Design, synthesis, spectroscopic characterization, in vitro tyrosinase inhibition, antioxidant evaluation, in silico and kinetic studies of substituted indole-carbohydrazides.

In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including 1H NMR, 13C NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC50 values in the range of 0.070 to > 100 µM. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC50 = 0.070 µM), 8f (R = 4-OH, IC50 = 0.072 µM), and 19e (IC50 = 0.19 µM) with para-OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 µM and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 µM, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281.

Evaluating the effects of disubstituted 3-hydroxy-1H-pyrrol-2(5H)-one analog as novel tyrosinase inhibitors.

In the present study, a series of 3-hydroxy-1H-pyrrol-2(5H)-one derivative were rationally designed and synthesized. The structure of targeted compounds was confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. Next, all derivatives were evaluated as tyrosinase inhibitors, and among the synthesized derivatives, compound 6a was proved to be the most potent inhibitor with an IC50 value of 6.98 ± 1.05 µM. Kinetic study of compound 6a confirmed the mixed type of inhibitory activity towards tyrosinase. Furthermore, the results of the molecular docking study showed that this compound fitted well in the active site of tyrosinase and exhibited interaction with important residues of the binding site.

5-Oxo-hexahydroquinoline and 5-oxo-tetrahydrocyclopentapyridine derivatives as promising antiproliferative agents with potential apoptosis-inducing capacity.

Discovery of novel anticancer agents is of crucial importance to expand the therapeutic options for cancer patients. In this study, a series of 49 5-oxo-hexahydroquinoline and 5-oxo-tetrahydrocyclopentapyridine analogs, containing different pyridine alkyl carboxylates at C3 and various aliphatic, aromatic, and heteroaromatic substitutions at the C4 position of the central core, were synthesized. The target compounds were tested for antiproliferative effect against three human cancer cell lines including MOLT-4 (acute lymphoblastic leukemia), K562 (chronic myelogenous leukemia), and MCF-7 (breast adenocarcinoma) by MTT assay, and the effect of the most potent derivatives on cell cycle was evaluated by RNase/propidium iodide (PI) flow cytometric assay. Generally, 5-oxo-hexahydroquinoline derivatives (E series) possessed superior antiproliferative activities compared to their 5-oxo-tetrahydrocyclopentapyridine counterparts (F series). 5-Oxo-hexahydroquinoline compounds bearing 2-pyridyl propyl carboxylate (group D) and 3-pyridyl propyl carboxylate (group E) were better antiproliferative agents than those bearing other pyridyl alkyl carboxylates. Five best compounds with IC50 values in the range of 9.5-22.9 µM against MOLT-4 cells were selected for cell-cycle analysis, which revealed that derivatives D5, E3, and E5 with 2,3-dichlorophenyl, 3-nitrophenyl, and 2-nitrophenyl substitutions at C4 position, respectively, may induce apoptosis in MOLT-4 cells. Molecular docking analysis, which was employed to make some predictions on the interaction of the most active derivatives with the binding site of Bcl-2 and Bcl-xL proteins, suggested that the compounds may be well accommodated within the binding sites of these anti-apoptotic proteins via hydrogen-bonding and hydrophobic interactions. The findings of this study present 5-oxo-hexahydroquinoline derivatives as antiproliferative agents with potential apoptosis-inducing ability in cancer cells.

Rational Design, Synthesis, in Vitro, and in Silico Studies of Chlorophenylquinazolin-4(3H)-One Containing Different Aryl Acetohydrazides as Tyrosinase Inhibitors.

Tyrosinase plays a pivotal role in the hyperpigmentation and enzymatic browning of fruit and vegetable. Therefore, tyrosinase inhibitors can be of interest in industries as depigmentation compounds as well as anti-browning agents. In the present study, a series of chlorophenylquinazolin-4(3H)-one derivative were rationally designed and synthesized. The formation of target compounds was confirmed by spectral characterization techniques such as IR, 1 H-NMR, 13 C-NMR, and elemental analysis. Among the synthesized derivatives, compound 8l was proved to be the most potent inhibitor with an IC50 value of 25.48±1.19 µM. Furthermore, the results of the molecular docking study showed that this compound fitted well in the active site of tyrosinase with the binding score of -10.72.

The natural-based optimization of kojic acid conjugated to different thio-quinazolinones as potential anti-melanogenesis agents with tyrosinase inhibitory activity.

Melanin pigment and melanogenesis are a two-edged sword. Melanin has a radioprotection role while melanogenesis has undesirable effects. Targeting the melanogenesis pathway, a series of kojyl thioether conjugated to different quinazolinone derivatives were designed, synthesized, and evaluated for their inhibitory activity against mushroom tyrosinase. All the synthesized compounds were screened for their anti-tyrosinase activity and all derivatives displayed better potency than kojic acid as the positive control. In this regard, 5j and 5h as the most active compounds showed an IC50 value of 0.46 and 0.50 µM, respectively. In kinetic evaluation against tyrosinase, 5j depicted an uncompetitive inhibition pattern. Designed compounds also exhibited mild antioxidant capacity. Moreover, 5j and 5h achieved good potency against the B16F10 cell line to reduce the melanin content, whilst showing limited toxicity against malignant cells. The proposed binding mode of new inhibitors evaluated through molecular docking was consistent with the results of structure-activity relationship analysis.

Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations.

A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of l-dopa and l-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC50 value of 0.11 µM and 0.17 µM in the presence of l-tyrosine and l-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC50 value of 9.28 µM for l-tyrosine and 9.30 µM for l-dopa. According to Lineweaver-Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC50 value of 68.43 µM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.

4H-benzochromene derivatives as novel tyrosinase inhibitors and radical scavengers: synthesis, biological evaluation, and molecular docking analysis.

A series of ethyl 2-amino-4H-benzo[h]chromene-3-carboxylate derivatives, having phenyl ring with diverse substituents at C4 position of 4H-benzochromene nucleus, were synthesized via one-pot three-component reaction between various aromatic aldehydes, α-naphthol, and ethyl cyanoacetate. The synthesized compounds were screened for their antityrosinase activity. Compound 4i, bearing 4-dimethylamino substitution on C4-phenyl ring, was the most potent tyrosinase inhibitor (IC50 = 34.12 µM). The inhibition kinetic analysis of 4i indicated that the compound was a competitive tyrosinase inhibitor. Compounds 4a, 4g, 4i and 4j were the effective radical scavengers with EC50s in the range of 0.144-0.943 mM. According to the in silico drug-like and ADME predictions, 4i can be considered as a suitable candidate. Molecular docking results confirmed that the derivative was well accommodated within the mushroom tyrosinase binding site. Therefore, 4i can be introduced as a novel tyrosinase inhibitor that might be a promising lead in medicine, cosmetics, and food industry.

Design, synthesis, in vitro and in silico studies of novel Schiff base derivatives of 2-hydroxy-4-methoxybenzamide as tyrosinase inhibitors.

Due to the fact that tyrosinase is responsible for biosynthesis and regulation of melanins and browning food products, tyrosinase inhibitors can be favorable agents in cosmetics and medicinal industries. A series of novel 2-hydroxy-4-methoxybenzohydrazide were designed, synthesized, and their new application as tyrosinase inhibitors was also disclosed. Based on in vitro tyrosinase inhibitory assay, 4d as the strongest inhibitor of tyrosinase with an IC50 value of 7.57 µM showed approximately 2.5-fold better inhibition than kojic acid as positive control followed by two compounds 4b (IC50  = 8.19 ± 0.25 µM) and 4j (IC50  = 8.92 ± 0.016) which displayed preferable tyrosinase inhibitory activity. Detailed investigations on the mechanism of action of the 4d reported mix type of inhibition. More importantly, molecular modeling assessments proposed the ability of 4d for potential interaction with Cu (metal)-His (residue) within tyrosinase active site. Overall, 4d is a promising candidate for the development of anti-tyrosinase agents.

Novel 2-amino-1,4-naphthoquinone hybrids: Design, synthesis, cytotoxicity evaluation and in silico studies.

In the present work, a novel series of 2-amino-1,4-naphthoquinones bearing oxyphenyl moiety (5a-5m) were designed and synthesized via a two-step route and evaluated for their in vitro cytotoxic activity against three different cancer cell lines (MCF-7, HL-60 and U937) and normal human cell line (HEK-293) by MTT assay. Compounds 5b (4-nitro-benzyl-) and 5k (4-bromo-benzyl-) were identified to possess the highest cytotoxic activity against MCF-7 cancerous cells (IC50 values of 27.76 and 27.86 µM, respectively). At the same time, none of the compounds exert significant toxicity against HEK-293 normal human kidney cells. Cell cycle analysis showed that the selected derivatives increased the population of MCF-7 cells in the S phase at 25 and 50 µM concentrations. Annexin V-FITC/PI staining assay also confirmed that compounds 5b and 5k induced apoptosis in the cell death pathway. Molecular docking and molecular dynamics studies were also performed to evaluate the probable interactions between the hybrids and human ATP binding domain of topo IIα protein. Our findings may provide new insight for further development of novel naphthoquinone-containing compounds.

One-pot synthesis of thioxo-tetrahydropyrimidine derivatives as potent ß-glucuronidase inhibitor, biological evaluation, molecular docking and molecular dynamics studies.

A series of N,N-diethyl phenyl thioxo-tetrahydropyrimidine carboxamide have been synthesized and investigated for their ß-glucuronidase inhibitory activities. All molecules exhibited excellent inhibition with IC50 values ranging from 0.35 to 42.05 µM and found to be even more potent than the standard d-saccharic acid. Structure-activity relationship analysis indicated that the meta-aryl-substituted derivatives significantly influenced ß-glucuronidase inhibitory activities while the para-substitution counterpart outperforming moderate potency. The most potent compound in this series was 4g bearing thiophene motif with IC50 of 0.35 ± 0.09 µM. To verify the SAR, molecular docking and molecular dynamics studies were also performed.

Novel small molecule therapeutic agents for Alzheimer disease: Focusing on BACE1 and multi-target directed ligands.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that effects 50 million people worldwide. In this review, AD pathology and the development of novel therapeutic agents targeting AD were fully discussed. In particular, common approaches to prevent Aß production and/or accumulation in the brain including α-secretase activators, specific γ-secretase modulators and small molecules BACE1 inhibitors were reviewed. Additionally, natural-origin bioactive compounds that provide AD therapeutic advances have been introduced. Considering AD is a multifactorial disease, the therapeutic potential of diverse multi target-directed ligands (MTDLs) that combine the efficacy of cholinesterase (ChE) inhibitors, MAO (monoamine oxidase) inhibitors, BACE1 inhibitors, phosphodiesterase 4D (PDE4D) inhibitors, for the treatment of AD are also reviewed. This article also highlights descriptions on the regulator of serotonin receptor (5-HT), metal chelators, anti-aggregants, antioxidants and neuroprotective agents targeting AD. Finally, current computational methods for evaluating the structure-activity relationships (SAR) and virtual screening (VS) of AD drugs are discussed and evaluated.

5,6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer's disease modifying agents.

In this study, new derivatives of 5,6-diphenyl triazine-thio methyl triazole hybrid were designed, synthesized and evaluated as multifunctional agents for Alzheimer's disease. Among all synthesized compounds, 4a and 4h showed the best inhibitory activities against BACE1 (40% and 37.5% µM inhibition at 50 µM, respectively). Molecular docking studies showed that compound 4a occupied the entire BACE1 enzyme and the thio triazine fragment deeply penetrates into S2 binding site via two hydrogen bonds with Thr72 and Gln73 amino acids. Different aromatic moieties occupy S'2 pocket via hydrophobic interactions. 6-Phenyl ring also had a potential hydrophobic interaction with S1 pocket. In vitro ChE inhibitory assay demonstrated that most of the derivatives exhibited more selectivity toward BuChE than AChE. 4c as the most potent BuChE inhibitor displayed an IC50 value of 6.4 µM, and 4b exhibited AChE inhibitory activity with 25.1% inhibition at 50 µM. Further, molecular docking studies revealed that the thiazolidinones moiety plays a key role in the inhibition mechanism by well fitting into the enzyme bounding pocket. Moreover, molecular docking study of 4a, 4b and 4c with ChE active site was also performed.

A Series of Benzylidenes Linked to Hydrazine-1-carbothioamide as Tyrosinase Inhibitors: Synthesis, Biological Evaluation and Structure-Activity Relationship.

Tyrosinase is a type 3 copper enzyme responsible for skin pigmentation disorders, skin cancer, and enzymatic browning of vegetables and fruits. In the present article, 12 small molecules of 2-benzylidenehydrazine-1-carbothioamide were designed, synthesized and evaluated for their anti-tyrosinase activities followed by molecular docking and pharmacophore-based screening. Among synthesized thiosemicarbazone derivatives, one compound, (2E)-2-[(4-nitrophenyl)methylidene]hydrazine-1-carbothioamide, is the strongest inhibitor of mushroom tyrosinase with IC50 of 0.05 µM which demonstrated a 128-fold increase in potency compared to the positive control. Kinetic studies also revealed mix type inhibition by this compound. Docking studies confirmed the complete fitting of the synthesized compounds into the tyrosinase active site. The results underline the potential of 2-benzylidenehydrazine-1-carbothioamides as potent pharmacophore to extend the tyrosinase inhibition in drug discovery.

1,2,3-Triazole-linked 5-benzylidene (thio)barbiturates as novel tyrosinase inhibitors and free-radical scavengers.

In this study, benzyl-1,2,3-triazole-linked 5-benzylidene (thio)barbiturate derivatives 7a-d and 8a-h were designed as potential tyrosinase inhibitors and free-radical scavengers. The twelve derivatives were synthesized via the [3+2] cycloaddition reaction of the corresponding benzyl azide as a dipole and the corresponding alkyne as a dipolarophile in the presence of copper(I) species, generated in situ from copper(II)/ascorbate. The thiobarbiturate derivative 8h and the barbiturate derivative 8b bearing 4-fluoro and 4-bromo groups on the benzyl-triazole moiety were found to be the most potent tyrosinase inhibitors with IC50 values of 24.6 ± 0.9 and 26.8 ± 0.8 µM, respectively. Almost all the compounds showed a good radical scavenging activity with EC50 values in the range of 29.9-324.9 µM. Derivatives 7a, 8f, and 8h were the most potent free-radical scavengers with EC50 values of 29.9 ± 0.8, 36.8 ± 0.9, and 39.2 ± 1.1 µM, respectively. The kinetic analysis revealed that compound 8h was a mixed-type tyrosinase inhibitor. The molecular docking analysis indicated that 8b and 8h were well accommodated in the active site of the tyrosinase enzyme and possessed the most negative binding energy values of -8.55 and -8.81 kcal/mol, respectively. Moreover, it was found that the two residues, Asn81 and Glu322, played a significant role in forming stable enzyme-inhibitor complexes.

5-Oxo-hexahydroquinoline Derivatives and Their Tetrahydroquinoline Counterparts as Multidrug Resistance Reversal Agents.

Cancer is a leading cause of death worldwide. Multidrug resistance (MDR) is a main reason of chemotherapy failure in many patients and is often related to overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1). Agents that are capable of modulation of the activity of these transporters might be effective in overcoming MDR. In this study, a new set of 1,4,5,6,7,8-hexahydro 5-oxo quinoline-3-carboxamide derivatives bearing 4-methylthiazole moiety and their tetrahydroquinoline counterparts were synthesized. MDR reversal activity of these 16 newly synthesized derivatives was tested in P-gp overexpressing MES-SA-DX5 human uterine sarcoma cells by flow cytometric determination of Rhodamine123 efflux. The effect of the most potent compounds in induction of apoptosis and alterations of cell cycle was examined in these cells by a flow cytometric method. Inherent cytotoxicity of the synthesized compounds was evaluated against MCF-7, A-549 and K562 cancer cell lines, as well as MES-SA-DX5 and their parental non-resistant MES-SA and also HEK-293 non-cancerous cells by MTT assay. Compounds A1 and A2 with 5-oxo-hexahydroquinoline structure bearing 2,4-dichlorophenyl and 4-bromophenyl moieties, respectively, and their tetrahydroquinoline counterparts B1 and B2 significantly blocked P-gp efflux, induced apoptosis and showed the highest cytotoxicities against MES-SA-DX5 cells. However, only A2 and B2 compounds were relatively selective against cancer and MDR cells as compared to non-resistant and non-cancerous cells. These findings demonstrate that 5-oxo-hexahydroquinoline and 5-oxo-tetrahydroquinoline derivatives represent promising agents with therapeutic potential in drug resistant cancers.

Prediction of cytotoxic activity of a series of 1H-pyrrolo[2,3-b]pyridine derivatives as possible inhibitors of c-Met using molecular fingerprints.

Cancer is a leading cause of death all over the world. HGF/MET signaling pathway is involved in many cancers and its inhibition has great potential as an effective therapeutic intervention. A series of 1H-pyrrolo [2,3-b]pyridine derivatives has recently been identified with cytotoxic activity, and most of them exhibited considerable potencies with IC50 values under 10 µM. The present study was carried out with the specific aim to shed light upon the quantitative structure activity relationship (QSAR) to design and predict the activity of new potent inhibitors using molecular fingerprints and some 2D and 3D descriptors. The built model was statistically significant in terms of R2 = 0.90 and R2pred = 0.91 values. Fingerprint PubchemFP759 (1-chloro-2-methylbenzene) was the most effective fragment in the biological activity and just appeared in the most active compound 7j with a pIC50 value of 8.0. A similarity search study was applied based on compounds 7c and 17e, with reported inhibitory activity against c-Met kinase, which showed that also other compounds could possess similar effects against c-Met enzyme. The most promising compound 7g-cl was subjected to docking and molecular dynamics simulation. Two hydrogen bonds between Lys1110, Met1160, and 7g-cl were stable during the equilibrium time range. The suggested modifications might be considered in future studies to design more efficient anticancer agents.

5-Oxo-hexahydroquinoline derivatives as modulators of P-gp, MRP1 and BCRP transporters to overcome multidrug resistance in cancer cells.

Multidrug resistance (MDR) in cancer cells is often associated with overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2). Modulators of these transporters might be helpful in overcoming MDR. Moreover, exploiting collateral sensitivity (CS) could be another approach for efficient treatment of cancer. Twelve novel 5-oxo-hexahydroquinoline derivatives bearing different aromatic substitutions at C4, while having 2-pyridyl alkyl carboxylate substituents at the C3 were synthesized and evaluated for MDR reversal activity by flow cytometric determination of rhodamine 123, calcein and mitoxantrone accumulations in P-gp, MRP1 and BCRP-overexpressing cell lines, respectively. Furthermore, to confirm the P-gp inhibitory activity, the effect of compounds on the reduction of doxorubicin's IC50 of drug-resistant human uterine sarcoma cell line, MES-SA/DX5, was evaluated. Compounds D6, D5 and D3 (bearing 3-chlorophenyl, 2,3-dichlorophenyl and 4-chlorophenyl substituents at C4 position of 5-oxo-hexahydroquinoline core) were the most potent P-gp, MRP1 and BCRP inhibitors, respectively, causing significant MDR reversal at concentrations of 1-10 µM. Additionally, D4 (containing 3-flourophenyl) was the most effective MRP1-dependent CS inducing agent. Overall, chlorine containing compounds D6, C4 and D3 were capable of significant inhibition of all 3 important efflux pumps in cancer cells. Moreover, D6 also induced CS triggered by reducing glutathione efflux. In conclusion, some of the 5-oxo-hexahydroquinoline derivatives are effective efflux pump inhibitors capable of simultaneously blocking 3 important ABC transporters involved in MDR, and represent promising agents to overcome MDR in cancer cells.

Veratric acid derivatives containing benzylidene-hydrazine moieties as promising tyrosinase inhibitors and free radical scavengers.

Tyrosinase enzyme plays a crucial role in melanin biosynthesis and enzymatic browning process of vegetables and fruits. A series of veratric acid derivatives containing benzylidene-hydrazine moieties with different substitutions were synthesized and their inhibitory effect on mushroom tyrosinase and free radical scavenging activity were evaluated. The results indicated that N'-(4-chlorobenzylidene)-3,4-dimethoxybenzohydrazide (D5) and N'-(2,3-dihydroxybenzylidene)-3,4-dimethoxybenzohydrazide (D12) showed the highest tyrosinase inhibitory activity with IC50 values of 19.72 ±â€¯1.84 and 20.63 ±â€¯0.79 µM, respectively, that were comparable with the IC50 value of kojic acid (19.08 ±â€¯1.21 µM). D12 was also a potent radical scavenger with EC50 value of 0.0097 ±â€¯0.0011 mM. The free radical scavenging activity of D12 was comparable with the standard quercetin. The inhibition kinetic analyzed by Lineweaver-Burk plots revealed that compound D5 was a competitive tyrosinase inhibitor. Molecular docking study was carried out for the derivatives demonstrating tyrosinase inhibitory activity. D5 and D12 possessed the most negative estimated free energies of binding in mushroom tyrosinase active site. Therefore, D5 and D12 could be introduced as potent tyrosinase inhibitors that might be promising leads in medicine, cosmetics and food industry.

Multi-target inhibitors against Alzheimer disease derived from 3-hydrazinyl 1,2,4-triazine scaffold containing pendant phenoxy methyl-1,2,3-triazole: Design, synthesis and biological evaluation.

Alzheimer's disease (AD) is a complex neurological disorder with diverse underlying pathological processes. Several lines of evidence suggest that BACE1 is a key enzyme in the pathogenesis of AD and its inhibition is of particular importance in AD treatment. Ten new 3-hydrazinyl-1,2,4-triazines bearing pendant aryl phenoxy methyl-1,2,3-triazole were synthesized as multifunctional ligands against AD. We show that compounds containing Cl and NO2 groups at the para position of the phenyl ring, namely compounds 7c (IC50 = 8.55 ±â€¯3.37 µM) and 7d (IC50 = 11.42 ±â€¯2.01 µM), possess promising BACE1 inhibitory potential. Furthermore, we assessed the neuroprotective activities of 7c and 7d derivatives in PC12 neuronal cell line, which showed moderate protection against amyloid ß peptide toxicity. In addition, compound 7d demonstrated metal chelating activity and moderate antioxidant potential (IC50 = 44.42 ±â€¯7.33 µM). Molecular docking studies of these molecules revealed high-affinity binding to several amino acids of BACE1, which are essential for efficient inhibition. These results demonstrate that 1,2,4-triazine derivatives bearing an aryl phenoxy methyl-1,2,3-triazole have promising properties as therapeutic agents for AD.

1,2,3-Triazole-based kojic acid analogs as potent tyrosinase inhibitors: Design, synthesis and biological evaluation.

A series of kojic acid-derived compounds 6a-p bearing aryloxymethyl-1H-1,2,3-triazol-1-yl moiety were designed by modifying primary alcoholic group of kojic acid as tyrosinase inhibitors. The target compounds 6a-p were synthesized via click reaction. All compounds showed very potent anti-tyrosinase activity (IC50s = 0.06-6.80 µM), being superior to reference drug, kojic acid. In particular, the naphthyloxy analogs 6o and 6p were found to be 31-155 times more potent than kojic acid. The metal-binding study of selected compound 6o revealed that the prototype compound possesses metal-chelating ability, particularly with Cu2+ ions. The promising compounds 6o and 6p had acceptable safety profile as demonstrated by cytotoxicity assay against melanoma (B16) cell line and Human Foreskin Fibroblast (HFF) cells.