Design, synthesis, in vitro, and in silico evaluations of kojic acid derivatives linked to amino pyridine moiety as potent tyrosinase inhibitors.

In the present study, novel series of kojic acid derivatives conjugated to amino pyridine moiety were designed and synthesized to explore their inhibitory activity against tyrosinase. To this end, the structure of all derivatives was characterized by 1H NMR, 13C NMR, FT-IR, and elemental analysis. Next, all derivatives were evaluated against tyrosinase compared to the kojic acid as positive control and exhibited different inhibitory potencies. Furthermore, the antioxidant potential of all derivatives was determined. The kinetic analysis of the most active agent revealed that 3-hydroxy-6-(hydroxymethyl)-2-((3-nitrophenyl)(pyridin-2-ylamino)methyl)-4H-pyran-4-one (4h) binds to the enzyme in the uncompetitive mode of action. The docking analysis and molecular dynamic simulations showed considerable binding affinity and significant interactions with tyrosinase enzyme to target the melanogenesis pathway, proposing them as potent candidates to control hyperpigmentation in the future.

Functionalization of Fe3O4@SiO2 nanoparticles with Cu(i)-thiosemicarbazone complex as a robust and efficient heterogeneous nanocatalyst for N-arylation of N-heterocycles with aryl halides.

In this research, the functionalized silica-coated magnetite nanoparticles with Cu(i)-thiosemicarbazone complex (Fe3O4@SiO2-[CuL]) has been designed and synthesized as a magnetically retrievable nanocatalyst. Different techniques were employed to characterize the structure of Fe3O4@SiO2-[CuL] comprising FT-IR, FE-SEM, TEM, DLS, XRD, EDX, TGA, AAS, and VSM analysis. The catalytic performance of Fe3O4@SiO2-[CuL] was perused in Ullmann-type N-arylation of nucleobases, xanthines, and other N-heterocycles with diverse aryl halides which acquired the desired N-aryl products in good to excellent yields. Fe3O4@SiO2-[CuL] is a thermal and chemical stable, easy to prepare and recyclable, inexpensive, and ecofriendly catalyst that needs no additional additive or ligand as promoters. This catalyst could be separated without difficulty by a simple magnet and reused for at least seven sequential runs without a significant decline in its catalytic performance.

Design, synthesis, anticancer and in silico assessment of 8-piperazinyl caffeinyl-triazolylmethyl hybrid conjugates.

In this paper, we have assessed the design, synthesis, characterization, anticancer properties, toxicity, and in silico study of 8-piperazinyl caffeinyl-triazolylmethyl derivatives as new caffeine hybrid conjugates. These compounds consist of four moieties comprising 8-caffeinyl, piperazinyl, 1,2,3-triazolyl, and alkyl substituents. The synthesis of these compounds was started by bromination of caffeine to attain 8-BC, SNAr reaction with piperazine to acquire 8-PC, N-propargylation of 8-PC and finally click Huisgen cycloaddition with diverse alkyl azides. These compounds were in vitro tested against two significant cancer cell lines comprising breast cancer MCF-7 (ATCC HTB-22) and melanoma cancer A-375 (ATCC CRL-1619) cell lines and activities compared with methotrexate (MTX) as a reference drug. Anticancer assessments indicated 12j (IC50 = 323 ± 2.6) and 12k (IC50 = 175 ± 3.2) were the most potent compounds against A-375 and MCF-7 cell growth, respectively and their activities were even stronger than MTX (IC50 = 418 ± 2 for A375 and IC50 = 343 ± 3.6 for MCF-7). Toxicities were determined by screening compounds against normal cell line HEK-293 (ATCC CRL-11268) and indicated that except 12i (IC50 = 371 ± 2.3), 12j (IC50 = 418 ± 2.4), and MTX (IC50 = 199 ± 2.4), all compounds are non-toxic. Docking was conducted for 12j and 12k and determined the strong binding affinities to B-RAF kinase and hDHFR enzymes, respectively. In silico pharmacokinetic and physiochemical profiles of tested compounds were investigated which indicated that most compounds obeyed Lipinski's rule of five (RO5). The DFT study on M06-2X/6-311G (d,p) was used to indicate HOMO, LUMO, MEP, and other parameters for a better understanding of 12j and 12k reactivity. Owing to anticancer properties, toxicity, and in silico data, 12j and 12k can be proposed for further research in the future.

N-sulfonyl peptide-hybrids as a new class of dengue virus protease inhibitors.

Dengue virus (DENV) from the Flaviviridae family causes an epidemic disease that seriously threatens human life. The viral serine protease NS2B-NS3 is a promising target for drug development against DENV and other flaviviruses. We here report the design, synthesis, and in-vitro characterization of potent peptidic inhibitors of DENV protease with a sulfonyl moiety as N-terminal cap, thereby creating sulfonamide-peptide hybrids. The in-vitro target affinities of some synthesized compounds were in the nanomolar range, with the most promising derivative reaching a Ki value of 78 nM against DENV-2 protease. The synthesized compounds did not have relevant off-target activity nor cytotoxicity. The metabolic stability of compounds against rat liver microsomes and pancreatic enzymes was remarkable. In general, the integration of sulfonamide moieties at the N-terminus of peptidic inhibitors proved to be a promising and attractive strategy for further drug development against DENV infections.

Design, synthesis, anticancer and in silico assessment of 8-caffeinyl-triazolylmethoxy hybrid conjugates.

In this research the synthesis, characterization, anticancer and the cytotoxicity assessments of novel 8-caffeinyl-triazolylmethoxy hybrid conjugates have been described. These compounds are the first caffeine-1,2,3-triazolyl hybrid molecules that structurally are composed of three compartments comprising caffeinyl, 1,2,3-triazolyl and N-alkyl/aryl residues. The in vitro evaluations of synthesized compounds on cancer cell lines, including two breast cancer cell lines MDA-MB-468 (ATCC HTB-22), MCF-7 (ATCC HTB-22), melanoma cell line A-375 (ATCC CRL-1619) and normal cell line HEK-293 (ATCC CRL-11268) have determined that 22c (IC50 < 12.5 µM) demonstrated potent activity against A375 and its toxicity is even stronger than methotrexate (MTX) as a standard drug. Additionally, 22c involves more selectivity than MTX regarding its non-toxicity for the HEK-293 cell line. Among the tested compounds against two breast cancer cell lines, 22f (IC50 = 136 ± 0.2 and 126 ± 0.6 µM for MCF-7 and MDA-MB-468, respectively) and 22i (IC50 = 165 ± 1.8 and 175 ± 1.4 µM for MCF-7 and MDA-MB-468, respectively) were the most potent compounds but their activities were less than MTX, moreover 22f showed more selectivity regarding its lower toxicity against HEK-293. Overall, 22f displayed general toxicity and selectivity on all tested cancer cell lines. The in silico physicochemical properties, pharmacokinetic profile, and drug likeness predictions were also carried out for all the studied compounds. Most new compounds exhibited zero violation of Lipinski's rule (RO5). A molecular docking study was also conducted to predict the binding mode and the interaction of 22c as the most active anti-melanoma entry with B-RAF V600E kinase enzyme. The docking results determined that 22c exhibited a strong binding affinity to the active site of the enzyme. These findings demonstrated 22c and 22f as potential future anticancer drug candidates.

Design, synthesis, in vitro, and in silico biological evaluations of coumarin-indole hybrids as new anti-α-glucosidase agents.

BACKGROUND: A series of coumarin-indole hybrids was synthesized as the new α-glucosidase inhibitors. The title hybrids were considered as α-glucosidase inhibitors because had two active pharmacophores against α-glucosidase: coumarin and indole. METHODS: The thirteen various derivatives 4a-m were synthesized, purified, and fully characterized. These compounds were evaluated against α-glucosidase in vitro and in silico. In silico pharmacokinetic studies of the most potent compounds were also performed. RESULTS: Most of the title compounds exhibited high anti-α-glucosidase activity in comparison to standard drug acarbose. In particular, the phenoxy derivative 4d namely 3-((1H-indol-3-yl)(3-phenoxyphenyl)methyl)-4-hydroxy-2H-chromen-2-one showed promising activity. This compound is a competitive inhibitor against α-glucosidase and showed the lowest binding energy at the α-glucosidase active site in comparison to other potent synthesized compounds and acarbose. CONCLUSION: Compound 4d can be a lead compound for further structural development to obtain effective and potent α-glucosidase inhibitors.

Synthesis of some novel 8-(4-Alkylpiperazinyl) caffeine derivatives as potent anti-Leishmania agents.

In this paper, the synthesis, characterization and the leishmanicidal assessments of novel 8-(4-alkylpiperazinyl) caffeine derivatives have been described. These compounds are new caffeine hybrid molecules that are structurally composed of three compartments comprising caffeinyl, piperazinyl and N-alkyl/aryl residues. The synthesis was carried out through the bromination of caffeine via NBS to attain the 8-bromocaffeine (8-BC) followed by the SNAr-type reaction with the piperazine which afforded the 8­piperazinyl caffeine (8-PC). Ultimately, the N-alkylation of 8-PC with diverse alkyl halides acquired the products in good to excellent yields (68-96 %). The in vitro evaluation of synthesized compounds on promastigotes of Leishmania major (MHOM/IR/2002/Mash2) has showed that compounds 9d (ie: 8-(4-heptylpiperazin-1-yl)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione), 9e (ie: 1,3,7-trimethyl-8-(4-octylpipera zin-1-yl)-1H-purine-2,6(3H,7H)-dione) and 9f (ie: 8-(4-decylpiperazin-1-yl)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione) with IC50 = 84 µM, IC50 = 94 µM and IC50 = 89 µM displayed remarkable leishmanicidal activity even stronger than metronidazole (MTZ) and miltefosine as the reference drugs. The SAR analysis indicated the leishmanicidal activity of title compounds depended upon the type of substituents on N4 of piperazine. The in silico physicochemical properties, pharmacokinetic profile, and drug likeness predictions were also carried out for the all synthesized compounds and MTZ. The molecular docking study was also conducted to predict the binding mode and the interaction of 9d as the most and 9a as the least active compounds with pteridine reductase 1 (PTR1) enzyme. The docking results determined that 9d exhibited a strong binding affinity to the active site of the enzyme.

Shedding light on the bimolecular interactions of Cafaminol and human serum albumin: spectroscopic characterization and in-silico investigation.

Cafaminol, also known as methylcoffanolamine, is a vasoconstrictor and anticatarrhal of the methylxanthine family, which is used as a nasal decongestant. This study aimed to investigate the interaction mechanisms of human serum albumin (HSA) with Cafaminol, through several spectroscopic (fluorescence quenching, UV-visible absorption, and circular dichroism (CD) spectroscopies) and molecular modeling techniques. Stern-Volmer plots were employed to specify the fluorescence quenching mechanism, while the simulation methods were utilized to deduce the approximate binding position of Cafaminol on HSA. On the other hand, thermodynamic parameters, enthalpy and entropy changes, were determined to be, respectively, -105.88 (kJ mol-1) and -282.34 (J mol-1 K-1), using the Van't Hoff equation and analyzed later to specify the main acting forces between Cafaminol and HSA. Overall results revealed the binding of Cafaminol to the site I of HSA, as a result of an enthalpy-driven process, mainly through the van der Waals and hydrogen bonding interactions. Static quenching mechanism was found to be responsible for the fluorescence quenching of HSA in the Cafaminol presence, while the number of binding sites and apparent binding constant were measured accordingly. Docking results proposed that Cafaminol and HSA interact with a binding free energy (ΔG) of -6.5 kcal mol-1Communicated by Ramaswamy H. Sarma.

Synthesis of fish scale derived hydroxyapatite silica propyl bis aminoethoxy ethane cuprous complex (HASPBAEECC) as a novel hybrid nano-catalyst for highly efficient synthesis of new benzimidazole-1,2,3-triazole hybrid analogues as antifungal agents.

The preparation, characterization and application of hydroxyapatite silica propyl bis aminoethoxy ethane cuprous complex (HASPBAEECC) as a novel hybrid nano-catalyst for synthesis of new benzimidazole-1,2,3-triazole hybrid analogues as promising antifungal agents have been described. HASPBAEECC is fully characterized by different microscopic, spectroscopic and physical techniques, including scanning electron microscopy (SEM), transmission, X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA) and FT-IR. The 'Click̕ Huisgen cycloaddition reaction of N-propargyl benzimidazole with diverse azidoalkyls in a THF-water media at ambient temperature provides the products in good-to-excellent yields using HASPBAEECC. HASPBAEECC is proved to be a stable, low cost, reusable and environmentally benign nanohybrid catalyst. The target compounds were screened against some pathogenic fungal comprising Candida albicans, Candida krusei, Candida parapsilosis, Aspergillus fumigatus and Aspergillus flavus in which it was determined that compounds 11f and 11 h have displayed promising antifungal activity similar to fluconazole as a reference drug. HASPBAEECC is a novel hybrid nano-catalyst for highly efficient synthesis of new benzimidazole-1,2,3- triazole hybrid analogues as antifungal agents.

Chitosan-silica Sulfate Nano Hybrid: An Efficient Biopolymer Based-heterogeneous Nano Catalyst for Solvent-free Synthesis of 3,4-Dihydropyrimidine-2(1H)-one/thiones.

A green and highly efficient approach for the synthesis of 3,4-dihydropyrimidine-2(1H)-one/thione derivatives is described. In this approach, the three-component Biginelli reaction between (thio)urea, methyl acetoacetate and aldehydes under solvent-free condition in the presence of chitosan-silica sulfate nano hybrid (CSSNH) as a green and heterogeneous nano catalyst affords the corresponding products in good to excellent yields and in short reaction times. CSSNH is a cheap, eco-friendly, and non-toxic nano catalyst that could be easily prepared, handled, and reused for many reaction runs without significant loss of its activity.

Butyl methyl imidazolium silica sulfate (BMIm)SS: A novel hybrid nano-catalyst for highly efficient synthesis of new 1,2-diol monoesters of ibuprofen as the novel prodrugs of ibuprofen having potent analgesic property.

The fabrication, characterization of butyl methyl imidazolium silica sulfate [BMIm]SS as a novel nano hybrid catalyst and its application in synthesis of new ibuprofen (IBP) 1,2-diol mono esters were described. [BMIm]SS catalyzed the reaction of IBP with epoxides to afford the new IBP 1,2-diol mono esters in good to excellent yields. The products were tested in vivo for the analgesic properties on female mice using formalin test. The test results revealed that most compounds, in particular compounds 1h, 1k and 1o displayed potent analgesic activity compare to IBP as a reference drug. No mortality was observed due to the toxicity of the synthesized compounds. The docking analysis was conducted that confirmed the strong binding affinity of active compounds to active site of murine cyclooxygenase-2 (COX-2) enzyme compare to IBP. The in silico pharmacokinetic profile, drug likeness and toxicity predictions were carried out for all compounds which determined that 1h can be suggested as an appropriate future drug candidate.

Design, synthesis, and in silico studies of novel eugenyloxy propanol azole derivatives having potent antinociceptive activity and evaluation of their ß-adrenoceptor blocking property.

The design, synthesis, antinociceptive and ß-adrenoceptor blocking activities of several eugenyloxy propanol azole derivatives have been described. In this synthesis, the reaction of eugenol with epichlorohydrin provided adducts 3 and 4 which were N-alkylated by diverse azoles to obtain the eugenyloxy propanol azole analogues in good yields. Adducts 3 and 4 were also reacted with azide ion to obtain the corresponding azide 6. The 'Click' Huisgen cycloaddition reaction of 6 with diverse alkynes afforded the title compounds in good yields. The synthesized eugenyloxy propanol azole derivatives were in vivo studied for the acute antinociception on male Spargue Dawley rats using tail-flick test. Compounds 5f, 5g, 7b and 11a exhibited potent analgesic properties in comparison with eugenol as a standard drug. In addition, all compounds were ex vivo tested for ß-adrenoceptor blocking properties on isolated left atrium of male rats which exhibited partial antagonist or agonist behaviour compared to the standard drugs. The molecular docking study on the binding site of transient receptor potential vanilloid subtype 1 (TRPV1) has indicated that like capsaicin, eugenyloxy propanol azole analogues exhibited the strong affinity to bind at site of TPRV1 in a "tail-up, head-down" conformation and the presence of triazolyl moieties has played undeniable role in durable binding of these ligands to TRPV1. The in silico pharmacokinetic profile, drug likeness and toxicity predictions carried out for all compounds determined that 5g can be considered as potential antinociceptive drug candidate for future research.

Synthesis, Antifungal Evaluation and Molecular Docking Studies of Some Tetrazole Derivatives.

A facile and simple protocol for the [3+2] cycloaddition of alkyl nitriles (RCN) with sodium azide (NaN3) in the presence of copper bis(diacetylcurcumin) 1,2-diaminobenzene Schiff base complex, SiO2-[Cu-BDACDABSBC] as a heterogeneous catalyst in the presence of ascorbic acid and a solution of water/i-PrOH (50:50, V/V) media at reflux condition is described. The supported catalyst was prepared by immobilization of a copper bis(diacetylcurcumin) 1,2-diaminobenzene Schiff base complex [Cu-BDACDABSBC] on silica gel. The complex has high selectivity, catalytic activity, and recyclability. The significant features of this procedure are high yields, broad substrate scope and simple and efficient work-up procedure. According to this synthetic methodology, excellent yields of 5-substituted 1H-tetrazoles having bioactive N-heterocyclic cores were synthesized. The in vitro antifungal activities of title compounds were screened against various pathogenic fungal strains, such as Candida species involving C. albicans, C. glabrata, C. krusei, C. parapsilosis as well as filamentous fungi like Aspergillus species consisting of A. fumigatus and A. flavus. The molecular docking analysis is discussed for one most potent compound against fungi. The docking study determined a remarkable interaction between the most potent compounds and the active site of Mycobacterium P450DM.

Ultrasound promoted rapid and green synthesis of thiiranes from epoxides in water catalyzed by chitosan-silica sulfate nano hybrid (CSSNH) as a green, novel and highly proficient heterogeneous nano catalyst.

The synthesis and characterization of chitosan-silica sulfate nano hybrid (CSSNH) as a novel, green and highly efficient heterogeneous nano catalyst is described. The catalytic activity of this new biopolymeric nano catalyst was investigated in the ultrasonic assisted green synthesis of structurally diverse thiiranes from epoxides using thiourea in water at room temperature. CSSNH was characterized using some different microscopic and spectroscopic techniques such as scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), N2 adsorption isotherm, Fourier transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The green nature, cheapness, efficiency, ease of preparation, handling and reusability of this new catalyst makes this catalyst to be useful for green industrial processes.

Design, synthesis and biological evaluation of novel 1,2,3-triazolyl ß-hydroxy alkyl/carbazole hybrid molecules.

The design, synthesis and biological study of several novel 1,2,3-triazolyl [Formula: see text]-hydroxy alkyl/carbazole hybrid molecules as a new type of antifungal agent has been described. In this synthesis, the N-alkylation reaction of carbazol-9-ide potassium salt with 3-bromoprop-1-yne afforded 9-(prop-2-ynyl)-9H-carbazole. The 'Click' Huisgen cycloaddition reaction of 9-(prop-2-ynyl)-9H-carbazole with diverse [Formula: see text]-azido alcohols in the presence of copper-doped silica cuprous sulphate led to target molecules in excellent yields. The in vitro antifungal and antibacterial activities of title compounds were screened against various pathogenic fungal strains, Gram-positive and/or Gram-negative bacteria. In particular, 1-(4-((9H-carbazol-9-yl) methyl)-1H-1,2,3-triazol-1-yl)-3-butoxypropan-2-ol (10e) proved to have potent antifungal activity against all fungal tests compared with fluconazole and clotrimazole as studied reference drugs. Our molecular docking analysis revealed an appropriate fitting and a potential powerful interaction between compound 10e and an active site of the Mycobacterium P450DM enzyme. The strong hydrogen bondings between [Formula: see text]-hydroxyl and ether groups in 10e were found to be the main factors that drive the molecule to fit in the active site of enzyme. The in silico pharmacokinetic studies were used for a better description of 10a-10n as potential lead antifungal agents for future investigations.

Design, synthesis, and biological activities of novel azole-bonded ß-hydroxypropyl oxime O-ethers.

The synthesis and biological effects of 15 novel azole-bonded ß-hydroxypropyl oxime O-ethers have been described. In this synthesis, the oximation of aromatic ketones followed by an O-alkylation reaction with epichlorohydrin and/or epibromohydrin led to the corresponding O-oxime ether adducts. Subsequently, the attained O-oxime ether adducts were used to synthesize the target molecules after treating them with the appropriate azole derivatives. The in vitro antifungal and antibacterial activities of title compounds were obtained against several pathogenic fungi, Gram-positive and/or Gram-negative bacteria. Benzophenone O-2-hydroxy-3-(2-phenyl-1 H-imidazol-1-yl) propyl oxime and 9H-fluoren-9-one O-2-hydroxy-3-(2-phenyl-1 H-imidazol-1-yl)propyl oxime proved to have considerable antifungal activity against Candida albicans, Candida krusei, Aspergillus niger, and Trichophyton rubrum. These two compounds demonstrated comparable antifungal activity to clotrimazole and fluconazole (standard drugs). All compounds were also tested against Escherichia coli and Staphylococcus aureus as Gram-negative and Gram-positive bacteria, respectively, and their activities were compared to gentamycin and ampicillin (reference drugs). In general, marginal antibacterial activity against tested bacteria was observed for the title compounds. A molecular docking study is also discussed for the two most potent compounds against fungi. The docking study reveals a considerable interaction between the two most potent compounds and the active site of Mycobacterium P450DM. Moreover, these two compounds are much strongly bound to the active site of Mycobacterium P450DM compared to fluconazole.

Ph3P/CCl4 as a highly efficient reagent for one-pot N-alkylation of sulfonamides from alcohols: a rapid route to N-alkyl sulfonamides synthesis.

A mild, efficient, and selective protocol for the one-pot N-alkylation of sulfonamides with alcohols using triphenylphosphine and carbon tetrachloride is described. In this method, treatment of alcohols with a mixture of triphenylphosphine, carbon tetrachloride, and potassium sulfonylamide salts in refluxing anhydrous DMF furnishes the corresponding N-alkyl sulfonamides in good to excellent yields. This protocol is highly efficient for various structurally diverse alcohols and potassium sulfonylamide salts. In this paper the influence of solvents and various reagents as sources for electrophilic-halogen instead of carbon tetrachloride in combination with triphenylphosphine have been examined. This protocol demonstrates the selectivity between primary and secondary alcohols. A plausible mechanism for this protocol has been described.

The base-free chemoselective ring opening of epoxides with carboxylic acids using [bmim]Br: a rapid entry into 1,2-diol mono-esters synthesis.

A facile and highly convenient base-free protocol for the chemoselective preparation of 1,2-diol mono-esters is described. In this method, the regioselective ring opening of epoxides with carboxylic acids in the presence of [bmim]Br furnishes the corresponding 1,2-diol mono-esters in excellent yields. This method is efficient for various structurally diverse epoxides and carboxylic acids and it can be efficiently applied for the scale up synthesis of 1,2-diol mono-esters in reasonable to good yields. [bmim]Br remarkably influences the reaction progress and acts as both solvent and catalyst in this protocol.

Synthesis of some novel hydrazono acyclic nucleoside analogues.

The syntheses of novel hydrazono acyclic nucleosides similar to miconazole scaffolds are described. In this series of acyclic nucleosides, pyrimidine as well as purine and other azole derivatives replaced the imidazole function in miconazole and the ether group was replaced with a hydrazone moiety using phenylhydrazine. To interpret the dominant formation of (E)-hydrazone derivatives rather than (Z)-isomers, PM3 semiempirical quantum mechanic calculations were carried out which indicated that the (E)-isomers had the lower heats of formation.