Publications by authors named "Zaman Ashraf"

48 Publications

Methoxy-Substituted Tyramine Derivatives Synthesis, Computational Studies and Tyrosinase Inhibitory Kinetics.

Molecules 2021 Apr 23;26(9). Epub 2021 Apr 23.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand.

Targeting tyrosinase for melanogenesis disorders is an established strategy. Hydroxyl-substituted benzoic and cinnamic acid scaffolds were incorporated into new chemotypes that displayed in vitro inhibitory effects against mushroom and human tyrosinase for the purpose of identifying anti-melanogenic ingredients. The most active compound 2-((4-methoxyphenethyl)amino)-2-oxoethyl ()-3-(2,4-dihydroxyphenyl) acrylate (Ph9), inhibited mushroom tyrosinase with an IC of 0.059 nM, while 2-((4-methoxyphenethyl)amino)-2-oxoethyl cinnamate (Ph6) had an IC of 2.1 nM compared to the positive control, kojic acid IC 16700 nM. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound (Ph9) and Ph6 exhibited 94.6% and 92.2% inhibitory activity respectively while the positive control kojic acid showed 72.9% inhibition. Enzyme kinetics reflected a mixed type of inhibition for inhibitor Ph9 ( 0.093 nM) and non-competitive inhibition for Ph6 ( 2.3 nM) revealed from Lineweaver-Burk plots. In silico docking studies with mushroom tyrosinase (PDB ID:2Y9X) predicted possible binding modes in the catalytic site for these active compounds. Ph9 displayed no PAINS (pan-assay interference compounds) alerts. Our results showed that compound Ph9 is a potential candidate for further development of tyrosinase inhibitors.
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http://dx.doi.org/10.3390/molecules26092477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122972PMC
April 2021

Antihyperlipidemic effect of selected pyrimidine derivatives mediated through multiple pathways.

Fundam Clin Pharmacol 2021 Apr 19. Epub 2021 Apr 19.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, China.

Hyperlipidemia is worth-mentioning risk factor in quickly expanding atherosclerosis, myocardial infarction, and stroke. This study attempted to determine effectiveness of selected pyrimidine derivatives: 5-(3-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-5), 5-(4-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-8), 5-(3-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-9), and 5-(4-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-10) against hyperlipidemia. In silico results revealed that SR-5, SR-8, SR-9, and SR-10 exhibited high affinity with 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) possessing binding energy values of -8.2, -8.4, -8.6, and -9.5 Kcal/mol, respectively, and moderate (<-8 Kcal/mol) against other selected targets. In vivo findings showed that test drugs (25 and 50 mg/Kg) significantly decreased HFD rat total cholesterol, triglycerides, low-density lipoprotein, very-low-density lipoprotein, atherogenic index, coronary risk index, alkaline phosphatase, aspartate transaminase, alanine transaminase, and bilirubin and increased high-density lipoprotein (p < 0.05, p < 0.01, p < 0.001 vs HFD group). In animal liver tissues, SR-5, SR-8, SR-9, and SR-10 inhibited HMGCoA reductase enzyme, enhanced glutathione-s-transferase, reduced glutathione, catalase levels, improved cellular architecture in histopathological examination, and decreased expression of inflammatory markers: cyclo-oxygenase 2, tumor necrosis factor alpha, phosphorylated c-Jun N-terminal kinase, and phosphorylated-nuclear factor kappa B, evidenced in immunohistochemistry and enzyme-linked immunosorbent assay molecular investigations. This study indicates that SR-5, SR-8, SR-9, and SR-10 exhibit antihyperlipidemic action, mediated possibly through HMGCoA inhibition, hepatoprotection, antioxidant, and anti-inflammatory pathways.
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http://dx.doi.org/10.1111/fcp.12682DOI Listing
April 2021

Enzyme Inhibitory Kinetics and Molecular Docking Studies of Halo-Substituted Mixed Ester/Amide-Based Derivatives as Jack Bean Urease Inhibitors.

Biomed Res Int 2020 24;2020:8867407. Epub 2020 Dec 24.

Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, Pakistan.

A series of halo-substituted mixed ester/amide-based analogues have been prepared as jack bean urease inhibitor, which showed good to excellent inhibition of enzyme activity. The role of halo-substituted benzoyl moieties and alkyl substituted anilines in urease inhibitory kinetics was also investigated. The alkyl-substituted anilines reacted with chloroacetyl chloride to afford intermediates , which were then reacted with different halo-substituted benzoic acids to prepare the title compounds . The chemical structures of final products were ascertained by FTIR, H NMR, C NMR, and mass spectra. The compound showed remarkable activity with IC1.6 ± 0.2 nM, better than the standard thiourea having IC472.1 ± 135.1 nM. The 2-chloro-substituted phenyl ring on one side of compound and 4-isopropyl-substituted benzene on the other side play an essential role in inhibition of urease activity. Lineweaver-Burk plots (kinetics study) indicated about derivative as a mixed type of inhibitor. The virtual screening performed against urease enzyme (PDBID 4H9M) showed that compounds and have binding energies of -7.8 and -7.9 Kcal/mol, respectively. Based upon our results, it was found that derivative is a highly potent urease inhibitor, better than the standard thiourea.
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http://dx.doi.org/10.1155/2020/8867407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775144PMC
May 2021

Synthesis, density functional theory (DFT) studies and urease inhibition activity of chiral benzimidazoles.

Heliyon 2020 Oct 14;6(10):e05187. Epub 2020 Oct 14.

Department of Chemistry, School of Science, Chung Yuan Christian University, Taoyuan 32023, Taiwan.

A variety of benzimidazole by the heterocyclization of orthophenylenediamine were synthesized in 69-86% yields. The synthesized compounds and 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 () were not showing significant urease inhibition. The value obtained for had shown their significant urease inhibition for both theoretical and experimental. Notably, the compound having S-configuration () (22.26 ± 6.2 μM) was good as compared to its R enantiomer (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.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567930PMC
October 2020

Charge transfer and opto-electronic properties of some newly designed polycatenar discotic liquid crystal derivatives: a DFT study.

J Mol Model 2020 Sep 29;26(10):291. Epub 2020 Sep 29.

School of Chemical and Material Engineering (SCME), National University of Sciences and Technology Islamabad, Pakistan (NUST), H-12 Campus, Islamabad, 44000, Pakistan.

Herein, we demonstrate effect of substituents on optoelectronic properties of discotic liquid crystals (DLCs) by using density functional theory (DFT) calculations at B3LYP/Lanl2Z level of theory. Three parent DLCs, namely, (1) benzene-1,3,5-triyl tris(3,5-dialkoxybenzoate), (2) N, N, N-tris(3-alkoxyphenyl)benzene-1,3,5-tricarboxamide, and (3) trialkyl 4, 4', 4″-(benzenetricarbonyltris (azanediyl)) tribenzoate benzoate and their -N and -S group derivatives of 1, 2, and 3, were investigated to observe the change in optoelectronic response of these systems. The frontier molecular orbital studies and electron affinity values indicate that the studied compounds are stable against the oxygen and moisture present in air. The calculated charge transfer integrals, electron, and hole mobility values revealed that parent DLCs and their derivatives can be employed as an effective n-type material for OLEDs; however, derivatives have enhanced charge transfer values compared with their parents. For better understanding of the thermochemistry and effect of substituents, frequency calculations were carried out. P-D derivative having R = -NH-CO-CH terminal group came out to be theoretically the most favored having the lowest ΔG value. Computed UV/visible spectroscopic analysis showed minimum absorbance and maximum transmittance for derivative P-D having -S-NH substituent. Molecular electrostatic potential surfaces mapped at potential range, i.e., - 8.531e-3esu to + 8.531e-3esu, describe electrophilic and nucleophilic characteristics. Introduction of electron donor groups enhanced electrical conductivity, excitation energy, and charge transfer integral, thus increasing optoelectronic properties of DLCs. However, these claims require further experimental verification.
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http://dx.doi.org/10.1007/s00894-020-04550-xDOI Listing
September 2020

Synthesis, in-vitro, in-vivo anti-inflammatory activities and molecular docking studies of acyl and salicylic acid hydrazide derivatives.

Bioorg Chem 2020 11 28;104:104168. Epub 2020 Aug 28.

Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Pakistan. Electronic address:

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 H NMR analysis. Schiff base derivative of 4-amiontirazole (24) with IC 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.
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http://dx.doi.org/10.1016/j.bioorg.2020.104168DOI Listing
November 2020

Understanding the enzymatic inhibition of intestinal alkaline phosphatase by aminophenazone-derived aryl thioureas with aided computational molecular dynamics simulations: synthesis, characterization, SAR and kinetic profiling.

Mol Divers 2020 Aug 29. Epub 2020 Aug 29.

Department of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan.

The work presented in this paper aims toward the synthesis of aryl thiourea derivatives 4a-l of pyrazole based nonsteroidal anti-inflammatory drug named 4-aminophenazone, as potential inhibitors of intestinal alkaline phosphatase enzyme. The screening of synthesized target compounds 4a-l for unraveling the anti-inflammatory potential against calf intestinal alkaline phosphatase gives rise to lead member 4c possessing IC value 0.420 ± 0.012 µM, many folds better than reference standard used (KHPO IC = 2.8 ± 0.06 µM and L-phenylalanine IC = 100 ± 3.1 µM). SAR for unfolding the active site binding pocket interaction along with the mode of enzyme inhibition based on kinetic studies is carried out which showed non-competitive binding mode. The enzyme inhibition studies were further supplemented by molecular dynamic simulations for predicting the protein behavior against active inhibitors 4c and 4g during docking analysis. The preliminary toxicity of the synthesized compounds was determined by using brine shrimp assay. This work also includes detailed biochemical analysis along with RO5 parameters for all the newly synthesized drug derivatives 4a-l.
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http://dx.doi.org/10.1007/s11030-020-10136-9DOI Listing
August 2020

Succinamide Derivatives Ameliorate Neuroinflammation and Oxidative Stress in Scopolamine-Induced Neurodegeneration.

Biomolecules 2020 03 13;10(3). Epub 2020 Mar 13.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518000, China.

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 (H-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-α), 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.
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http://dx.doi.org/10.3390/biom10030443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175202PMC
March 2020

Sulfonamide-Based Azaheterocyclic Schiff Base Derivatives as Potential Carbonic Anhydrase Inhibitors: Synthesis, Cytotoxicity, and Enzyme Inhibitory Kinetics.

Biomed Res Int 2020 20;2020:8104107. Epub 2020 Feb 20.

Institute of Fundamental Medicine and Biology, Department of Genetics, Kazan Federal University, 420008 Kazan, Russia.

A series of sulfonamide-bearing azaheterocyclic Schiff base derivatives were synthesized as carbonic anhydrase inhibitors. The substituted benzene sulfonyl chlorides were reacted with NH to get aromatic sulfonyl hydrazides . The intermediate hydrazides were treated with substituted aldehydes to afford azaheterocyclic sulfonamide Schiff bases . The spectral data of synthesized compounds confirmed the formation of the final products. The inhibitory effects of on carbonic anhydrase activity were determined, and it was found that derivative exhibited the most potent activity with IC0.84 ± 0.12 M among all other derivatives and is also more active than standard acetazolamide (IC0.91 ± 0.12). The enzyme inhibitory kinetics results determined by Lineweaver-Burk plots revealed that compound inhibits the enzyme by noncompetitive mode of inhibition with value 8.6 M. The molecular docking investigations of the synthesized analogues were evaluated which assured that synthesized compounds bind well inside the active binding site of the target enzyme. Cytotoxicity on human keratinocyte (HaCaT) and MCF-7 cell lines was performed, and it was found that most of the synthesized analogues were nontoxic on these cell lines and the toxic effects follow the dose-dependent manner. Based on our investigations, it was suggested that analogue may serve as core structure to project carbonic anhydrase inhibitors with greater potency.
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http://dx.doi.org/10.1155/2020/8104107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054763PMC
December 2020

Hydroxyl substituted benzoic acid/cinnamic acid derivatives: Tyrosinase inhibitory kinetics, anti-melanogenic activity and molecular docking studies.

Bioorg Med Chem Lett 2020 01 24;30(1):126722. Epub 2019 Oct 24.

Institute for Molecular Biosciences (IMB), The University of Queensland (UQ), St Lucia 4072, Qld, Australia. Electronic address:

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 IC of 5.7 µM, while (2-(3-methoxyphenoxy)-2-oxoethyl 2, 4-dihydroxybenzoate) 4d had an IC of 23.8 µM. In comparison, the positive control, kojic acid showed tyrosinase inhibition with an IC = 16.7 µM. Analysis of enzyme kinetics revealed that 6c and 4d displayed noncompetitive reversible inhibition of the second tyrosinase enzymatic reaction with K 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 vitro6c 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.
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http://dx.doi.org/10.1016/j.bmcl.2019.126722DOI Listing
January 2020

Synthesis, computational studies, tyrosinase inhibitory kinetics and antimelanogenic activity of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives.

J Enzyme Inhib Med Chem 2019 Dec;34(1):1-11

Department of Chemistry, Siedlce University of Natural Sciences and Humanities , Siedlce , Poland.

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 and as antimelanogenic agents. The tyrosinase inhibitory activity of synthesized derivatives and was determined and it was found that derivative possesses excellent activity with IC = 0.0089 µM compared to standard kojic acid (IC = 16.69 µM). The presence of hydroxyl groups at the and the position of cinnamic acid phenyl ring in compound plays a vital role in tyrosinase inhibitory activity. The compound also exhibited good activity (IC = 8.26 µM) compared to standard kojic acid. The enzyme inhibitory kinetics results showed that compound is a competitive inhibitor while is a mixed-type inhibitor. The mode of binding for compounds and 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 formed stable complex with target protein. The cytotoxicity results showed that compound is safe at a dose of 12 µg/mL against murine melanoma (B16F10) cells. The same dose of 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 may serve as a lead structure to design more potent antimelanogenic agents.
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http://dx.doi.org/10.1080/14756366.2019.1654468DOI Listing
December 2019

Design, synthesis and biological evaluation of trinary benzocoumarin-thiazoles-azomethines derivatives as effective and selective inhibitors of alkaline phosphatase.

Bioorg Chem 2019 10 23;91:103137. Epub 2019 Jul 23.

Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bioorg.2019.103137DOI Listing
October 2019

4-Aminocoumarin based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies.

Med Chem 2020 ;16(2):229-243

Department of Biology, College of Natural Sciences, Kongju National University, Gongju, Korea.

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.

Conclusions: Based upon our investigations, it is proposed that 5i derivative may serve as a lead structure for devising more potent urease inhibitors.
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http://dx.doi.org/10.2174/1573406415666190715164834DOI Listing
September 2020

Substituted phenyl[(5-benzyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetates/acetamides as alkaline phosphatase inhibitors: Synthesis, computational studies, enzyme inhibitory kinetics and DNA binding studies.

Bioorg Chem 2019 09 3;90:103108. Epub 2019 Jul 3.

Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan.

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 value 0.420 ± 0.012 µM while IC value of standard (KHPO) 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 106.71 µM while the standard potassium dichromate showed LD 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 and 7.95 × 10 M 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.
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http://dx.doi.org/10.1016/j.bioorg.2019.103108DOI Listing
September 2019

Dexibuprofen amide derivatives as potential anticancer agents: synthesis, in silico docking, bioevaluation, and molecular dynamic simulation.

Drug Des Devel Ther 2019 14;13:1643-1657. Epub 2019 May 14.

Department of Pharmaceutical Chemistry, School of Chemical Sciences & Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia,

Background: The amide derivatives of nonsteroidal anti-inflammatory drugs have been reported to possess antitumor activity. The present work describes the synthesis of dexibuprofen amide analogues () as potential anticancer agents.

Methods: The title amides () were obtained by simple nucleophilic substitution reaction of dexibuprofen acid chloride with substituted amines in good yield and chemical structures were confirmed by FTIR, 1H NMR, 13C NMR and mass spectral data.

Results: The brine shrimp lethality assay results showed that all of the synthesized compounds are non-toxic to shrimp larvae. The inhibitory effects on tumor growth were evaluated and it was observed that N-(2,5-dichlorophenyl)-2-(4-isobutylphenyl) propionamide () and N-(2-chlorophenyl)-2-(4-isobutylphenyl) propionamide () exhibited excellent antitumor activity compared to all other derivatives. The compound bearing 2,5-dichloro substituted phenyl ring and possesses 2-chloro substituted phenyl ring exhibited 100% inhibition of the tumor growth. The anticancer activity was evaluated against breast carcinoma cell line (MCF-7) and it was observed that derivative exhibited excellent growth inhibition of cancer cells with IC value of 0.01±0.002 µm, which is better than the standard drugs. The docking studies against breast cancer type 1 susceptibility protein BRCA1 (PDBID 3K0H) exhibited good binding affinities, which are in good agreement with the wet lab results. The compounds and showed the binding energy values of -6.39 and -6.34 Kcal/mol, respectively. The molecular dynamic (MD) simulation was also carried out to evaluate the residual flexibility of the best docking complexes of compounds and . The MD simulation analysis assured that the formed a more stable complex with the target protein than the . The synthesized amide derivatives exhibited were devoid of gastrointestinal side effects and no cytotoxic effects against human normal epithelial breast cell line (MCF-12A) were found.

Conclusion: Based upon our wet lab and dry lab findings we propose that dexibuprofen analogue may serve as a lead structure for the design of more potent anticancer drugs.
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http://dx.doi.org/10.2147/DDDT.S178595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524612PMC
January 2020

Synthesis and docking studies of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamide analogues as potential alkaline phosphatase inhibitors.

Drug Dev Res 2019 08 29;80(5):646-654. Epub 2019 Apr 29.

Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.

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 IC value 0.420 μM, whereas IC value of standard (KH PO ) 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.
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http://dx.doi.org/10.1002/ddr.21542DOI Listing
August 2019

Novel Amide Derivatives as Potent Tyrosinase Inhibitors; In-vitro, In-vivo Antimelanogenic Activity and Computational Studies.

Med Chem 2019 ;15(7):715-728

Plasma Bioscience Research Center, Kwangwoon University, 20 Kwangwoon-gil, Nowon-gu, Seoul 139-701, South Korea.

Background: Tyrosinase is involved in the melanin biosynthesis and the abnormal accumulation of melanin pigments leading to hyperpigmentation disorders. Controlling the melanogenesis could be an important strategy for treating abnormal pigmentation.

Methods: In the present study, a series of amide derivatives (3a-e and 5a-e) were synthesized aiming to inhibit tyrosinase activity and melanin production. All derivatives were screened for tyrosinase inhibition in a cell-free system. The possible interactions of amide derivatives with tyrosinase enzyme and effect of these interactions on tyrosinase structure were checked by molecular docking in silico and by Circular Dichroism (CD) studies, respectively. The most potent amide derivative (5c) based on cell-free experiments, was further tested for cellular ROS inhibition and for tyrosinase activity using mouse skin melanoma (B16F10) cells.

Results: The tyrosinase inhibitory concentration (IC50) for tested compounds was observed between the range of 68 to 0.0029 µg/ml with a lowest IC50 value of compound 5c which outperforms the reference arbutin and kojic acid. The cellular tyrosinase activity and melanin quantification assay demonstrate that 15µg/ml of 5c attenuates 36% tyrosinase, 24% melanin content of B16F10 cells without significant cell toxicity. Moreover, the zebrafish in vivo assay reveals that 5c effectively reduces melanogenesis without perceptible toxicity. Furthermore, the molecular docking demonstrates that compound 5c interacts with copper ions and multiple amino acids in the active site of tyrosinase with best glide score (-5.387 kcal/mol), essential for mushroom tyrosinase inhibition and the ability to diminish the melanin synthesis in-vitro and in-vivo.

Conclusion: Thus, we propose compound 5c as a potential candidate to control tyrosinase rooted hyperpigmentation in the future.
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http://dx.doi.org/10.2174/1573406415666190319101329DOI Listing
December 2019

Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF).

Sci Rep 2019 02 27;9(1):2905. Epub 2019 Feb 27.

Cure Brain Cancer Foundation Biomarkers and Translational Research Group, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Recurrence in patients with glioblastoma (GBM) is inevitable resulting in short survival times, even in patients with O-6-Methylguanine-DNA Methyltransferase (MGMT) methylation. Other pathways must be activated to escape from temozolomide (TMZ) treatment, however acquired resistance mechanisms to TMZ are not well understood. Herein, frozen tumors from 36 MGMT methylated patients grouped according to overall survival were extracted and proteins were profiled using surface-enhanced laser desorption/ionization (SELDI) with time-of flight (TOF) proteomics to identify low molecular weight proteins that associated with poor survival outcomes. Overexpression of macrophage migration inhibitory factor (MIF) was identified in human GBM specimens that were MGMT methylated but showed poor survival. This correlation was confirmed in an independent cohort of human GBM. MIF overexpression has been reported in several cancer types, including GBM. We repurposed ibudilast, a specific MIF inhibitor, and treated patient derived cell lines. Ibudilast showed modest anti-proliferative activity however, when combined with TMZ, significant synergism was observed, resulting in cell cycle arrest and apoptosis. In vivo, combined ibudilast and TMZ treatment of a patient derived xenograft (PDX) model resulted in significantly longer overall survival. Our findings have significant clinical implications for people with GBM. Since clinical trials involving ibudilast have shown no adverse side effects and the drug readily penetrates the blood brain barrier, treatment of GBM with this combination is clinically achievable.
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http://dx.doi.org/10.1038/s41598-019-39427-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393433PMC
February 2019

Synthesis, carbonic anhydrase inhibitory activity and antioxidant activity of some 1,3-oxazine derivatives.

Drug Dev Res 2018 11 10;79(7):352-361. Epub 2018 Oct 10.

School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa.

Hit, Lead & Candidate Discovery A series of 1-(6-methyl-2-substituted phenyl-4-thioxo-4H-1,3-oxazin-5-yl)ethanones (3a-n) were synthesized by the reaction of benzoyl isothiocyanates with active methylene compound acetylacetone in the presence of triethyl amine in a one-pot process. The structures of the products were elucidated by elemental analyses, FT-IR, H NMR, C NMR, and mass spectroscopy. These new 1,3-oxazine derivatives were evaluated for their inhibitory activity against carbonic anhydrase II. Results for in vitro assay revealed that compound 3b having 4-methoxy phenyl moiety was the most potent inhibitor with IC value of 0.144 ± 0.008 μM. It exhibited higher enzyme inhibitory activity as compared to the standard acetazolamide (IC  = 0.997 ± 0.061 μM). The compounds 3c, 3h, and 3n also displayed superior inhibitory activities compared to the rest of the synthesized oxazine derivatives. The radical scavenging activity of oxazine derivatives was also performed and it was found that compounds showed moderate antioxidant activity. Lipinski rule confirmed the therapeutic potential of the synthesized compounds. Molecular docking studies were also performed to further understand the binding affinity of these compounds with PDBID 1V9E which confirmed that the synthesized derivatives bind in the active binding site of the target protein. Based upon our results, it is proposed that compound 3b may serve as a lead structure to design more potent carbonic anhydrase inhibitors.
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http://dx.doi.org/10.1002/ddr.21464DOI Listing
November 2018

Antihyperlipidemic studies of newly synthesized phenolic derivatives: in silico and in vivo approaches.

Drug Des Devel Ther 2018 9;12:2443-2453. Epub 2018 Aug 9.

Department of Pharmacy, COMSATS Institute of Information Technology Abbottabad, Abbottabad, Pakistan.

Background: Hyperlipidemia is a worth-mentioning risk factor in quickly expanding cardiovascular diseases, including myocardial infarction and, furthermore, in stroke.

Methods: The present work describes the synthesis of phenolic derivatives - and - with the aim of developing antihyperlipidemic agents. The structures of the synthesized compounds were confirmed by spectroscopic data. The in silico docking studies were performed against human 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase enzyme (PDB ID: 1HWK), and it was observed that compounds and exhibited maximum binding affinity with target protein having binding energies -8.3 and -7.9 kcal, respectively.

Results: Compound interacts with amino acids Val805 with distance 1.89 Å and Met656, Thr558, and Glu559 with bonding distances 2.96, 2.70, and 2.20 Å, respectively. The in vivo antihyperlipidemic activity results revealed that compound indicated minimum weight increment, ie, 20% compared with 35% weight increment with standard drug atorvastatin during 6 weeks of treatment. Moreover, increment in high-density lipoprotein cholesterol and decrease in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were more prominent in case of compared to atorvastatin with <0.05. The synthesized compounds were nontoxic and well tolerated because none of the mice were found to suffer from any kind of morbidity and death during 6 weeks of dosing.

Conclusion: Based on our pharmacological evaluation, we may propose that compound may act as a lead structure for the design and development of more potent antihyperlipidemic drugs.
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http://dx.doi.org/10.2147/DDDT.S158554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089105PMC
December 2018

Synthesis of aryl pyrazole via Suzuki coupling reaction, in vitro mushroom tyrosinase enzyme inhibition assay and in silico comparative molecular docking analysis with Kojic acid.

Bioorg Chem 2018 09 30;79:293-300. Epub 2018 Apr 30.

Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan.

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 = 1.568 ± 0.01 µM) showed relatively better potential compared to reference kojic acid (IC = 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.
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http://dx.doi.org/10.1016/j.bioorg.2018.04.026DOI Listing
September 2018

Synthesis, computational studies and enzyme inhibitory kinetics of substituted methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates as mushroom tyrosinase inhibitors.

Bioorg Med Chem 2017 11 18;25(21):5929-5938. Epub 2017 Sep 18.

Department of Chemistry, Quaid-i-Azam University, 45320 Islamabad, Pakistan.

The present article describes the synthesis and enzyme inhibitory kinetics of methyl[2-(arylmethylene-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates 5a-j as mushroom tyrosinase inhibitors. The title compounds were synthesized via cyclocondensation of thiosemicarbazones 3a-j with dimethyl but-2-ynedioate (DMAD) 4 in good yields under solvent-free conditions. The synthesized compounds were evaluated for their potential to inhibit the activity of mushroom tyrosinase. It was unveiled that compounds 5i showed excellent enzyme inhibitory activity with IC 3.17µM while IC of standard kojic acid is 15.91µM. The presence of heterocyclic pyridine ring in compound 5i play important role in enzyme inhibitory activity as rest of the functional groups are common in all synthesized compounds. The enzyme inhibitory kinetics of the most potent derivative 5i determined by Lineweaver-Burk plots and Dixon plots showed that it is non-competitive inhibitor with Ki value 1.5µM. It was further investigated that the wet lab results are in good agreement with the computational results. The molecular docking of the synthesized compounds was performed against tyrosinase protein (PDBID 2Y9X) to delineate ligand-protein interactions at molecular level. The docking results showed that the major interacting residues are His244, His85, His263, Val 283, His 296, Asn260, Val248, His260, His261 and Phe264 which are located in active binding site of the protein. The molecular modeling demonstrates that the oxygen atom of the compound 5i coordinated with the key residues in the active site of mushroom tyrosinase contribute significantly against inhibitory ability and diminishing the human melanin synthesis. These results evident that compound 5i is a lead structure in developing most potent mushroom tyrosinase inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2017.09.009DOI Listing
November 2017

Synthesis, enzyme inhibitory kinetics, and computational studies of novel 1-(2-(4-isobutylphenyl) propanoyl)-3-arylthioureas as Jack bean urease inhibitors.

Chem Biol Drug Des 2018 02 7;91(2):434-447. Epub 2017 Nov 7.

Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan.

In this article, synthesis of a novel 1-(2-(4-isobutylphenyl)propanoyl)-3-arylthioureas (4a-j) as jack bean urease inhibitors has been described. Freshly prepared 2-(4-isobutylphenyl) propanoyl isothiocyanate was treated with substituted aromatic anilines in one pot using anhydrous acetone. The compounds 4e, 4h, and 4j showed IC values 0.0086 nm, 0.0081 nm, and 0.0094 nm, respectively. The enzyme inhibitory kinetics results showed that compound 4h inhibit the enzyme competitively while derivatives 4e and 4j are the mixed type inhibitors. The compound 4h reversibly binds the urease enzyme showing Ki value 0.0012 nm. The Ki values for 4e and 4j are 0.0025 nm and 0.003 nm, respectively. The antioxidant activity results reflected that compounds 4b, 4i, and 4j showed excellent radical scavenging activity. Moreover, the cytotoxic activity of the target compounds was evaluated using brine shrimp assay and it was found that all of the synthesized compounds exhibited no cytotoxic effects to brine shrimps. The computational molecular docking and molecular dynamic simulation of title compounds were also performed, and results showed that the wet laboratory findings are in good agreement to the dry laboratory results. Based upon our results, it is proposed that compound 4h may act as a lead candidate to design the clinically useful urease inhibitors.
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http://dx.doi.org/10.1111/cbdd.13090DOI Listing
February 2018

Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies.

Drug Des Devel Ther 2017 5;11:2029-2046. Epub 2017 Jul 5.

Department of Biology, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea.

The present work describes the synthesis of few hydroxylated amide derivatives as melanogenesis inhibitors. In vitro, in vivo and computational studies proved that compound is a highly potent melanogenesis inhibitor compared to standard kojic acid. The title amides - and - were synthesized following simple reaction routes with excellent yields. Most of the synthesized compounds exhibited good mushroom tyrosinase inhibitory activity, but compound showed excellent activity (IC 0.15 µM) compared to standard kojic acid (IC 16.69 µM). Lineweaver-Burk plots were used for the determination of kinetic mechanism, and it was found that compounds and showed non-competitive inhibition while and showed mixed-type inhibition. The kinetic mechanism further revealed that compound formed irreversible complex with the target enzyme tyrosinase. The values determined for compounds , , and are 0.188, 0.84, 2.20 and 0.217 µM respectively. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound exhibited 91.9% inhibi-tory activity at a concentration of 50 µg/mL. In vivo cytotoxicity evaluation of compound in zebrafish embryos showed that it is non-toxic to zebrafish. Melanin depigmentation assay performed in zebrafish indicated that compound possessed greater potential in decreasing melanin contents compared to kojic acid at the same concentration. Computational studies also supported the wet lab findings as compound showed a highest binding affinity with the target protein (PDBID: 2Y9X) with a binding energy value of -7.90 kcal/mol. Molecular dynamic simulation studies also proved that amide formed the most stable complex with tyrosinase. Based upon our in vitro, in vivo and computational studies, we propose that compound is a promising candidate for the development of safe cosmetic agent.
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http://dx.doi.org/10.2147/DDDT.S137550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503496PMC
June 2018

Carvacrol derivatives as mushroom tyrosinase inhibitors; synthesis, kinetics mechanism and molecular docking studies.

PLoS One 2017 23;12(5):e0178069. Epub 2017 May 23.

School of Chemical Sciences & Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia.

The present work describesthe development of highly potent mushroom tyrosinase inhibitor better than the standard kojic acid. Carvacrol derivatives 4a-f and 6a-d having substituted benzoic acid and cinnamic acidresidues were synthesized with the aim to possess potent tyrosinase inhibitory activity.The structures of the synthesized compounds were ascertained by their spectroscopic data (FTIR, 1HNMR, 13CNMR and Mass Spectroscopy).Mushroom tyrosinase inhibitory activity of synthesized compounds was determined and it was found that one of the derivative 6c possess higher activity (IC50 0.0167μM) than standard kojic acid (IC50 16.69μM). The derivatives 4c and 6b also showed good tyrosinase inhibitory activity with (IC50 16.69μM) and (IC50 16.69μM) respectively.Lineweaver-Burk and Dixon plots were used for the determination of kinetic mechanism of the compounds 4c and 6b and 6c. The kinetic analysis revealed that compounds 4c and 6b showed mixed-type inhibition while 6c is a non-competitive inhibitor having Ki values19 μM, 10 μM, and 0.05 μMrespectively. The enzyme inhibitory kinetics further showed thatcompounds 6b and 6c formed irreversible enzyme inhibitor complex while 4c bind reversibly with mushroom tyrosinase.The docking studies showed that compound 6c have maximum binding affinity against mushroom tyrosinase (PDBID: 2Y9X) with binding energy value (-7.90 kcal/mol) as compared to others.The 2-hydroxy group in compound 6c interacts with amino acid HIS85 which is present in active binding site. The wet lab results are in good agreement with the dry lab findings.Based upon our investigation we may propose that the compound 6c is promising candidate for the development of safe cosmetic agent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178069PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441849PMC
September 2017

First macrocyclic 3-generation ALK inhibitor for treatment of ALK/ROS1 cancer: Clinical and designing strategy update of lorlatinib.

Eur J Med Chem 2017 Jul 13;134:348-356. Epub 2017 Apr 13.

Centre for Genetics and Inherited Diseases, Taibah University, Al-Madinah Al-Munawwarah, Kingdom of Saudi Arabia. Electronic address:

Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to 2-generation ALK inhibitors. Lorlatinib (PF-06463922) (6) is a 3-generation macrocyclic ALK-TKI that demonstrates many advantages over 2-generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings.
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http://dx.doi.org/10.1016/j.ejmech.2017.04.032DOI Listing
July 2017

Pharmacoinformatics exploration of polyphenol oxidases leading to novel inhibitors by virtual screening and molecular dynamic simulation study.

Comput Biol Chem 2017 Jun 15;68:131-142. Epub 2017 Mar 15.

Department of Biology, College of Natural Sciences, Kongju National University, Gongju 32588, Republic of Korea. Electronic address:

Polyphenol oxidases (PPOs)/tyrosinases are metal-dependent enzymes and known as important targets for melanogenesis. Although considerable attempts have been conducted to control the melanin-associated diseases by using various inhibitors. However, the exploration of the best anti-melanin inhibitor without side effect still remains a challenge in drug discovery. In present study, protein structure prediction, ligand-based pharmacophore modeling, virtual screening, molecular docking and dynamic simulation study were used to screen the strong novel inhibitor to cure melanogenesis. The 3D structures of PPO1 and PPO2 were built through homology modeling, while the 3D crystal structures of PPO3 and PPO4 were retrieved from PDB. Pharmacophore modeling was performed using LigandScout 3.1 software and top five models were selected to screen the libraries (2601 of Aurora and 727, 842 of ZINC). Top 10 hit compounds (C1-10) were short-listed having strong binding affinities for PPO1-4. Drug and synthetic accessibility (SA) scores along with absorption, distribution, metabolism, excretion and toxicity (ADMET) assessment were employed to scrutinize the best lead hit. C4 (name) hit showed the best predicted SA score (5.75), ADMET properties and drug-likeness behavior among the short-listed compounds. Furthermore, docking simulations were performed to check the binding affinity of C1-C10 compounds against target proteins (PPOs). The binding affinity values of complex between C4 and PPOs were higher than those of other complexes (-11.70, -12.1, -9.90 and -11.20kcal/mol with PPO1, PPO2, PPO3, or PPO4, respectively). From comparative docking energy and binding analyses, PPO2 may be considered as better target for melanogenesis than others. The potential binding modes of C4, C8 and C10 against PPO2 were explored using molecular dynamics simulations. The root mean square deviation and fluctuation (RMSD/RMSF) graphs results depict the significance of C4 over the other compounds. Overall, bioactivity and ligand efficiency profiles suggested that the proposed hit may be more effective inhibitors for melanogenesis.
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http://dx.doi.org/10.1016/j.compbiolchem.2017.02.012DOI Listing
June 2017

Synthesis, characterization of amide substituted dexibuprofen derivatives and their spectral, voltammetric and docking investigations for DNA binding interactions.

J Photochem Photobiol B 2017 Apr 3;169:134-147. Epub 2017 Mar 3.

Research Center for Modeling and Simulations, National University of Sciences and Technology, Islamabad, Pakistan.

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) and Gibbs free energy changes (-ΔG) were evaluated greater at pH7.4 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 values i.e., {UV-visible: pH 4.7 (2.36×10M); pH7.4 (2.42×10M), fluorescence: pH4.7 (2.24×10M); pH7.4 (2.56×10M) and CV: pH4.7 (4.06×10M); pH7.4 (4.89×10M)}. 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<1 indicated the possibility of binding via groove or electrostatic interactions. Electrochemical processes were found diffusion controlled and diffusion coefficients (D) 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.
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http://dx.doi.org/10.1016/j.jphotobiol.2017.02.021DOI Listing
April 2017

Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen-Antioxidant Mutual Prodrugs.

Int J Mol Sci 2016 Dec 21;17(12). Epub 2016 Dec 21.

Department of Biology, College of Natural Sciences, Kongju National University, Gongju 314701, Korea.

Dexibuprofen-antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen - were obtained by reacting its -COOH group with chloroacetyl derivatives -. The in vitro hydrolysis data confirmed that synthesized prodrugs - 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 ( < 0.001) is more significant than the parent dexibuprofen. The prodrug produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs and showed significant inhibition of pyrexia ( < 0.001). The analgesic activity of is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 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 - 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.
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http://dx.doi.org/10.3390/ijms17122151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187951PMC
December 2016

Isolation, characterization, and in silico, in vitro and in vivo antiulcer studies of isoimperatorin crystallized from Ostericum koreanum.

Pharm Biol 2017 Dec;55(1):218-226

a Department of Biological Sciences College of Natural Sciences , Kongju National University , Gongju , Chungnam , Republic of Korea.

Context: Ostericum koreanum (Maxim.) Kitagawa (Apiaceae) roots are traditionally used as an analgesic and antiulcer agent. However, the antiulcer potential of isoimperatorin isolated from O. koreanum has not yet been explored.

Aim: To evaluate the antiulcer activity of isoimperatorin isolated from the roots of O. koreanum.

Materials And Methods: Isoimperatorin was isolated as cubic crystals by repeated column chromatography of the ethyl acetate fraction and structure was verified with H NMR, C NMR and high-resolution mass spectrometry (HRMS-FAB). The crystals obtained were analyzed with the single crystal X-ray method. The MTT assay was used to determine its cytotoxicity against chondrocytes at different concentrations (0.0-737.74 μM, 24 h). The in vivo antiulcer activity of isoimperatorin (40 mg/kg) was determined against ethanol-, indomethacin- and pyloric ligation-induced ulcers in Sprague-Dawley rats. Furthermore, the effect of isoimperatorin (0.0-737.74 μM, 24 h) on the expression of type II collagen in chondrocytes was determined using western blot method. The in vitro urease inhibitory activity of isoimperatorin (0-80 μM) and molecular docking was also performed against urease.

Results And Discussion: Isoimperatorin demonstrated significant inhibitory activity (IC 36.43 μM) against urease as compared to the standard drug thiourea (IC 33.57 μM) without cytotoxic effects. It provided 70.9%, 67.65% and 54.25% protection in ulcer models induced by ethanol, indomethacin and pyloric ligation, respectively. Isoimperatorin showed the highest expression level of type II collagen at 368.87 μM. The docking results confirmed strong binding affinity with the target protein.

Conclusion: Isoimperatorin may be used to develop antiulcer drugs with decreased side effects.
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http://dx.doi.org/10.1080/13880209.2016.1257641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130598PMC
December 2017