Health-Related Quality of Life After Percutaneous Radiofrequency Ablation of Cold,Solid, Benign Thyroid Nodules: A 2-Year Follow-Up Study in 40 Patients

Objective: We studied the impact of radiofrequency ablation (RFA) on health-related quality of life (HRQL) in patients with benign thyroid nodules (TN) in a 2-year follow-up.Methods: Forty patients (35 women and 5 men; age, 54.9 ± 14.3 years) with cold thyroid solitary nodules or a dominant nodule within a normofunctioning multi-nodular goiter (volume range, 6.5 to 90.0 mL) underwent RFA of thyroid nodular tissue under ultrasound real-time assistance.Results: Data are mean and standard deviation. Energy delivered was 37,154 ± 18,092 joules, with an output power of 37.4 ± 8.8 watts. Two years after RFA, nodule volume decreased from 30.0 ± 18.2 mL to 7.9 ± 9.8 mL (-80.1 ± 16.1% of initial volume; P<.0001). Thyroid-stimulating hormone, free triiodothyronine, and free thyroxine levels remained stable. Symptom score measured on a 0- to 10-cm visual analogue scale (VAS) declined from 5.6 ± 3.1 cm to 1.9 ± 1.3 cm (P<.0001). Cosmetic score (VAS 0–10 cm) declined from 5.7 ± 3.2 cm to 1.9 ± 1.5 cm (P<.0001). Two patients became anti-thyroglobulin antibody–positive. Physical Component Summary (PCS)-12 improved from 50.4 ± 8.9 to 54.5 ± 5.3, and the Mental Component Summary (MCS)-12 improved from 36.0 ± 13.3 to 50.3 ± 6.3 (P<.0001 for both score changes).Conclusion: Our 2-year follow-up study confirms that RFA of benign TNs is effective in reducing nodular volume and compressive and cosmetic symptoms, without causing thyroid dysfunction or life-threatening complications. Our data indicate that the achievement of these secondary endpoints is associated with HRQL improvement, measured both as PCS and MCS.Abbreviations: fT₃ = free triiodothyronine fT₄ = free thyroxine HRQL = health-related quality of life MCS-12 = Mental Component Summary-12 PLA = percutaneous laser ablation PCS-12 = Physical Component Summary-12 RF = radiofrequency RFA = radiofrequency ablation SF-12 = Short-Form 12 Health Survey TgAb = anti-thyroglobulin antibody TN = thyroid nodule TRAb = anti-TSH-receptor antibody TSH = thyroid-stimulating hormone US = ultrasound VAS = visual analogue scale     

Investigations into specificity of azepinomycin for inhibition of guanase: Discrimination between the natural heterocyclic inhibitor and its synthetic nucleoside analogues

In our long and broad program to explore structure–activity relationships of the natural product azepinomycin and its analogues for inhibition of guanase, an important enzyme of purine salvage pathway of nucleic acid metabolism, it became necessary to investigate if the nucleoside analogues of the heterocycle azepinomycin, which are likely to be formed in vivo, would be more or less potent than the parent heterocycle. To this end, we have resynthesized both azepinomycin (1) and its two diastereomeric nucleoside analogues (2 and 3), employing a modified, more efficient procedure, and have biochemically screened all three compounds against a mammalian guanase. Our results indicate that the natural product is at least 200 times more potent toward inhibition of guanase as compared with its nucleoside analogues, with the observed K_i of azepinomycin (1) against the rabbit liver guanase = 2.5 (±0.6) × 10^?6 M, while K_i of Compound 2 = 1.19 (±0.02) × 10^?4 M and that of Compound 3 = 1.29 (±0.03) × 10^?4 M. It is also to be noted that while IC₅₀ value of azepinomycin against guanase in cell culture has long been reported, no inhibition studies nor K_i against a pure mammalian enzyme have ever been documented. In addition, we have, for the first time, determined the absolute stereochemistry of the 6-OH group of 2 and 3 using conformational analysis coupled with 2-D ¹H NMR NOESY     

Synthesis,molecular docking,acetylcholinesterase and butyrylcholinesterase inhibitory potential of thiazole analogs as new inhibitors for Alzheimer disease

A series of thirty (30) thiazole analogs were prepared, characterized by ¹H NMR, ¹³C NMR and EI-MS and evaluated for Acetylcholinesterase and butyrylcholinesterase inhibitory potential. All analogs exhibited varied butyrylcholinesterase inhibitory activity with IC₅₀ value ranging between 1.59 ± 0.01 and 389.25 ± 1.75 μM when compared with the standard eserine (IC₅₀, 0.85 ± 0.0001 μM). Analogs 15, 7, 12, 9, 14, 1, 30 with IC₅₀ values 1.59 ± 0.01, 1.77 ± 0.01, 6.21 ± 0.01, 7.56 ± 0.01, 8.46 ± 0.01, 14.81 ± 0.32 and 16.54 ± 0.21 μM respectively showed excellent inhibitory potential. Seven analogs 15, 20, 19, 24, 28, 30 and 25 exhibited good acetylcholinesterase inhibitory potential with IC50 values 21.3 ± 0.50, 35.3 ± 0.64, 36.6 ± 0.70, 44.81 ± 0.81, 46.36 ± 0.84, 48.2 ± 0.06 and 48.72 ± 0.91 μM respectively. All other analogs also exhibited well to moderate enzyme inhibition. The binding mode of these compounds was confirmed through molecular docking.     

Triazinoindole analogs as potent inhibitors of α-glucosidase: Synthesis,biological evaluation and molecular docking studies

A new series of triazinoindole analogs 1–11 were synthesized, characterized by EI-MS and ¹H NMR, evaluated for α-glucosidase inhibitory potential. All eleven (11) analogs showed different range of α-glucosidase inhibitory potential with IC₅₀ value ranging between 2.46 ± 0.008 and 312.79 ± 0.06 μM when compared with the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). Among the series, compounds 1, 3, 4, 5, 7, 8, and 11 showed excellent inhibitory potential with IC₅₀ values 2.46 ± 0.008, 37.78 ± 0.05, 28.91 ± 0.0, 38.12 ± 0.04, 37.43 ± 0.03, 36.89 ± 0.06 and 37.11 ± 0.05 μM respectively. All other compounds also showed good enzyme inhibition. The binding modes of these analogs were confirmed through molecular docking.     

Development of an equation to predict net protein requirements for the growth of Zebu beef cattle

The accurate estimation of protein requirements for beef cattle is a key factor in increasing livestock profitability and decreasing the environmental impacts of excessive N excretion due to mismatching between assumed requirements and diet formulation. A meta-analysis was conducted to evaluate and validate a new equation to predict the net protein requirements for growth (NPg) of Zebu beef cattle. For the development of the new approach, a database of 552 observations comprised of bulls, steers, and heifers of different genetic groups (Zebu, beef crossbreed, and dairy crossbreed) was assembled. The new approach was evaluated and compared to current models devised by the international nutrient requirements system committees (Agricultural Research Council, 1980; Beef Cattle Nutrient Requirements Model, 2016; BR-CORTE, 2016) to predict NPg. The model evaluation was performed through the model evaluation system (version 3.1.16) using an independent data set (n = 177 observations). An equation was considered the best estimator of NPg if the following conditions were met: (1) the intercept and slope of the regression between ordinary residues and/or predicted NPg values must have been equal to zero and one, respectively; and (2) the greatest concordance correlation coefficient (CCC) and determination coefficient (R), and lowest mean squared error of prediction (MSEP) were attained. Based on the regression models of the observed v. predicted NPg of Zebu beef cattle, both the new approach and that of the ARC (1980) correctly estimated NPg, since the intercept and slope were not different (P > 0.05) from zero and one, respectively. Additionally, the new approach’s determination coefficient was the greatest and the closest to one. The fact that the new model achieved a higher CCC and lower MSEP than the existing models indicated its superior reproducibility and accuracy. The equations proposed by BR-CORTE (2016) and the BCNRM (2016) did not correctly estimate NPg in that the intercept and slope were different (P < 0.01) from zero and one, respectively. Thus, the equations proposed by the new approach and the ARC (1980) accurately and precisely estimated NPg and are recommended for Zebu cattle. Furthermore, the inclusion of equivalent empty BW (EQEBW) in the new approach improves the estimation of NPg. We suggest the use of the following equation to calculate NPg for Zebu beef cattle: NPg = 176.01 × EBG – 0.381 × EQEBW^0.75 × EBG^1.035 (R = 0.80 and CCC = 0.75); where NPg = net protein requirements for growth, EBG = empty body gain, and EQEBW = equivalent empty BW.     

Syntheses of 4,6-dihydroxypyrimidine diones,their urease inhibition,in vitro,in silico,and kinetic studies

A library of 4,6-dihydroxypyrimidine diones (1–35) were synthesized and evaluated for their urease inhibitory activity. Structure-activity relationships, and mechanism of inhibition were also studied. All compounds were found to be active with IC₅₀ values between 22.6 ± 1.14–117.4 ± 0.73 µM, in comparison to standard, thiourea (IC₅₀ = 21.2 ± 1.3 µM). Kinetics studies on the most active compounds 2–7, 16, 17, 28, and 33 were performed to investigate their modes of inhibition, and dissociation constants K_i. Compounds 2, 3, 7, 16, 28, and 33 were found to be mixed-type of inhibitors with K_i values in the range of 7.91 ± 0.024–13.03 ± 0.013 µM, whereas, compounds 4–6, and 17 were found to be non-competitive inhibitors with K_i values in the range of 9.28 ± 0.019–13.05 ± 0.023 µM. In silico study was also performed, and a good correlation was observed between experimental and docking studies. This study is continuation of our previously reported urease inhibitory activity of pyrimidine diones, representing potential leads for further research as possible treatment of diseases caused by ureolytic bacteria.     

Carbohydrazones as new class of carbonic anhydrase inhibitors: Synthesis,kinetics, and ligand docking studies

Discovery and development of carbonic anhydrase inhibitors is crucial for their clinical use as antiepileptic, diurectic and antiglaucoma agents. Keeping this in mind, we have synthesized carbohydrazones 1–27 and evaluated them for their in vitro carbonic anhydrase inhibitory potential. Out of twenty-seven compounds, compounds 1 (IC₅₀ = 1.33 ± 0.01 µM), 2 (IC₅₀ = 1.85 ± 0.24 µM), 3 (IC₅₀ = 1.37 ± 0.06 µM), and 9 (IC₅₀ = 1.46 ± 0.12 µM) have showed carbonic anhydrase inhibition better than the standard drug zonisamide (IC₅₀ = 1.86 ± 0.03 µM). Moreover, compounds 4 (IC₅₀ = 2.32 ± 0.04 µM), 5 (IC₅₀ = 3.96 ± 0.35 µM), 7 (IC₅₀ = 2.33 ± 0.02 µM), and 8 (IC₅₀ = 2.67 ± 0.01 µM) showed good inhibitory activity. Cheminformatic analysis has shown that compounds 1 and 2 possess lead-like properties. In addition, kinetic and molecular docking studies were also performed to investigate the binding interaction between carbohydrazones and carbonic anhydrase enzyme. This study has identified a novel and potent class of carbonic anhydrase inhibitors with the potential to be investigated further.     

Isatin based Schiff bases as inhibitors of α-glucosidase: Synthesis,characterization, in vitro evaluation and molecular docking studies

Isatin base Schiff bases (1–20) were synthesized, characterized by ¹H NMR and EI/MS and evaluated for α-glucosidase inhibitory potential. Out of these twenty (20) compounds only six analogs showed potent α-glucosidase inhibitory potential with IC₅₀ value ranging in between 2.2 ± 0.25 and 83.5 ± 1.0 μM when compared with the standard acarbose (IC₅₀ = 840 ± 1.73 μM). Among the series compound 2 having IC₅₀ value (18.3 ± 0.56 μM), 9 (83.5 ± 1.0 μM), 11 (3.3 ± 0.25 μM), 12 (2.2 ± 0.25 μM), 14 (11.8 ± 0.15 μM), and 20 (3.0 ± 0.15 μM) showed excellent inhibitory potential many fold better than the standard acarbose. The binding interactions of these active analogs were confirmed through molecular docking.     

Design,synthesis and evaluation of novel metalloproteinase inhibitors based on l-tyrosine scaffold

A series of novel l-tyrosine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and histone deacetylase 8 (HDAC-8). The results showed that these l-tyrosine derivatives exhibited inhibitory profiles against MMP-2 and HDAC-8. The compounds 6h (IC₅₀ = 0.013 ± 0.001 μM) and 6j (IC₅₀ = 0.017 ± 0.001 μM) were equal potent MMP-2 inhibitors to the positive control NNGH (IC₅₀ = 0.014 ± 0.001 μM). As for HDAC-8 inhibition, some of the hydroxamate compounds, such as 6d (IC₅₀ = 3.6 ± 0.2 μM) and 6c (IC₅₀ = 5.8 ± 0.5 μM), were equal potent to the positive control SAHA (IC₅₀ = 1.6 ± 0.1 μM). Structure–activity relationships were also briefly discussed.     

Synthesis of 4-thiazolidinone analogs as potent in vitro anti-urease agents

4-Thiazolidinone analogs 1–20 were synthesized, characterized by ¹H NMR and EI–MS and investigated for urease inhibitory activity. All twenty (20) analogs exhibited varied degree of urease inhibitory potential with IC₅₀ values 1.73–69.65 μM, if compared with standard thiourea having IC₅₀ value of 21.25 ± 0.15 μM. Among the series, eight derivatives 3, 6, 8, 10, 15, 17, 19, and 20 showed outstanding urease inhibitory potential with IC₅₀ values of 9.34 ± 0.02, 14.62 ± 0.03, 8.43 ± 0.01, 7.3 ± 0.04, 2.31 ± 0.002, 5.75 ± 0.003, 8.81 ± 0.005, and 1.73 ± 0.001 μM, respectively, which is better than the standard thiourea. The remaining analogs showed good to excellent urease inhibition. The binding interactions of these compounds were confirmed through molecular docking studies.     

Synthesis and antioxidant evaluation of (S,S)- and (R,R)-secoisolariciresinol diglucosides (SDGs)

Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7 through a concise route that involved chromatographic separation of diastereomeric diglucoside derivatives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties (EC₅₀ = 292.17 ± 27.71 μM and 331.94 ± 21.21 μM, respectively), which compared well with that of natural (S,S)-SDG-1 (EC₅₀ = 275.24 ± 13.15 μM). These values are significantly lower than those of ascorbic acid (EC₅₀ = 1129.32 ± 88.79 μM) and α-tocopherol (EC₅₀ = 944.62 ± 148.00 μM). Compounds (S,S)-SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural (S,S)-SDG-1: 3.68 ± 0.27; synthetic (S,S)-SDG-1: 2.09 ± 0.16; synthetic (R,R)-SDG-2: 1.96 ± 0.27], peroxyl [natural (S,S)-SDG-1: 2.55 ± 0.11; synthetic (S,S)-SDG-1: 2.20 ± 0.10; synthetic (R,R)-SDG-2: 3.03 ± 0.04] and DPPH [natural (S,S)-SDG-1: EC₅₀ = 83.94 ± 2.80 μM; synthetic (S,S)-SDG-1: EC₅₀ = 157.54 ± 21.30 μM; synthetic (R,R)-SDG-2: EC₅₀ = 123.63 ± 8.67 μM] radicals. These results confirm previous studies with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxidants and free radical scavengers for potential in vivo use.     

Design,synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors

Two series of afatinib derivatives bearing cinnamamide moiety (10a–n and 11a–h) were designed, synthesized and evaluated for the IC₅₀ values against four cancer cell lines (A549, PC-3, MCF-7 and Hela). Two selected compounds (10e, 10k) were further evaluated for the inhibitory activity against EGFR and VEGFR2/KDR kinases. Seven of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ values in single-digit μM to nanomole range. Three of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 10k showed the best activity against A549, PC-3, MCF-7 and Hela cancer cell lines and EGFR kinase, with the IC₅₀ values of 0.07 ± 0.02 μM, 7.67 ± 0.97 μM, 4.65 ± 0.90 μM and 4.83 ± 1.28 μM, which were equal to more active than afatinib (0.05 ± 0.01 μM, 4.1 ± 2.47 μM, 5.83 ± 1.89 μM and 6.81 ± 1.77 μM), respectively. Activity of compounds 10e (IC₅₀ 9.1 nM) and 10k (IC₅₀ 3.6 nM) against EGFR kinase were equal to the reference compound afatinib (IC₅₀ 1.6 nM). Structure–activity relationships (SARs) and docking studies indicated that replacement of the aqueous solubility 4-(dimethylamino)but-2-enamide group by cinnamamide moiety didn’t decrease the antitumor activity. The results suggested that methoxy substitution had a significant impact on the activity and methoxy substituted on C-4 or C-2,3,4 position was benefit for the activity.     

Synthesis,in vitro evaluation and molecular docking studies of thiazole derivatives as new inhibitors of α-glucosidase

A series of thiazole derivatives 1–21 were prepared, characterized by EI-MS and ¹H NMR and evaluated for α-glucosidase inhibitory potential. All twenty one derivatives showed good α-glucosidase inhibitory activity with IC₅₀ value ranging between 18.23 ± 0.03 and 424.41 ± 0.94 μM when compared with the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). Compound (8) (IC₅₀, 18.23 ± 0.03 μM) and compound (7) (IC₅₀ = 36.75 ± 0.05 μM) exhibited outstanding inhibitory potential much better than the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). All other analogs also showed good to moderate enzyme inhibition. Molecular docking studies were carried out in order to find the binding affinity of thiazole derivatives with enzyme. Studies showed these thiazole analogs as a new class of α-glucosidase inhibitors.     

Active compounds from a diverse library of triazolothiadiazole and triazolothiadiazine scaffolds: Synthesis,crystal structure determination,cytotoxicity, cholinesterase inhibitory activity,and binding mode analysis

In an effort to identify novel cholinesterase candidates for the treatment of Alzheimer’s disease (AD), a diverse array of potentially bioactive compounds including triazolothiadiazoles (4a–h and 5a–f) and triazolothiadiazines (6a–h) was obtained in good yields through the cyclocondensation reaction of 4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol (3) with various substituted aryl/heteroaryl/aryloxy acids and phenacyl bromides, respectively. The structures of newly prepared compounds were confirmed by IR, ¹H and ¹³C NMR spectroscopy and, in case of 4a, by single crystal X-ray diffraction analysis. The purity of the synthesized compounds was ascertained by elemental analysis. The newly synthesized conjugated heterocycles were screened for cholinesterase inhibitory activity against electric eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE). Among the evaluated hybrids, several compounds were identified as potent inhibitors. Compounds 5b and 5d were most active with an IC₅₀ value of 3.09 ± 0.154 and 11.3 ± 0.267 μM, respectively, against acetylcholinesterase, whereas 5b, 6a and 6g were most potent against butyrylcholinesterase, with an IC₅₀ of 0.585 ± 0.154, 0.781 ± 0.213, and 1.09 ± 0.156 μM, respectively, compared to neostigmine and donepezil as standard drugs. The synthesized heteroaromatic compounds were also tested for their cytotoxic potential against lung carcinoma (H157) and vero cell lines. Among them, compound 6h exhibited highest antiproliferative activity against H157 cell lines, with IC₅₀ value of 0.96 ± 0.43 μM at 1 mM concentration as compared to vincristine (IC₅₀ = 1.03 ± 0.04 μM), standard drug used in this study.     

Genetic parameters for carcase measurements and age at slaughter in commercial cattle

Genetic parameters were estimated for cold carcase weight (CCW), carcase conformation (CON), carcase fat class (FAT), age at slaughter (AGE) and average daily carcase gain (ADCG) in 14 common UK breeds of cattle. These included crossbred animals but purebred datasets were also analysed for the most populous sire-breeds. Heritability estimates for beef breeds that were significant ranged from 0.24 to 0.44, 0.12 to 0.35, 0.12 to 0.36, 0.15 to 0.38 and 0.26 to 0.43 for CCW, CON, FAT, AGE and ADCG, respectively. For Holstein-Friesian, a dairy breed, heritability estimates were consistently lower than most beef breeds with estimates of 0.12, 0.13, 0.13, 0.06 and 0.15 for CCW, CON, FAT, AGE and ADCG, respectively. In all breed groups, genetic correlations were positive between CCW, CON and ADCG. In general, genetic correlations were moderate between CCW and CON (0.13 to 0.77), moderate to strong between CCW and ADCG (0.57 to 0.98) and weak or moderate between CON and ADCG (0.12 to 0.82). Genetic correlations for FAT with CCW (−  0.20 to −  0.42) and CON (−  0.16 to −  0.52) tended to be negative in the beef breed but were positive in the dairy breed, although not significant between CCW and FAT. For most beef breeds genetic correlations between AGE and carcase traits were not significant with the exceptions of AGE and CCW for Simmental (−  0.15) and Salers (−  0.24), AGE and CON for Limousin (0.15) and Simmental (0.14) and AGE and FAT from three sire-breeds (−  0.17 to −  0.35). However, the correlation between AGE and ADCG was negative and moderate to strong in magnitude (−  0.23 to −  0.67) in all beef breeds as expected since faster-growing animals reach slaughter age earlier. For Holstein-Friesian, all genetic correlations with AGE were negative and moderate to strong. Genetic correlations indicate that selection for increased carcase weight should simultaneously increase growth rate and improve conformation in all breeds and reduce carcase fatness in the majority of beef breeds. The results indicate that there is genetic variation in all five traits suitable for undertaking genetic improvement of carcase traits and age at slaughter; however, there are apparent breed differences. The use of abattoir-derived phenotypes for undertaking genetic improvement is an example where the supply chain can work together to share information to enable the cattle industry to move forward.     

[RuIII(medtra)(H2O)] (medtra = N-methylethylenediaminetriacetate) complex – A highly efficient NO inhibitor with low toxicity

Stopped-flow kinetic measurements were used to compare the reactivities of [Ru(medtra)(H₂O)] (medtra³⁻ = N-methylethylenediaminetriacetate) (1) and [Ru(hedtra)(H₂O)] (2) (hedtra³⁻ = N-hydroxyethylethylenediaminetriacetate) with NO in aqueous solution at 15 °C, pH 7.2 (phosphate buffer). The measured second-order rate constants (3 × 10³ and 6 × 10⁴ M⁻¹ s⁻¹ for 1 and 2, respectively) are three to four order of magnitudes lower than that for the reaction between [Ru^III(edta)(H₂O)]⁻ (3) with NO. However, NO scavenging studies of complexes 1–3, conducted by measuring the difference in nitrite production between treated and untreated murine macrophage cells, revealed that despite being less kinetically reactive toward NO, the [Ru(medtra)(H₂O)] complex exhibited the highest NO scavenging ability and lowest toxicity of compounds 1–3.     

Design,synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a–e, 13a–f, 14a–f and 15a–i) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC₅₀ values of 1.04 ± 0.11 μM, 0.02 ± 0.01 μM and 9.11 ± 0.55 μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC₅₀ values: 0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.     

Unsymmetrically disubstituted urea derivatives: A potent class of antiglycating agents

A series of unsymmetrically disubstituted urea derivatives 1–28 has been synthesized and screened for their antiglycation activity in vitro. Compounds 26 (IC₅₀ = 4.26 ± 0.25 μM), 1 (IC₅₀ = 5.8 ± 0.08 μM), 22 (IC₅₀ = 4.26 ± 0.25 μM), 6 (IC₅₀ = 6.4 ± 0.02 μM), 5 (IC₅₀ = 6.6 ± 0.26 μM), 2 (IC₅₀ = 7.02 ± 0.31 μM), 3 (IC₅₀ = 7.14 ± 0.84 μM), 27 (IC₅₀ = 7.27 ± 0.36 μM), 4 (IC₅₀ = 8.16 ± 1.04 μM), 21 (IC₅₀ = 8.4 ± 0.15 μM), 23 (IC₅₀ = 9.0 ± 0.35 μM) and 13 (IC₅₀ = 15.22 ± 6.7 μM) showed an excellent antiglycation activity far better than the standard (rutin, IC₅₀ = 41.9 ± 2.3 μM). This study thus provides a series of potential molecules for further studies of antiglycation agents.     

Novel biphenyl bis-sulfonamides as acetyl and butyrylcholinesterase inhibitors: Synthesis,biological evaluation and molecular modeling studies

A series of new biphenyl bis-sulfonamide derivatives 2a–3p were synthesized in good to excellent yield (76–98%). The inhibitory potential of the synthesized compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was investigated. Most of the screened compounds showed modest in vitro inhibition for both AChE and BChE. Compared to the reference compound eserine (IC₅₀ 0.04 ± 0.0001 μM for AChE) and (IC₅₀ 0.85 ± 0.0001 μM for BChE), the IC₅₀ values of these compounds were ranged from 2.27 ± 0.01 to 123.11 ± 0.04 μM for AChE and 7.74 ± 0.07 to <400 μM for BuChE. Among the tested compounds, 3p was found to be the most potent against AChE (IC₅₀ 2.27 ± 0.01 μM), whereas 3g exhibited the highest inhibition for BChE (IC₅₀ 7.74 ± 0.07 μM). Structure–activity relationship (SAR) of these compounds was developed and elaborated with the help of molecular docking studies.     

Synthesis of alpha amylase inhibitors based on privileged indole scaffold

Twenty five derivatives of indole carbohydrazide (1–25) had been synthesized. These compounds were characterized using ¹H NMR and EI-MS, and further evaluated for their α-amylase inhibitory potential. The analogs (1–25) showed varying degree of α-amylase inhibitory potential.ranging between 9.28 and 599.0 µM when compared with standard acarbose having IC₅₀ value 8.78 ± 0.16 µM. Six analogs, 25 (IC₅₀ = 9.28 ± 0.153 µM), 22 (IC₅₀ = 9.79 ± 0.43 µM), 4 (IC₅₀ = 11.08 ± 0.357 µM), 1 (IC₅₀ = 12.65 ± 0.169 µM), 8 (IC₅₀ = 21.37 ± 0.07 µM) and 14 (IC₅₀ = 43.21 ± 0.14 µM) showed potent α-amylase inhibition as compared to the standard acarbose (IC₅₀ = 8.78 ± 0.16 µM). All other analogs displayed good to moderate inhibitory potential. Structure-activity relationship was established through the interaction of the active compounds with enzyme active site with the help of docking studies.