Design and synthesis of biphenyl derivatives as mushroom tyrosinase inhibitors

Two new series of biphenyls, analogs of aglycone of natural product fortuneanoside E, were prepared using Suzuki–Miyaura cross-coupling and selective magnesium iodide demethylation/debenzylation, and their mushroom tyrosinase inhibitory activity was evaluated. Most of the 4-hydroxy-3,5-dimethoxyphenyl biphenyl compounds (series II, 20–36) were in general more active than 3,4,5-trimethoxyphenyl biphenyl compounds (series I, 1–19). Structure–activity relationships study showed that monosaccharide substituents, such as glucose, were not necessary and the presence of 4-hydroxy-3,5-dimethoxyphenyl moiety was crucial for inhibitory activity. Among the compounds synthesised, compound 21 (IC₅₀ = 0.02 mM) was found to be the most active one, which exhibited an activity that was 7 times higher than that of fortuneanoside E (IC₅₀ = 0.14 mM) and 10 times higher than that of arbutin (IC₅₀ = 0.21 mM), known as potent tyrosinase inhibitors. The inhibition kinetics analyzed by Lineweaver–Burk plots revealed that compound 21 was a competitive inhibitor (K_i = 0.015 mM).     

Synthesis,activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives

Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC₅₀ values of 6.35 ± 0.43 μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC₅₀ values of 3.39 ± 0.37 μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What’s more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.     

Design,synthesis and anticholinesterase activity of a novel series of 1-benzyl-4-((6-alkoxy-3-oxobenzofuran-2(3H)-ylidene) methyl) pyridinium derivatives

A novel series of benzofuranone-ylidene-methyl benzylpyridinium derivatives (6a–u) were synthesized as acetylcholinesterase inhibitors. The anticholinesterase activity of synthesized compounds was measured using colorimetric Ellman’s method. It was revealed that some synthesized compounds exhibited high anticholinesterase activity, among them compound 6b was the most active compound (IC₅₀ = 10 ± 6.87 nM).     

Synthesis and antimicrobial activity of polyhalo isophthalonitrile derivatives

A series of polyhalo isophthalonitrile derivatives (3 and 4) that incorporate a variety of substituents at the 2-, 4-, 5- and/or 6-positions of the isophthalonitrile moieties have been designed and synthesized. These derivatives were evaluated for their antimicrobial activity against Staphylococcus aureus, Bacillus cereus (Gram-positive bacteria), Escherichia coli, Pseudomonas aeruginosa (Gram-negative bacteria); and Candida albicans (Fungi). Compounds 3 and 4 showed stronger inhibition of Gram-positive bacteria and fungi growth, and the antimicrobial ability of compound 3j (a 4-(benzylamino)-5-chloro-2,6-difluoro analog, MIC[SA] = 0.5 μg/mL; MIC[BC] = 0.4 μg/mL; MIC[CA] = 0.5 μg/mL) were close to nofloxacin and fluconazole and identified as the most potent antimicrobial agents in the series. The preliminary analysis of structure–activity relationships is also discussed.     

Comparing anti-HIV,antibacterial, antifungal,micellar, and cytotoxic properties of tricarboxylato dendritic amphiphiles

Three series of homologous dendritic amphiphiles—RCONHC(CH₂CH₂COOH)₃, 1(n); ROCONHC(CH₂CH₂COOH)₃, 2(n); RNHCONHC(CH₂CH₂COOH)₃, 3(n), where R = n-C_nH_2n+1 and n = 13–22 carbon atoms—were assayed for their potential to serve as antimicrobial components in a topical vaginal formulation. Comparing epithelial cytotoxicities to the ability of these homologues to inhibit HIV, Neisseria gonorrhoeae, and Candida albicans provided a measure of their prophylactic/therapeutic potential. Measurements of the ability to inhibit Lactobacillus plantarum, a beneficial bacterium in the vagina, and critical micelle concentrations (CMCs), an indicator of the potential detergency of these amphiphiles, provided additional assessments of safety. Several amphiphiles from each homologous series had modest anti-HIV activity (EC₅₀ = 110–130 μM). Amphiphile 2(18) had the best anti-Neisseria activity (MIC = 65 μM), while 1(19) and 1(21) had MICs against C. albicans of 16 and 7.7 μM, respectively. Two measures of safety showed promise as all compounds had relatively low cytotoxic activity (EC₅₀ = 210–940 μM) against epithelial cells and low activity against L. plantarum, 1(n), 2(n), and 3(n) had MICs ? 490, 1300, and 940 μM, respectively. CMCs measured in aqueous triethanolamine and in aqueous potassium hydroxide showed linear dependences on chain length. As expected, the longest chain in each series had the lowest CMC—in triethanolamine: 1(21), 1500 μM; 2(22), 320 μM; 3(22), 340 μM, and in potassium hydroxide: 1(21), 130 μM; 3(22), 40 μM. The CMC in triethanolamine adjusted to pH 7.4 was 400 μM for 1(21) and 3900 μM for 3(16). The promising antifungal activity, low activity against L. plantarum, relatively high CMCs, and modest epithelial cytotoxicity in addition to their anti-Neisseria properties warrant further design studies with dendritic amphiphiles to improve their safety indices to produce suitable candidates for antimicrobial vaginal products.     

Synthesis,molecular docking and α-glucosidase inhibition of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides

A novel series of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides 5a–5q have been synthesized and evaluated for their α-glucosidase inhibitory activity. All newly synthesized compounds exhibited potent α-glucosidase inhibitory activity in the range of IC₅₀ = 12.46 ± 0.13–72.68 ± 0.20 μM, when compared to the standard drug acarbose (IC₅₀ = 817.38 ± 6.27 μM). Among the series, compound 5j (12.46 ± 0.13 μM) with strong electron-withdrawing nitro group on the arylacetamide moiety was identified as the most potent inhibitor of α-glucosidase. Molecular docking study was carried out to explore the binding interactions of these compounds with α-glucosidase. Our study identifies a novel series of potent α-glucosidase inhibitors for further investigation.     

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.     

Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein

Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC₅₀ of 1.5 nM and 1.2 nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC₅₀’s of 10.9 nM and 6.1 nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC₅₀’s = 10.2 and 30.4 nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein.     

Synthesis and biological evaluation of a new series of cinnamic acid amide derivatives as potent haemostatic agents containing a 2-aminothiazole substructure

Ten new cinnamic acid derivatives containing a 2-aminothiazole substructure were designed and synthesized. This series of compounds exhibited good thermostabilities as demonstrated by thermogravimetric analysis. In coagulation assays (prothrombin time, activated partial thromboplastin time and thrombin time) in vitro, most compounds demonstrated excellent activities to promote blood coagulation. Among the studied series, compounds N1, N4, N5 and W5 exhibited a significant coagulation activity. Further studies indicated that compound N5 (IC₅₀ = 1.87 μmol/L) displayed the most suitable efficacy of promoting platelet aggregation than the clinically used haemostatic drug etamsylate (IC₅₀ = 46.22 μmol/L). Furthermore, the relationship between the functional groups of the compounds and the corresponding blood coagulant activity was explored in this study.     

Synthesis and evaluation of novel triazoles and mannich bases functionalized 1,4-dihydropyridine as angiotensin converting enzyme (ACE) inhibitors

A series of novel diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate embedded triazole and mannich bases were synthesized, and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. Screening of above synthesized compounds for ACE inhibition showed that triazoles functionalized compounds have better ACE inhibitory activity compared to that of mannich bases analogues. Among all triazoles we found 6h, 6i and 6j to have good ACE inhibition activity with IC₅₀ values 0.713 μM, 0.409 μM and 0.653 μM, respectively. Among mannich bases series compounds, only 7c resulted as most active ACE inhibitor with IC₅₀ value of 0.928 μM.     

Tetrahydropyridine derivatives with inhibitory activity on the production of proinflammatory cytokines: Part 2

We previously reported a novel pyrrole derivative 1 which possesses a tetrahydropyridine group at the β-position with a proinflammatory cytokine TNFα production inhibitor. Herein, we report the synthesis and biological activity of N- and α-position substituted tetrahydropyridine derivatives. In this series, we found that compound 3o showed good inhibitory activity in vitro (inhibition of lipopolysaccharide (LPS)-induced TNFα production in human whole blood, IC₅₀ = 0.44 μM) and compound 3i demonstrated potent inhibitory activity in vivo (inhibition of LPS-induced TNFα production in mice, ID₅₀ = 1.42 mg/kg).     

Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-κB inhibitor,DMAPT (LC-1)

A series of aminoparthenolide analogs (6–37) were synthesized and evaluated for their anti-leukemic activity. Eight compounds exhibited good anti-leukemic activity with LD₅₀’s in the low μM range (1.5–3.0 μM). Compounds 16, 24 and 30 were the most potent compounds in the series, causing greater than 90% cell death at 10 μM concentration against primary AML cells in culture, with LD₅₀ values of 1.7, 1.8 and 1.6 μM.     

Synthesis and structure–activity relationships of N-benzyl-N-(X-2-hydroxybenzyl)-N′-phenylureas and thioureas as antitumor agents

Two series of novel N-benzyl-N-(X-2-hydroxybenzyl)-N′-phenylureas and thioureas (1a–18a; 1b–18b) as potential EGFR and HER-2 kinase inhibitors have been discovered. These compounds displayed good EGFR and HER-2 inhibitory activity and the SARs are also been studied. Especially compound 7b demonstrated significant EGFR and HER-2 inhibitory activity (IC₅₀ = 0.08 μM for EGFR and IC₅₀ = 0.35 μM for HER-2). Docking simulation was performed to position compound 7b into the EGFR active site to determine the probable binding conformation and antiproliferative assay results indicating that these series of urea and thioureas own high antiproliferative activity against MCF-7. Above all, thiourea 7b would be a potential anticancer agent deserves further research.     

Synthesis,and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (14a–e, 15a–g, 16a–e and 17a–g) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds (15e, 16a–b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC₅₀ values of 0.14 ± 0.08 μM, 0.24 ± 0.07 μM and 0.02 ± 0.01 μM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (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 the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What’s more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity.     

Structural characteristics of thiosemicarbazones as inhibitors of melanogenesis

A series of thiosemicarbazones 2(e–s) have been synthesized and studied their structure–activity relationship as melanogenesis inhibitor. Among them, (Z)-2-(naphthalen-1-ylmethylene)hydrazinecarbothioamide (2q, >100% inhibition at 10 μM, IC₅₀ = 1.1 μM, C log P = 3.039) showed the strongest inhibitory activity. Regarding their structure–activity relationship, the hydrophobic substituents regardless the position on phenyl ring of benzaldehyde thiosemicarbazones enhance the inhibitory activity. Furthermore, the aromatic group of benzaldehydethiosemicarbazones can be replaced with sterically bulky cyclohexyl. Thus, hydrophobicity of the aryl or alkyl group on hydrazine of thiosemicarbazones is determinant factor for their inhibitory activity in melanogenesis rather than planarity.     

Synthesis and anti-parasitic activity of a novel quinolinone–chalcone series

A series of novel quinolinone–chalcone hybrids and analogues were designed, synthesized and their biological activity against the mammalian stages of Trypanosoma brucei and Leishmania infantum evaluated. Promising molecular scaffolds with significant microbicidal activity and low cytotoxicity were identified. Quinolinone–chalcone 10 exhibited anti-parasitic properties against both organisms, being the most potent anti-L. infantum agent of the entire series (IC₅₀ value of 1.3 ± 0.1 μM). Compounds 4 and 11 showed potency toward the intracellular, amastigote stage of L. infantum (IC₅₀ values of 2.1 ± 0.6 and 3.1 ± 1.05 μM, respectively). Promising trypanocidal compounds include 5 and 10 (IC₅₀ values of 2.6 ± 0.1 and 3.3 ± 0.1 μM, respectively) as well as 6 and 9 (both having IC₅₀ values of <5 μM). Chemical modifications on the quinolinone–chalcone scaffold were performed on selected compounds in order to investigate the influence of these structural features on antiparasitic activity.     

Synthesis and biological activity of oxadiazole and triazolothiadiazole derivatives as tyrosinase inhibitors

A series of 16 oxadiazole and triazolothiadiazole derivatives were designed, synthesized and evaluated as mushroom tyrosinase inhibitors. Five derivatives were found to display high inhibition on the tyrosinase activity ranging from 0.87 to 1.49 μM. Compound 5 exhibited highest tyrosinase inhibitory activity with an IC₅₀ value of 0.87 ± 0.16 μM. The in silico protein–ligand docking using autodock 4.1 was successfully performed on compound 5 with significant binding energy value of ?5.58 kcal/mol. The docking results also showed that the tyrosinase inhibition might be due to the metal chelating effect by the presence of thione functionality in compounds 1–5. Further studies revealed that the presence of hydrophobic group such as cycloamine derivatives played a major role in the inhibition. Piperazine moiety in compound 5 appeared to be involved in an extensive hydrophobic contact and a 2.9 Å hydrogen bonding with residue Glu 182 in the active site.     

Synthesis, molecular modeling and biological evaluation of guanidine derivatives as novel antitubulin agents

A series of novel chalcone guanidine derivatives (4a–4q) have been designed and synthesized, and their biological activity were also evaluated as potential antiproliferative and antitubulin polymerization inhibitors. Compound 4q showed the most potent biological activity (IC₅₀ = 0.09 ± 0.01 μM for MCF-7 and IC₅₀ = 8.4 ± 0.6 μM for tubulin), which is comparable to the positive controls. Docking simulation was performed to position compound 4q into the colchicine binding site to determine the probable binding model, which suggested probable inhibition mechanism.     

Synthesis of new triazole acetamides with inotropic effects

A series of new triazole acetamides 5a–w were synthesized and evaluated for their positive inotropic activity of left atrium stroke volume on isolated rabbit-heart preparations. The majority of the derivatives presented favorable in vitro activity compared with the reference drug, milrinone. Among them triazole acetamide 5a was identified as the most potent with 20.29 ± 0.18% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10^–5 M. The chronotropic effects of the compounds having inotropic effects were also evaluated.