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The over expression of melanogenic enzymes like tyrosinase caused many hyperpigmentaion disorders. The present work describes the synthesis of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives 3a–e and 5a–e as antimelanogenic agents. The tyrosinase inhibitory activity of synthesized derivatives 3a–e and 5a–e was determined and it was found that derivative 5c possesses excellent activity with IC50 = 0.0089 µM compared to standard kojic acid (IC50 = 16.69 µM). The presence of hydroxyl groups at the ortho and the para position of cinnamic acid phenyl ring in compound 5c plays a vital role in tyrosinase inhibitory activity. The compound 5d also exhibited good activity (IC50 = 8.26 µM) compared to standard kojic acid. The enzyme inhibitory kinetics results showed that compound 5c is a competitive inhibitor while 5d is a mixed-type inhibitor. The mode of binding for compounds 5c and 5d with tyrosinase enzyme was also assessed and it was found that both derivatives irreversibly bind with target enzyme. The molecular docking and molecular dynamic simulation studies were also performed to find the position of attachment of synthesized compounds at tyrosinase enzyme (PDB ID 2Y9X). The results showed that all of the synthesized compounds bind well with the active binding sites and most potent derivative 5c formed stable complex with target protein. The cytotoxicity results showed that compound 5c is safe at a dose of 12 µg/mL against murine melanoma (B16F10) cells. The same dose of 5c was selected to determine antimelanogenic activity; the results showed that it produced antimelenogenic effects in murine melanoma (B16F10) cells. Based on our investigations, it was proposed that compound 5c may serve as a lead structure to design more potent antimelanogenic agents.

This paper presents a self-grounded directional Bow-Tie antenna with a novel feed structure for sub-6 GHz applications in 5G communication systems covering 3.35-4.4. The antenna consists of two petal shaped metal structures that are interconnected to each other with a microstrip line. The petals are anchored on a common ground-plane. The feed mechanism used to excite the petals is by EM coupling from a single open-circuited microstrip line implemented behind the ground-plane. The couples EM energy is controlled via an I-shaped slot printed on the ground-plane. The proposed antenna offers good impedance matching across its operating frequency range with VSWR

Design, synthesis and characterization of new trinary Benzocoumarin-Thiazoles-Azomethine derivatives having three bioactive scaffolds in a single structural unit were carried out. The newly synthesized molecules were investigated for the inhibitory activity on human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP) isozymes. All the tested compounds exhibited the potent inhibition profile on both isozymes of alkaline phosphatase i.e., h-TNAP and h-IAP. Molecular docking studies were performed to explore the putative binding mode of interactions of selective inhibitors. Moreover, the synthesized derivatives were evaluated against cervical cancer cell line, HeLa and a few compounds exhibited significant inhibition in the range of 21.0–69.7%. The derivatives can be potential and selective alkaline phosphatase inhibitors for future studies.

A series of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a-i were synthesized as alkaline phosphatase inhibitors. The intermediate 5-substituted 1,3,4-oxadiazole-2-thione 4 was synthesized starting with hippuric acid. Hippuric acid in the first step was converted into corresponding methyl ester 2 which upon reaction with hydrazine hydrate furnished the formation of hydrazide 3. The hippuric acid hydrazide was then cyclized into 5-substituted 1,3,4-oxadiazole-2-thione 4. The intermediate 4 was then reacted with alkyl or aryl halides 5a-5i to afford the title compounds N-(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a-i. The bioassay results showed that compounds 6a-i exhibited good to excellent alkaline phosphatase inhibitory activity. The most potent activity was exhibited by the compound 6i having IC50 value 0.420 μM, whereas IC50 value of standard (KH2 PO4 ) was 2.80 μM. Molecular docking studies was performed against alkaline phosphatase enzyme (PDBID 1EW2) to check binding affinity of the synthesized compounds 6a-i against target protein. The docking results showed that three compounds 6c, 6e, and 6i have maximum binding interactions with binding energy values of -8 kcal/mol. The compound 6i displayed the interactions of oxadiazole ring nitrogen with amino acid His265 having a binding distance 2.13 Ǻ. It was concluded from our results that synthesized compounds, especially compound 6i may serve as lead structure to design more potent inhibitors of human alkaline phosphatase.

In the crystal of the title compound, a supra­molecular sheet structure is formed through N—H⋯O, O—H⋯O and C—H⋯O hydrogen bonds., In the title compound, C19H19NO5, the amide carbonyl O atom is positioned anti to the other two carbonyl O atoms. The 4-hy­droxy­hydro­cinnamate fragment is disordered over two positions with an occupancy ratio of 0.729 (12):0.271 (12). The N—(C=O)—C plane of the acetamide group and the acetate O—(C=O)—C plane are almost co-planar; the acetamide plane makes dihedral angles of 1.9 (6) and 16.0 (19)°, respectively, with the acetate planes of the major and minor occupancy components. In the crystal, N—H⋯O, O—H⋯O and C—H⋯O hydrogen bonds link the mol­ecules into a supra­molecular sheet structure parallel to (102).

Zaman Ashraf,1,2 Alamgeer,3 Munazza Kanwal,1 Mubashir Hassan,2 Sahar Abdullah,3 Mamuna Waheed,3 Haseeb Ahsan,3 Song Ja Kim2 1Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan; 2Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea; 3Department of Pharmacology, Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan Abstract: Flurbiprofen–antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (–COOH) was temporarily masked by esterification with phenolic –OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, ­suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (P

Research studies on human tyrosinase inhibitors and exploration for better cytotoxic agents remain an important line in drug discovery and development at the present time. Recently, multiple inhibitors are being used to cure melanogenesis by targeting human tyrosinase. A series of coumarin (C1-C9)-, thymol (T1-T8)- and vanillin (V1-V8)-based derivatives have been theoretically analyzed for their inhibitory effects against human tyrosinase. The crystal structure of human tyrosinase is not available in Protein Data Bank. Therefore, homology modeling approach was used to predict three-dimensional (3D) crystal structure of human tyrosinase. The reliability and efficacy of predicted 3D structure were validated by using Ramachandran plots which indicate that 95.01 % residues are present in favored regions. Moreover, multiple computational approaches such as molecular docking and molecular dynamic (MD) simulation along with various online tools were employed to screen the best inhibitor against melanogenesis. The results revealed that V7 and C9 compounds showed significant binding energy values (-7.79 and -7.40 kcal/mol, respectively) compared with the standard drugs such as kojic acid (-4.21 kcal/mol) and arbutin (-4.62 kcal/mol). Moreover, MD simulation results also justified that V7 showed little fluctuations throughout the simulation period as depicted by the root mean square deviation and root mean square fluctuation graphs. Thus, the present in silico study provides a deeper insight into the structural attributes of V7 compound and its overall molecular interactions against human tyrosinase and gives a hypothetical gateway to use this compound as a potential inhibitor against melanogenesis.

Over the course of time several drugs have been synthesized and are available in market for the treatment of inflammation. However, they were unable to cure effectively and associated with side effects. To effectively deal with such diseases, heterocycles and their derivatives have gained their special position. For this reason 1,3,4-oxadiazole (15–16), 1,2,4-triazole (17–18), Schiff base (19–24) and 3,5-disubstituted pyrazole (25) derivatives were synthesized starting from salicylic acid and acyl acid hydrazides (12–14) as COX-1 and COX-2 inhibitors. In vivo anti-inflammatory activities were also tested by carrageenan-induced mice paw edema against albino mice of any sex. Structures of all the synthesized compounds were confirmed by FT-IR and 1H NMR analysis. Schiff base derivative of 4-amiontirazole (24) with IC50 value of 1.76 ± 0.05 (COX-2) and 117.8 ± 2.59 emerged as potent COX-2 inhibitor. Furthermore, we also performed in-vivo anti-inflammatory investigations by using carrageenan induced paw edema test. From in-vivo anti-inflammatory activities, it was found that after 1 h the maximum percentage inhibition 15.8% was observed by compound 14 which is comparable with that of the standard drug followed by the compound 18 with percentage inhibition of 10.5%. After 3 h, the maximum percentage inhibition was observed by compound 18 with 22.2% and compound 14 with 16.7%. After 5 h the maximum percentage inhibition was observed by compound 18 with 29.4% followed by compound 16 with 23.5%. We further explore the mechanism of the inhibition by using docking simulations. Docking studies revealed that the selective COX-2 inhibitors established interactions with additional COX-2 enzyme pocket residues.

A variety of benzimidazole by the heterocyclization of orthophenylenediamine were synthesized in 69–86% yields. The synthesized compounds 3a-f and 6a-f were characterized and further investigated as jack bean urease inhibitors. Density functional theory (DFT) studies were performed utilizing the basis set B3LYP/6-31G (d, p) to acquire perception into their structural properties. Frontier molecular orbital (FMO) analysis of all compounds 3a–f and 6a-f was computed at the same level of theory to get a notion about their chemical reactivity and stability. The mapping of the molecular electrostatic potential (MEP) over the entire stabilized molecular geometry indicated the reactive centers. They exhibited urease inhibition activity with IC50 between 22 and 99 μM. Compounds containing withdrawing groups on the benzene ring (3d, 6d) were not showing significant urease inhibition. The value obtained for 3a, 3b, 3f had shown their significant urease inhibition for both theoretical and experimental. Notably, the compound having S-configuration (3a) (22.26 ± 6.2 μM) was good as compared to its R enantiomer 3f (31.42 ± 23.3 μM). Despite this, we elaborated the computational studies of the corresponding compounds, to highlight electronic effect which include HOMO, LUMO, Molecular electrostatic potential (MEP) and molecular docking., Organic chemistry; Pharmaceutical chemistry; Theoretical chemistry, Benzimidazole; Urease inhibition; Density functional theory; HOMO; LUMO; Molecular docking

In this paper, N-functionalized derivatives of methyl anthranilate (1–3) were prepared by reacting it with various acid chlorides to give amide derivatives (1–3) which were further converted to benzohydrazide derivatives (4–6) by reacting them with hydrazine. These N-functionalized derivatives of 2-aminobenzohydrazide (4–6) were reacted with 4-triflouromethyl benzaldehyde to give schiff base derivatives (7–9). All the synthesized compounds (1–9) were characterized by Mass spectrometry as well as NMR and FTIR spectroscopic techniques. Single Crystal X-ray diffraction analysis technique (XRD) was utilized to analyze crystalline compound 1. AChE and BChE enzymes inhibition potential was checked for the synthesized compounds. Putative binding approaches of screened compounds were explored by molecular docking studies. Synthesized compounds were also checked for antioxidant activity. Enzyme inhibition analysis showed that compounds 2 and 9 exhibited good AChE inhibition showing 68% and 60% percentage inhibition, respectively, while very good BChE inhibition activities were shown by compounds 2 (70%) and 5 (76%). Enzyme inhibition results were also supported by molecular docking studies with lowest binding energy values of −9.79 kcal mol−1 for BChE and −9.55 kcal mol−1 for AChE for compound 9. Hydrazide derivatives (4–6) showed very significant results for antioxidant activity with percentage scavenging greater than 90%.

Oxidative stress-mediated neuroinflammatory events are the hallmark of neurodegenerative diseases. The current study aimed to synthesize a series of novel succinamide derivatives and to further investigate the neuroprotective potential of these compounds against scopolamine-induced neuronal injury by in silico, morphological, and biochemical approaches. The characterization of all the succinamide derivatives was carried out spectroscopically via proton NMR (1H-NMR), FTIR and elemental analysis. Further in vivo experiments showed that scopolamine induced neuronal injury, characterized by downregulated glutathione (GSH), glutathione S-transferase (GST), catalase, and upregulated lipid peroxidation (LPO). Moreover, scopolamine increased the expression of inflammatory mediators such as cyclooxygenase2 (COX2), nuclear factor kappa B (NF-kB), tumor necrosis factor (TNF-&alpha, ), further associated with cognitive impairment. On the other hand, treatment with succinamide derivatives ameliorated the biochemical and immunohistochemical alterations induced by scopolamine, further supported by the results obtained from molecular docking and binding affinities.

The inhibition of tyrosinase is an established strategy for treating hyperpigmentation. Our previous findings demonstrated that cinnamic acid and benzoic acid scaffolds can be effective tyrosinase inhibitors with low toxicity. The hydroxyl substituted benzoic and cinnamic acid moieties of these precursors were incorporated into new chemotypes that displayed in vitro inhibitory effect against mushroom tyrosinase. The most active compound, (2-(3-methoxyphenoxy)-2-oxoethyl (E)-3-(4-hydroxyphenyl) acrylate) 6c, inhibited tyrosinase with an IC50 of 5.7 µM, while (2-(3-methoxyphenoxy)-2-oxoethyl 2, 4-dihydroxybenzoate) 4d had an IC50 of 23.8 µM. In comparison, the positive control, kojic acid showed tyrosinase inhibition with an IC50 = 16.7 µM. Analysis of enzyme kinetics revealed that 6c and 4d displayed noncompetitive reversible inhibition of the second tyrosinase enzymatic reaction with Ki values of 11 µM and 130 µM respectively. In silico docking studies with mushroom tyrosinase (PDB ID 2Y9X) predicted possible binding modes in the catalytic site for these active compounds. The phenolic para-hydroxy group of the most active compound 6c is predicted to interact with the catalytic site Cu++ ion. The methoxy part of this compound is predicted to form a hydrogen bond with Arg 268. Compound 6c had no observable toxic effects on cell morphology or cell viability at the highest tested concentration of 91.4 µM. When dosed at 91.4 µM onto B16F10 melanoma cells in vitro 6c showed anti-melanogenic effects equivalent to kojic acid at 880 µM. 6c displayed no PAINS (pan-assay interference compounds) alerts. Our results show that compound 6c is a more potent tyrosinase inhibitor than kojic acid and is a candidate for further development. Our exposition of the details of the interactions between 6c and the catalytic pocket of tyrosinase provides a basis for rational design of additional potent inhibitors of tyrosinase, built on the cinnamic acid scaffold.

Aryl pyrazoles are well recognized class of heterocyclic compounds found in several commercially available drugs. Owing to their significance in medicinal chemistry, in this current account we have synthesized a series of suitably substituted aryl pyrazole by employing Suzuki cross-coupling reaction. All compounds were evaluated for inhibition of mushroom tyrosinase enzyme both in vitro and in silico. Compound 3f (IC 50 = 1.568 ± 0.01 µM) showed relatively better potential compared to reference kojic acid (IC 50 = 16.051 ± 1.27 µM). A comparative docking studies showed that compound 3f have maximum binding affinity against mushroom tyrosinase (PDBID: 2Y9X) with binding energy value (−6.90 kcal/mol) as compared to Kojic acid. The 4-methoxy group in compound 3f shows 100% interaction with Cu. Compound 3f displayed hydrogen binding interaction with His61 and His94 at distance of 1.71 and 1.74 Å which might be responsible for higher activity compared to Kojic acid. Fil: Channar, Pervaiz Ali. Quaid-i-azam University; Pakistán Fil: Saeed, Aamer. Quaid-i-azam University; Pakistán Fil: Larik, Fayaz Ali. Quaid-i-azam University; Pakistán Fil: Batool, Bakhtawar. Quaid-i-azam University; Pakistán Fil: Kalsoom, Saima. International Islamic University Islamabad; Pakistán Fil: Hasan, M.M.. Pakistan Institute Of Engineering And Applied Sciences; Pakistán Fil: Erben, Mauricio Federico. Facultad de Ciencias Exactas, Universidad Nacional de la Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; Argentina Fil: El-Seedi, Hesham R.. Uppsala Biomedicinska Centrum; Fil: Ali, Musrat. Quaid-i-azam University; Pakistán Fil: Ashraf, Zaman. Allama Iqbal Open University; Pakistán

The present study describes the efficient synthesis, structural characterization and DNA binding interactions of ethyl 2-(2-acetamidothiazol-4-yl)acetate 2. Theoretically and experimentally determined bond lengths, angles and DNA binding interactions are compared. The chemical structure of the synthesized compound 2 was confirmed by spectral data and single crystal X-ray diffraction. The presence of –NH signal at 12.16 ppm in 1HNMR spectrum and carbonyl carbon at 170.5 ppm in 13CNMR spectrum confirmed the formation of ethyl 2-(2-acetamidothiazol-4-yl)acetate 2. The bond lengths and angles calculated theoretically are in good agreement with experimentally determined values. Molecular docking studies of synthesized compound 2 against five different DNA structures were performed to check its binding affinity with these targets. It was found that compound 2 binds well with DNA (PDB 1BPX ) having binding energy value −5.7 kcal/mol. The DNA binding interactions was also determined experimentally by spectrophotometric and electrochemical methods. The results showed that compound 2 binds with DNA through intercalation and groove binding which reflected the mixed binding mode. The binding constants (Kb) calculated from these results are 1.45 × 103 M−1 (UV–Vis spectroscopy), 1.41 × 103 M−1 (Fluorescence spectroscopy) and 1.39 × 103 M-1 (Cyclic voltammetry) also revealed strong binding. Based upon our results it was proposed that the synthesized compound 2 may act as a lead structure to design more potent antitumor agents.

Background: Urease enzyme catalyzes the hydrolysis of urea into ammonia and CO2, excess ammonia causes global warming and crop reduction. Ureases are also responsible for certain human diseases such as stomach cancer, peptic ulceration, pyelonephritis, and kidney stones. New urease inhibitors are developed to get rid of such problems. Objective: This article describes the synthesis of a series of novel 1-aroyl-3-(2-oxo-2H-chromen-4- yl)thiourea derivatives (5a-j) as Jack bean urease inhibitors. Methods: Freshly prepared aryl isothiocyanates were reacted with 4-aminocoumarin in the same pot in an anhydrous medium of acetone. The structures of the title thioureas (5a-j) were ascertained by their spectroscopic data. The inhibitory effects against jack bean urease were determined. Results: It was found that compounds 5i and 5j showed excellent activity with IC50 values 0.0065 and 0.0293, µM respectively. Compound 5i bearing 4-methyl substituted phenyl ring plays a vital role in enzyme inhibitory activity. The kinetic mechanism analyzed by Lineweavere-Burk plots revealed that compound 5i inhibits the enzyme non-competitively. The Michaelis-Menten constant Km and inhibition constants Ki calculated from Lineweavere-Burk plots for compound 5i are 4.155mM and 0.00032µM, respectively. The antioxidant activity results displayed that compound 5j showed excellent radical scavenging activity. The cytotoxic effects determined against brine shrimp assay showed that all of the synthesized compounds are non-toxic to shrimp larvae. Molecular docking studies were performed against target protein (PDBID 4H9M) and it was determined that most of the synthesized compounds exhibited good binding affinity with the target protein. Molecular dynamics simulation (MDS) results revealed that compound 5i forms a stable complex with target protein showing little fluctuation. Conclusion: Based upon our investigations, it is proposed that 5i derivative may serve as a lead structure for devising more potent urease inhibitors.

In this paper,the classic variational method is applied for newly introduced inverted microstrip gapwaveguide.Then,the dielectric losses and the conductor losses among the microstrip, covered microstrip and inverted microstrip gap waveguide are analytically calculated based on the variational method in millimeter waves. According to our theory, the dielectric losses of microstrip and covered microstrip gap waveguide are at least 7 times higher than that of inverted microstrip gap waveguide. Therefore, inverted microstrip gap waveguide has huge advantage of low loss in millimeter waves.

This paper presents a gap waveguide-based compact monopulse array antenna, which is formed with four unconnected layers, for millimeter-wave tracking applications at W-band (85–105 GHz). Recently developed gap waveguide technology removes the need for galvanic contact among metallic layers of waveguide structures, and thereby, makes the proposed antenna suitable for easy and low-cost manufacturing. In this context, a low-loss planar Magic-Tee is designed to be used in a monopulse comparator network consisting of two vertically stacked layers. The gap waveguide planar monopulse comparator network is integrated with a high-efficiency 16x16 corporate-fed slot array antenna. The measured results of the comparator network show the amplitude and phase imbalance values to be less than 0.5 dB and 2°, respectively, over the frequency band of interest. The fabricated monopulse array antenna shows relative impedance bandwidths of 21% with input reflection coefficients better than −10 dB for the sum and difference ports. The null in the difference radiation pattern is measured to be 38 dB below the peak of the sum radiation pattern at 94 GHz. The measured gain is about 30 dBi for the same frequency. The low-loss performance of the comparator network and the feed network of the proposed array, together with the simple and easy manufacturing and mechanical assembly, makes it an excellent candidate for W -band compact direction-finding systems.

The present work reports the synthesis of several 2-iminothiazoline derivatives of sulfanilamide (3a-j) as inhibitors of jack bean ureases. The title compounds were synthesized by the heterocyclization of sulfanilamide thioureas with propragyl bromide in dry ethanol in the presence of 1,8-Diazabicyclo[5.4.0]undec-7-ene as a base. All of the compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (3h) and (3i) exhibited excellent enzyme inhibitory activity with IC50 0.064 and 0.058 μm, respectively, while IC50 of thiourea is 20.9 μm. The kinetic mechanism analyzed by Dixon plot showed that compound (3h) is a mixed-type inhibitor while (3i) is a competitive one. Docking studies suggested that Asp633, Ala636, His492, Ala440, Lue523, Asp494 and Arg439 are the major interacting residues in the binding site of the protein and may have an instrumental role in the inhibition of enzyme's function. 2-iminothiazoline analogues (3a-j) showed good docking score (-10.6466 to -8.7215 Kcal/mol) and binding energy (London dG ranging from -14.4825 to -10.4087 Kcal/mol) which is far better than the standard thiourea (binding score in S field -4.5790 Kcal/mol London dG -4.7726 Kcal/mol). Our results inferred compound (3i) may serve as a structural model for the design of most potent urease inhibitors.

The present studies reports the synthesis of hydoxylated thymol analogues (4a–e) and (6a–c) as mushroom tyrosinase inhibitors. The title compounds were obtained in good yield and characterized by FTIR, 1H NMR, 13C NMR, Mass spectral data and X-ray crystallography in case of compound (6a). The inhibitory effects on mushroom tyrosinase and DPPH were evaluated and it was observed that 2-[5-methyl-2-(propan-2-yl)phenoxy]-2-oxoethyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (6b) showed tyrosinase inhibitory activity (IC50 15.20 μM) comparable to kojic acid (IC50 16.69 μM) while 2-[5-methyl-2-(propan-2-yl)phenoxy]-2-oxoethyl 3,4-dihydroxybenzoate (4d) exhibited higher antioxidant potential (IC50 11.30 μM) than standard ascorbic acid (IC50 24.20 μM). The docking studies of synthesized thymol analogues was also performed against tyrosinase protein (PDBID 2ZMX) to compare the binding affinities with IC50 values. The predicted binding affinities are in good agreement with the IC50 values as compound (6b) showed highest binding affinity −7.1 kcal/mol. The kinetic mechanism analyzed by Lineweaver–Burk plots exhibited that compound (4d) and (6b) inhibit the enzyme by two different pathways displayed mixed-type inhibition. The inhibition constants Ki calculated from Dixon plots for compounds (4d) and (6b) are 34 μM and 25 μM respectively. It was also found from kinetic analysis that derivative (6b) formed reversible enzyme inhibitor complex. It is propose on the basis of our investigation that title compound (6b) may serve as lead structure for the design of more potent tyrosinase inhibitors.

Isocoumarins (1H-isochromen-1-ones), an important class of naturally occurring unsaturated lactones, exhibit a broad range of pharmacological activities including cytotoxicity toward HeLa cervical cancer cells,1 antioxidant activity in HepG2 cells exposed to oxidative stress conditions induced by H2O2,2 antiangiogenic,3 anticancer,4 , 5 antifungal,6 , 7 and antimicrobial activity.8 Isocoumarins are also important building blocks for the synthesis of a number of medicinally important heterocycles.9 – 11 A number of conventional methods have been used for the synthesis of isocoumarins starting from homophthalic acids,12 , 13 but metal-catalyzed synthesis of isocoumarins has attracted considerable attention due to its economic advantages and good functional group tolerance.14 , 15 Recent reports on the Cu-, Pd-, Ru-, and Rh-catalyzed synthesis of isocoumarins are reviewed here. Besides, an example of Re catalysis has appeared recently.16

4-Aminophenazone (Ap-1) Schiff bases i.e., 4-{(3,4,5-trimethoxybenzylidine) amino}phenazone (Ap-2), 4-{(2-chlorobenzylidine) amino}phenazone (Ap-3) and 4-{(4-chlorobenzylidine)amino} phenazone (Ap-4) were synthesized and characterized by different spectroscopic techniques. Interaction of these compounds with ds.DNA was investigated through UV-Visible spectroscopy, fluorescence spectroscopy and cyclic voltammetry at stomach (4.7) and blood (7.4) pH under 37 °C (human body temperature). Instrumental findings were further quantified both kinetically and thermodynamically. Results obtained through these techniques inferred intercalative mode of binding of all the compounds with DNA. The binding constant data, "Kb", and free energy change, ΔG, indicated comparatively greater binding affinity and more spontaneity of binding of compounds with DNA at stomach pH (4.7), respectively. However, among these compounds, Ap-4 showed comparatively greater binding at both the pH. Formation of compound-DNA complex was further confirmed through the decrease in diffusion rates after the addition of DNA. The in vivo anti-inflammatory activity of the compounds was evaluated using the carrageenan-induced hind paw edema method. The results revealed that among all the compounds, Ap-4 showed greater percentage of edema inhibition compared to standard drug.

A number of novel isocoumarin analogues have been synthesized by the condensation of homophthalic acid anhydride with different non-steroidal anti-inflammatory drugs (NSAIDs). To investigate the antimicrobial data on a structural basis, in silico docking studies of the synthesized compounds (4a–4g) into the crystal structure of UDP-N-acetylmuramate-L-alanine ligase using an Autodock PyRx virtual screening program were performed in order to predict the affinity and orientation of the synthesized compounds at the activities. UDP-N-acetylmuramate-L-alanine ligase is essential for D-glutamate metabolism and peptidoglycan biosynthesis in bacteria. R2 values showed good agreement with predicted binding affinities obtained by molecular docking studies. The results indicate that the basic nucleic portion of the (4c), (4g), (4f) and (4a) binds into the specificity pocket. In this pocket, the isocoumarin nucleus of these compounds interacts with the amino acid residue of the target. Moreover, it is verified by in vitro antimicrobial screening, in which all of the compounds were active against tested bacterial strains. Among these compounds (4c), (4g), (4f) and (4a) showed good bacterial zone inhibition.

The work reports antibacterial and antifungal activity of some 3-(substituted phenyl) isocoumarins (1H-2-benzopyran-1-ones), isocarbostyrils 1(2H)-isoquinolones, the nitrogen analogues of isocoumarins and isocoumarin-1-thiones, the thio derivatives of isocoumarins. The antimicrobial activity was determined against ten different Gram positive and Gram negative bacterial strains and three fungal strains. The bacterial strains were Klebsiella pneumonae (ATCC 6633), Staphylococcus aureus (ATCC 29213), Micrococcus luteus (ATCC 9341), Pseudomonas aeruginosa (ATCC 33347), Escherichia coli (ATCC 25922), Salmonella typhi (ATCC 19430), Lactobacillus bulgaricus, (ATCC 25929), Pasteurella multocida A (ATCC 9150), Staphylococcus epidermidis (ATCC 29232) and Proteus vulgaris (ATCC 49565) and fungal strains were Aspergillus flavus, Aspergillus nigar and Aspergillus pterus. Agar well diffusion method was followed for antibacterial activity and poison plate method was adopted for antifungal assay. Chloramphenicol and fluconazole used as standard drugs for antibacterial and antifungal activity respectively. In general, these compounds exhibited high antibacterial potential than antifungal. Comparative study reveals that the 1-thio derivatives are more active than parent isocoumarins but 1(2H)-isoquinolones, are less active. Most of these compounds showed poor activity but some of these compounds exhibited moderate to good activity against Staphylococcus epidermidis, Klebsiella pneumonae, Escherichia coli and Proteus vulgaris, compared with the standard drug.

Three amide derivatives – methyl-2-[2-(4-isobutylphenyl)propanamido]propanoate (Dex-2), methyl 2-[2-(4-isobutylphenyl) propanamido]-3-phenylpropanoate (Dex-3) and methyl 2-[2-(4-isobutylphenyl)-propanamido]-4-methylpentanoate (Dex-4) of dexibuprofen (Dex-1) 2-(4-isobutylphenyl)propanoic acid were synthesized and conformed for structures by physical data and spectral analysis. Further, all the compounds were studied for their binding with ds.DNA through experimental (UV-visible/and fluorescence spectroscopy, cyclic voltammetry) and theoretical (molecular docking) techniques. Spectral and voltammetric responses as well as kinetic and thermodynamic data interpretations at stomach (4.7) and blood (7.4) pH and at human body temperature (37 °C) indicated spontaneous interaction of all the compounds with DNA via intercalation and external bindings. The binding constants ( K b ) and Gibbs free energy changes (− Δ G ) were evaluated greater at pH 7.4 attributing comparatively more significant binding of all the compounds with DNA at blood pH. Among all compounds, Dex-4 showed greater binding with DNA at both pH with greater K b values i.e., {UV-visible: pH 4.7 (2.36 × 10 4 M − 1 ); pH 7.4 (2.42 × 10 4 M − 1 ), fluorescence: pH 4.7 (2.24 × 10 4 M − 1 ); pH 7.4 (2.56 × 10 4 M − 1 ) and CV: pH 4.7 (4.06 × 10 4 M − 1 ); pH 7.4 (4.89 × 10 4 M − 1 )}. Binding site size (n) at both pH values was evaluated n ≥ 1 for Dex-2 and Dex-4 which assured intercalation as a major mode of interaction between compounds and DNA. For Dex-1 and Dex-3 (n) was evaluated n ≤ 1 at both pH values and the values n o ) for all the compounds – DNA adducts were evaluated lesser than unbound compounds. Docking studies further supported DNA binding evidences obtained from spectral and electrochemical investigations.

Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001) is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001). The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug.

Substituted phenyl[(5-benzyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetates/acetamides 9a-j were synthesized as alkaline phosphatase inhibitors. Phenyl acetic acid 1 through a series of reactions was converted into 5-benzyl-1,3,4-oxadiazole-2-thione 4 . The intermediate oxadiazole 4 was then reacted with chloroacetyl derivatives of phenols 6a-f and anilines derivatives 8a-d to afford the title oxadiazole derivatives 9a-j . All of the title compounds 9a-j were evaluated for their inhibitory activity against human alkaline phosphatise (ALP). It was found that compounds 9a-j exhibited good to excellent alkaline phosphatase inhibitory activity especially 9h displayed potent activity with IC 50 value 0.420 ± 0.012 µM while IC 50 value of standard (KH 2 PO 4 ) was 2.80 µM. The enzyme inhibitory kinetics of most potent inhibitor 9h was determined by Line-weaever Burk plots showing non-competitive mode of binding with enzyme. Molecular docking studies were performed against alkaline phosphatase enzyme (1EW2) to check the binding affinity of the synthesized compounds 9a-j against target protein. The compound 9h exhibited excellent binding affinity having binding energy value (−7.90 kcal/mol) compared to other derivatives. The brine shrimp viability assay results proved that derivative 9h was non-toxic at concentration used for enzyme assay. The lead compound 9h showed LD 50 106.71 µM while the standard potassium dichromate showed LD 50 0.891 µM. The DNA binding interactions of the synthesized compound 9h was also determined experimentally by spectrophotometric and electrochemical methods. The compound 9h was found to bind with grooves of DNA as depicted by both UV–Vis spectroscopy and cyclic voltammetry with binding constant values 7.83 × 10 3 and 7.95 × 10 3 M −1 respectively revealing significant strength of 9h -DNA complex. As dry lab and wet lab results concise each other it was concluded that synthesized compounds, especially compound 9h may serve as lead compound to design most potent inhibitors of human ALP.