threat to the global population with no therapeutic option. DENV NS5 RNA-dependent RNA polymerase (RdRp) is the key replicating protein of the virus and thus an attractive target for drug development. Herein, we report on the synthesis and biological evaluation of a series of hybrid thiazolidinone-thiadiazole derivatives as a new class of DENV-2 NS5 RdRp inhibitors. This yielded compounds 12 and 21 with IC50 values of 2.3 µM and 2.1 µM, respectively, as promising leads. Limited SAR analysis indicated 3-fluorobenzylidene as the optimal substituent at C5-position of the thiazolidinone core, whereas both 2-chlorophenyl and 3-fluorophenyl substituents were equally effective at C5-position of the 1,3,4-thiadiazole core. Biophysical characterization and molecular docking studies conferred the binding site of this scaffold on DENV NS5 polymerase. Binding mode of compound 21 in Thumb pocket-II of DENV-2 NS5 polymerase will form the basis for future structure-activity relationship optimization.

Novel 4-thiazolidinones as non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase.

In continuation of our efforts to develop new derivatives as hepatitis C virus (HCV) NS5B inhibitors, we synthesized novel 5-arylidene-4-thiazolidinones. The novel compounds 29-42, together with their synthetic precursors 22-28, were tested for HCV NS5B inhibitory activity; 12 of these compounds displayed IC50 values between 25.3 and 54.1 µM. Compound 33, an arylidene derivative, was found to be the most active compound in this series with an IC50 value of 25.3 µM. Molecular docking studies were performed on the thumb pocket-II of NS5B to postulate the binding mode for these compounds.

2-Heteroarylimino-5-arylidene-4-thiazolidinones as a new class of non-nucleoside inhibitors of HCV NS5B polymerase.

Hepatitis C virus (HCV) NS5B polymerase is an important and attractive target for the development of anti-HCV drugs. Here we report on the design, synthesis and evaluation of twenty-four novel allosteric inhibitors bearing the 4-thiazolidinone scaffold as inhibitors of HCV NS5B polymerase. Eleven compounds tested were found to inhibit HCV NS5B with IC50 values ranging between 19.8 and 64.9 µM. Compound 24 was the most active of this series with an IC50 of 5.6 µM. A number of these derivatives further exhibited strong inhibition against HCV 1b and 2a genotypes in cell based antiviral assays. Molecular docking analysis predicted that the thiazolidinone derivatives bind to the NS5B thumb pocket-II (TP-II). Our results suggest that further optimization of the thiazolidinone scaffold may be possible to yield new derivatives with improved enzyme- and cell-based activity.

Some hydrazones of 2-aroylamino-3-methylbutanohydrazide: synthesis, molecular modeling studies, and identification as stereoselective inhibitors of HIV-1.

In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8(S) , 11(S) , and 12(S) showed anti-HIV-1 activity with a 50% inhibitory concentration (IC(50)) =123.8 µM (selectivity index, SI>3), IC(50) =12.1 µM (SI>29), IC(50) =17.4 µM (SI>19), respectively. Enantiomers 8(R) , 11(R) , and 12(R) were inactive against the HIV-1 strain III(B) . Hydrazones 8(S) , 11(S) , and 12(S) which were active against HIV-1 wild type showed no inhibition against a double mutant NNRTI-resistant strain (K103N;Y181C). Molecular docking calculations of R- and S-enantiomers of 8, 11, and 12 were performed using the hydrazone-bound novel site of HIV-1 RT.

Synthesis of some novel thiourea derivatives obtained from 5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones and evaluation as antiviral/anti-HIV and anti-tuberculosis agents.

As a continuation of our previous efforts on N-alkyl/aryl-N'-[4-(4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione-5-yl)phenyl]thioureas 1-19 and N-alkyl/aryl-N'-[4-(3-aralkylthio-4-alkyl/aryl-4H-1,2,4-triazole-5-yl)phenyl]thioureas 20-22, a series of novel 5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones 23-26 and several related thioureas, N-alkyl/aryl-N'-{4-[(4-alkyl/aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methoxy]phenyl}thioureas 27-42 were synthesized for evaluation of their antiviral potency. Structures of the synthesized compounds were confirmed by the use of (1)H NMR, (13)C NMR and HR-MS data. All compounds 1-42 were evaluated in vitro against HIV-1 (IIIB) and HIV-2 (ROD) strains in MT-4 cells, as well as other selected viruses such as HSV-1, HSV-2, Coxsackie virus B4, Sindbis virus and Varicella-zoster virus using HeLa, Vero, HEL and E6SM cell cultures, and anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv. Compounds 4 and 5 showed weak activity against HSV-1, HSV-2 and TK(-) HSV, whereas eight compounds showed marginal activity against Coxsackie virus B4. The most active derivative in this series was compound 38 which showed moderate protection against Coxsackie virus B4 with an MIC value of 16 microg/ml and a selectivity index of 5. This compound was also active against thymidine kinase positive Varicella-zoster virus (TK(+) VZV, OKA strain) with an EC(50) value of 9.9 microg/ml. Compound 38 was the most active compound with 79% inhibition against M. tuberculosis H37Rv.

Synthesis of some novel heterocyclic compounds derived from diflunisal hydrazide as potential anti-infective and anti-inflammatory agents.

Three novel series of 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid derivatives namely 4-substituted-1,2,4-triazoline-3-thiones (4a-g); 2-substituted-1,3,4-thiadiazoles (5a-g) and 2-substituted-1,3,4-oxadiazoles (6a-g) have been synthesized. Twenty-one of the newly synthesized compounds were tested against various bacteria, fungi, yeast species and virus. In addition, we have replaced the carboxylic acid group of diflunisal with heterocycles and the anti-inflammatory activity of heterocycles reported here. Compound (5d) showed activity against Escherichia coli A1 and Streptococcus pyogenes ATCC-176 at a concentration of 31.25 microg/mL, whereas cefepime, the drug used as standard, has been found less active against the bacteria mentioned above. Compound (4b) has exhibited activity against Aspergillus variecolor and Trichophyton rubrum at a concentration of 31.25 and 15.25 microg/mL, whereas Amphotericin B, the drug used as standard, has been found less active against the yeast and fungi. The highest antiviral activity was found in the 1,3,4-thiadiazole derivative (5a) having a methyl group at 2nd position against Sindbis virus at 9.6 microg/mL. Compound (4c) exhibited the highest anti-inflammatory activity (73.03%) whereas diflunisal, the drug used as standard, has been found less active (24.16%). Compound (5f) presented similar antinociceptive activity with the standard drug (paw withdrawal latency was 19.21 s compared to that of diflunisal which was 19.14s, in hot plate test).