Publications by authors named "Zahid Shafiq"

50 Publications

Development of coumarin-thiosemicarbazone hybrids as aldose reductase inhibitors: Biological assays, molecular docking, simulation studies and ADME evaluation.

Bioorg Chem 2021 Jul 13;115:105164. Epub 2021 Jul 13.

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

The over expression of aldose reductase (ALR2) in the state of hyperglycemia causes the conversion of glucose into sorbitol and initiates polyol pathway. Accumulation of sorbitol in insulin insensitive tissue like peripheral nerves, glomerulus and eyes, induces diabetic complications like neuropathy, nephropathy and retinopathy. For the treatment of diabetic complications, the inhibition of aldose reductase (ALR2) is a promising approach. A series of coumarin-based thiosemicarbazone derivatives was synthesized as potential inhibitor of aldose reductase. Compound N-(2-fluorophenyl)-2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)hydrazinecarbiothioamide (3n) was found to be the most promising inhibitor of ALR2 with an IC in micromolar range (2.07 µM) and high selectivity, relative to ALR1. The crystal structure of ALR2 complexed with 3n explored the types of interaction pattern which further demonstrated its high affinity. Compound 3n has excellent lead-likeness, underlined by its physicochemical parameters, and can be considered as a likely prospect for further structural optimization to get a drugable molecule.
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http://dx.doi.org/10.1016/j.bioorg.2021.105164DOI Listing
July 2021

An Efficient Synthesis, Spectroscopic Characterization, and Optical Nonlinearity Response of Novel Salicylaldehyde Thiosemicarbazone Derivatives.

ACS Omega 2021 Jun 11;6(24):16058-16065. Epub 2021 Jun 11.

Department of Chemistry, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia.

In this study, seven derivatives of salicylaldehyde thiosemicarbazones (-) were synthesized by refluxing substituted thiosemicarbazide and salicylaldehyde in an ethanol solvent. Different spectral techniques (UV-vis, IR, and NMR) were used to analyze the prepared compounds (-). Accompanied by the experimental study, quantum chemical studies were also carried out at the M06/6-311G(d,p) level. A comparative analysis of the UV-visible spectra and vibrational frequencies between computational and experimental findings was also performed. These comparative data disclosed that both studies were observed to be in excellent agreement. Furthermore, natural bond orbital investigations revealed that nonbonding transitions were significant for the stability of prepared molecules. In addition, frontier molecular orbital (FMO) findings described that a promising charge transfer phenomenon was found in -. The energies of FMOs were further used to determine global reactivity parameters (GRPs). These GRP factors revealed that all synthesized compounds (-) contain a greater hardness value (η = 2.1 eV) and a lower softness value (σ = 0.24 eV), which indicated that these compounds were less reactive and more stable. Nonlinear optical (NLO) evaluation displayed that compound consisted of greater values of linear polarizability ⟨α⟩ and third-order polarizability ⟨γ⟩ of 324.93 and 1.69 × 10 a.u., respectively, while compound exhibited a larger value of second-order polarizability (β) of 508.41 a.u. The NLO behavior of these prepared compounds may be significant for the hi-tech NLO applications.
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http://dx.doi.org/10.1021/acsomega.1c01938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223424PMC
June 2021

Synthesis of indole-substituted thiosemicarbazones as an aldose reductase inhibitor: an , selectivity and study.

Future Med Chem 2021 Jul 21;13(14):1185-1201. Epub 2021 Jun 21.

Natural & Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman.

Indole is an important component of many drug molecules, and its conjugation with thiosemicarbazone moiety would be advantageous in finding lead compounds for the development of diabetic complications. We have designed, synthesized and evaluated a series of 17 indole-thiosemicarbazones ( as aldose reductase (ALR2) and aldehyde reductase (ALR1) inhibitors. After evaluation, all indole-thiosemicarbazones showed significant inhibition against both enzyme ALR1 and ALR2 with IC in range of 0.42-20.7 and 1.02-19.1 μM, respectively. The docking study was also carried out to consider the putative binding of molecules with the target enzymes. Compound was found to be most active and selective for ALR2. The indole-thiosemicarbazones series described here has selective hits for diabetes-mellitus-associated complications.
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http://dx.doi.org/10.4155/fmc-2020-0060DOI Listing
July 2021

Synthesis, biological activity and docking calculations of bis-naphthoquinone derivatives from Lawsone.

Bioorg Chem 2021 Sep 8;114:105069. Epub 2021 Jun 8.

Department of Chemistry, Faculty of Science, Ataturk University, 25240 Erzurum, Turkey.

Some metabolic enzyme inhibitors can be used as Multi-target-Directed-Ligands (MTDL) in Medicinal chemistry therefore, synthesis and determination of alternative inhibitors are essential. In this study, novel bis-napthoquinone derivatives (5a-o) were synthesized through a multi-component cascade reaction of two molecules of 2-hydroxy-1,4-naphthoquinone with an aromatic aldehyde in basic media using triethylamine as a catalyst. This novel heterocyclic derivatives (5a-o) are applied to inhibit the carbonic anhydrase (hCA I and hCA II) isoform in low levels of nano molecules with Ki values exist between 4.62 ± 1.01 to 70.45 ± 9.03 nM for hCA I and for hCA II which is physiologically dominant Ks values are in the range of 5.61 ± 1.04 to 73.26 ± 10.25 nM. Further these novel derivatives (5a-o) efficiently inhibit AChE with Ki values in the range of 0.13 ± 0.02 to 3.16 ± 0.56 nM. The compounds are also applied for BChE with Ki values varying between 0.50 ± 0.10 to 9.23 ± 1.15 nM. For α-glycosidase, the most efficient Ki values of 5e and 5f are 76.14 ± 9.60 and 95.27 ± 12.55 nM respectively. Finally, molecular docking calculations against enzymes (acetylcholinesterase, butyrylcholinesterase, and the human carbonic anhydrase I and II) are compared using biological activities of heterocyclic derivatives. After these calculations, an ADME/T analysis is performed to study the future medicinal use of heterocyclic derivatives from lawsone.
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http://dx.doi.org/10.1016/j.bioorg.2021.105069DOI Listing
September 2021

Coumarin based thiosemicarbazones as effective chemosensors for fluoride ion detection.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Nov 29;261:120011. Epub 2021 May 29.

Institute of Chemical Sciences, Bahauddin Zakariya University, 60800 Multan, Pakistan.

Anion sensing have attained immense importance as these charged ions are prevailing in agriculture industry and in heavy industry and therefore in the environment around us, chemosensors are commencing to claim several applications as their role is being better perceived day by day. In the current study, coumarin based thiosemicarbazone R-1 (phenyl moiety) and R-2 (benzyl moiety) were synthesized. It was observed that there were variations in the sensing patterns of compound bearing benzyl group, as compared to the simple phenyl group bearing receptor. Different techniques were used to confirm the interaction of coumarin based receptors with anions. These techniques included naked-eye test, UV-visible, 1H NMR, and fluorescence spectroscopic techniques. The synthesized receptors showed selectivity for fluoride ions. Benesi-Hildebrand equation was employed for determining the detection limits and binding constants values. The synthesized receptors were employed as efficient chemosensors in real life samples and satisfactory results were obtained.
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http://dx.doi.org/10.1016/j.saa.2021.120011DOI Listing
November 2021

Exploring biologically active hybrid pharmacophore N-substituted hydrazine-carbothioamides for urease inhibition: In vitro and in silico approach.

Int J Biol Macromol 2021 Jul 9;182:534-544. Epub 2021 Apr 9.

Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address:

Urease is potential target for various human's health complications, such as peptic ulcer, gastric cancer and kidney stone formation. The present study was based on synthesis of new hybrid pharmacophore N-substituted hydrazine-carbothioamides as potential urease inhibitors. Presented method gave excellent yield in range of 85-95% for hydrazine-carbothioamides derivatives (3a-s) after reaction of mono- and disubstituted hydrazides (1a-k) and substituted isothiocyanates (2a-d). All newly derivatives were characterized by advanced spectroscopic techniques (FTIR, HNMR, CNMR, EMS) and were assessed for their urease inhibition potential. All analogs except for 3k, 3l and 3m demonstrated strong inhibitory potential for urease with IC values of 8.45 ± 0.14 to 25.72 ± 0.23 μM as compared to standard thiourea (IC 21.26 ± 0.35 μM). The structure-activity relationship and mode of interaction was established by molecular docking studies. It was revealed that the N-substituted hydrazine-carbothioamides interacted with nickel atoms present in the active site of urease and supported the correlations with the experimental findings. Therefore, the afforded hydrazine-carbothioamides derivatives are interesting hits for urease inhibition studies with future prospects of modification and optimization.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.04.036DOI Listing
July 2021

Synthesis of benzimidazole based hydrazones as non-sugar based α-glucosidase inhibitors: Structure activity relation and molecular docking.

Drug Dev Res 2021 Mar 5. Epub 2021 Mar 5.

Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman.

In search for α-glucosidase inhibitors used in the treatment of diabetes mellitus, a series of unique benzimidazole based hydrazones derivatives were synthesized (5a-5p), which were then investigated for their in vitro α-glucosidase inhibitory potential. The compounds of interest were characterized by modern spectroscopic approaches including CHN, HNM R, CN MR and FTIR. The structure of compound 5n was distinctively authenticated through single crystal X-ray study. All compounds depicted potent enzyme inhibitory potential with IC values in the range of 2.25 ± 0.01 to 81.16 ± 0.12 μM except 5n that showed IC value of 182.75 ± 0.13 μM. A limited structure-activity correlation demonstrated that substitutions of isatin, aldehydes and ketone in hydrazones moiety had remarkable contribution in the overall activity and that was further supported by molecular docking studies carried out in elucidating the mechanism of binding interaction of these compounds in the catalytic site of α-glucosidase.
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http://dx.doi.org/10.1002/ddr.21807DOI Listing
March 2021

Therapeutic potential of N-substituted thiosemicarbazones as new urease inhibitors: Biochemical and in silico approach.

Bioorg Chem 2021 04 2;109:104691. Epub 2021 Feb 2.

Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address:

Urease enzyme plays a key role in pathogenesis of gastritis and peptic ulcers. Its inhibition averts our bodies from many disorders including formation of urinary calculi. In agriculture, the high urease content causes severe environmental and hence economic problems. Due to deficiency of effective and safer drugs to tackle the aforementioned disorders, the quest for new scaffolds becomes mandatory in the field of medicinal chemistry. In this regard, we herein report a new series of N-substituted thiosemicarbazones 3a-v as potential candidates for urease inhibition. These new N-substituted thiosemicarbazones 3a-v of distant chemical scaffolds were characterized by advanced spectroscopic techniques, such as FTIR, HNMR, CNMR, ESI-MS and in the case of compound 3g by single crystal X-ray analysis. The compounds were evaluated for their urease inhibitory potential. All newly synthesized compounds showed significant urease inhibitions with IC values in range of 2.7 ± 0.320-109.2 ± 3.217 μM. Molecular docking studies were used for interactions pattern and structure-activity relationship for all compounds, which demonstrated excellent binding interactions with the active site residues, such as hydrogen bonding, π-π interactions, π-H and nickel atom coordination.
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http://dx.doi.org/10.1016/j.bioorg.2021.104691DOI Listing
April 2021

Probing 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones as multi-target directed ligands against cholinesterases, carbonic anhydrases and α-glycosidase enzymes.

Bioorg Chem 2021 02 15;107:104554. Epub 2020 Dec 15.

Department of Chemistry, Faculty of Science, Ataturk University, 25240 Erzurum, Turkey.

With the fading of 'one drug-one target' approach, Multi-Target-Directed Ligands (MTDL) has become a central idea in modern Medicinal Chemistry. The present study aimed to design, develop and characterize a novel series of 4-(Diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) and evaluates their biological activity against cholinesterase, carbonic anhydrases and α-glycosidase enzymes. The hCA I isoform was inhibited by these novel 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones (3a-p) in low nanomolar levels, the Ki of which differed between 407.73 ± 43.71 and 1104.11 ± 80.66 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Ks varying from 323.04 ± 56.88 to 991.62 ± 77.26 nM. Also, these novel 4-(diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) effectively inhibited AChE, with Ki values in the range of 121.74 ± 23.52 to 548.63 ± 73.74 nM. For BChE, Ki values were obtained with in the range of 132.85 ± 12.53 to 618.53 ± 74.23 nM. For α-glycosidase, the most effective Ki values of 3b, 3k, and 3g were with Ki values of 77.85 ± 10.64, 96.15 ± 9.64, and 124.95 ± 11.44 nM, respectively. We have identified inhibition mechanism of 3b, 3g, 3k, and 3n on α-glycosidase AChE, hCA I, hCA II, and BChE enzyme activities. Hydrazine-1-carbothioamide and hydroxybenzylidene moieties of compounds play an important role in the inhibition of AChE, hCA I, and hCA II enzymes. Hydroxybenzylidene moieties are critical for inhibition of both BChE and α-glycosidase enzymes. The findings of in vitro and in silico evaluations indicate 4-(diethylamino)-salicylaldehyde-based thiosemicarbazone scaffold to be a promising hit for drug development for multifactorial diseases like Alzheimer's disease.
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http://dx.doi.org/10.1016/j.bioorg.2020.104554DOI Listing
February 2021

Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, , Selectivity, and Kinetics Studies.

Front Chem 2020 1;8:598095. Epub 2020 Dec 1.

Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman.

Carbonic anhydrase-II (CA-II) is associated with glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. In search of potent CA-II inhibitors, a series of quinazolinones derivatives () were synthesized and characterized by IR and NMR spectroscopy. The inhibitory potential of all the compounds was evaluated against bovine carbonic anhydrase-II (CA-II) and human carbonic anhydrase-II (CA-II), and compounds displayed moderate to significant inhibition with IC values of 8.9-67.3 and 14.0-59.6 μM, respectively. A preliminary structure-activity relationship suggested that the presence of a nitro group on the phenyl ring at R position contributes significantly to the overall activity. Kinetics studies of the most active inhibitor, , against both CA-II and CA-II were performed to investigate the mode of inhibition and to determine the inhibition constants (Ki). According to the kinetics results, is a competitive inhibitor of CA-II and CA-II with Ki values of 13.0 ± 0.013 and 14.25 ± 0.017 μM, respectively. However, the selectivity index reflects that the compounds and are more selective for CA-II. The binding mode of these compounds within the active sites of CA-II and CA-II was investigated by structure-based molecular docking. The docking results are in complete agreement with the experimental findings.
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http://dx.doi.org/10.3389/fchem.2020.598095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736042PMC
December 2020

Synthesis, Characterization, and Studies of Novel Spirooxindole Derivatives as Ecto-5'-Nucleotidase Inhibitors.

ACS Med Chem Lett 2020 Dec 29;11(12):2397-2405. Epub 2020 Oct 29.

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

Ecto-5'-nucleotidase (ecto-5'-NT, CD73) inhibitors are promising drug candidates for cancer therapy. Traditional efforts used to inhibit the ecto-5'-nucleotidase have involved antibody therapy or development of small molecule inhibitors that can mimic the acidic and ionizable structure of adenosine 5'-monophosphate (AMP). Herein, we report an efficient, environment friendly route for the synthesis of non-nucleotide based small molecules, i.e., substituted spirooxindole derivatives - and investigated their inhibitory potential on human and rat recombinant ecto-5'-nucleotidase isozymes. These attempts have resulted in the identification of compound (IC = 0.15 ± 0.02 μM) inhibitor on -ecto-5'-NT which showed 280-fold higher inhibition and compound (IC ± 0.19 ± 0.03 μM) on -ecto-5'-NT with 406-fold enhanced inhibition than reference standard sulfamic acid. Moreover, studies were carried out to assess binding interactions of potent compounds within enzyme active sites and demonstrated excellent correlation with the experimental findings.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734640PMC
December 2020

Exploration of Chromone-Based Thiosemicarbazone Derivatives: SC-XRD/DFT, Spectral (IR, UV-Vis) Characterization, and Quantum Chemical Analysis.

ACS Omega 2020 Nov 10;5(46):30176-30188. Epub 2020 Nov 10.

Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Avenida Professor Lineu Prestes, 748, São Paulo 05508-000, Brazil.

By the condensation of thiosemicarbazide with coumarin aldehyde, two novel substituted thiosemicarbazones with chemical formulae CHNOS () and CHNOS () have been synthesized. The synthesized compounds were resolved using SC-XRD, and structure elucidation was carried out using H NMR, C NMR, UV-visible, and FT-IR spectroscopic analyses. Computational calculations at the B3LYP/6-311+G(d,p) level of theory were performed to countercheck the experimental (UV-vis, FT-IR) findings and explore the electronic (FMO, NBO, MEP) properties of . The nonlinear optical (NLO) properties of were estimated using B3LYP, HF, LC-BLYP, CAM-B3LYP, M062X, and M06 functionals in combination with the 6-311+G(d,p) basis set. The crystallographic data revealed that compounds were crystallized as an orthorhombic crystal lattice with the space group and the triclinic crystal lattice with the 1 space group. A good concurrence among experimental SC-XRD-generated bond lengths, bond angles, FT-IR, UV-vis, and corresponding DFT results was found, which confirms the purity of both compounds. The NBO analysis confirmed the presence of intramolecular hydrogen bonding and hyperconjugative interactions, which not only were the pivotal cause of stability of the investigated compounds but also led to an overwhelming NLO response. The energy differences calculated for HOMO/LUMO are 3.053 and 3.118 eV in and , respectively. The crystal showed a higher value of first-order polarizability at all levels of theory than . Overall results show that the crystals under investigation are polarized in nature with a good dipole moment. A comparative analysis with urea molecules clearly indicates that the studied compounds are acceptable NLO candidates and they can be used for future technological applications.
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http://dx.doi.org/10.1021/acsomega.0c04653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689885PMC
November 2020

Probing sulphamethazine and sulphamethoxazole based Schiff bases as urease inhibitors; synthesis, characterization, molecular docking and ADME evaluation.

Bioorg Chem 2020 12 6;105:104336. Epub 2020 Oct 6.

Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address:

In the current study, a novel series of Schiff base derivatives of (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (3a-3f) and (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (3g-3q) were synthesize. The structures of synthetic compounds were elucidated by various spectroscopic techniques such as FTIR, NMR and spectrometric HRMS analysis. Synthetic derivatives were evaluated for their Jack Bean urease inhibitory activity using established in-vitro assay. It is worth mentioning here that most of our derivatives of both series displayed moderate to strong inhibitory activity, ranging between IC = 2.48 ± 0.78 µM and 35.63 ± 1.26 µM, as compared to standard thiourea (IC = 20.03 ± 2.03 µM). Further, structure activity relationship studies suggest that the presence of halogen at ortho and para positions on the aryl ring in (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide derivatives and hydroxy and halogen in (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide derivatives increased the urease inhibitory activity. Furthermore, molecular docking studies were carried out in order to investigate the binding mode of this class of compounds to urease. In order to evaluate drug likeness of compounds ADME evaluation was done, and the synthesized compounds were found to be non-toxic and present passive gastrointestinal absorption. The data suggests the synthesized sulphamethazine and sulphamethoxazole derivatives can serve as a novel scaffold to inhibit urease.
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http://dx.doi.org/10.1016/j.bioorg.2020.104336DOI Listing
December 2020

CuO Hollow Cubic Caves Wrapped with Biogenic N-Rich Graphitic C for Simultaneous Monitoring of Uric Acid and Xanthine.

ACS Appl Mater Interfaces 2020 Oct 6;12(42):47320-47329. Epub 2020 Oct 6.

Interdisciplinary Research Centre in Biomedical Materials (IRCBM), COMSATS University Islamabad, Lahore Campus, Lahore 54000, Pakistan.

Herein, we synthesized hollow cubic caves of CuO (HC) and wrapped it with N-rich graphitic C (NC), derived from a novel biogenic mixture composed of dopamine (DA) and purine. The synthesized NC wrapped HC ([email protected]) sensor shows enhanced electrocatalytic efficacy compared to unwrapped CuO with shapes including HC, sponge (SP), cabbage (CB), and solid icy cubes (SC). The shape and composition of synthesized materials were confirmed through field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS), whereas interfacial surface energy was calculated through contact angle measurement. The designed [email protected] sensor shows a remarkable response toward the simultaneous detection of uric acid (UA) and xanthine (Xn) with detection limits of 0.017 ± 0.001 (S/N of 3) and 0.004 ± 0.001 μM (S/N of 3), respectively. In addition, this platform was successfully applied to monitor UA from the gout patient serum. To the best of our knowledge, this is the first report on using such novel [email protected] materials for the simultaneous monitoring of UA and Xn.
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http://dx.doi.org/10.1021/acsami.0c15243DOI Listing
October 2020

In Silico Modeling of New "Y-Series"-Based Near-Infrared Sensitive Non-Fullerene Acceptors for Efficient Organic Solar Cells.

ACS Omega 2020 Sep 8;5(37):24125-24137. Epub 2020 Sep 8.

Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran 31261, Kingdom of Saudi Arabia.

This work was inspired by a previous report [Janjua, M. R. S. A. Inorg. Chem. 2012, 51, 11306-11314] in which the optoelectronic properties were improved with an acceptor bearing heteroaromatic rings. Herein, we have designed four novel Y-series non-fullerene acceptors (NFAs) by end-capped acceptor modifications of a recently synthesized 15% efficient molecule for better optoelectronic properties and their potential use in solar cell applications. Density functional theory (DFT) along with time-dependent density functional theory (TDDFT) at the B3LYP/6-31G(d,p) level of theory is used to calculate the band gap, exciton binding energy along with transition density matrix (TDM) analysis, reorganizational energy of electrons and holes, and absorption maxima and open-circuit voltage of investigated molecules. In addition, the complex is also studied to understand the charge shifting from the donor polymer to the NFA blend. Results of all parameters suggest that the DA'D electron-deficient core and effective end-capped acceptors in molecules form a perfect combination for effective tuning of optoelectronic properties by lowering frontier molecular orbital (FMO) energy levels, reorganization energy, and binding energy and increasing the absorption maximum and open-circuit voltage values in selected molecules (. The combination of extended conjugation and excellent electron-withdrawing capability of the end-capped acceptor moiety in makes an excellent organic solar cell (OSC) candidate owing to promising photovoltaic properties including the lowest energy gap (1.924 eV), smallest electron mobility (λ = 0.0073 eV) and hole mobility (λ = 0.0083 eV), highest λ values (783.36 nm (in gas) and 715.20 nm (in chloroform) with lowest transition energy values ( ) of 1.58 and 1.73 eV, respectively), and fine open-circuit voltage ( = 1.17 V) with respect to HOMO-LUMO. Moreover, selected molecules are observed to have better photovoltaic properties than , thus paving the way for experimentalists to look for future developments of Y-series-based highly efficient solar cells.
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http://dx.doi.org/10.1021/acsomega.0c03796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513551PMC
September 2020

Probing 2-acetylbenzofuran hydrazones and their metal complexes as α-glucosidase inhibitors.

Bioorg Chem 2020 09 14;102:104082. Epub 2020 Jul 14.

Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address:

Inhibition of α-glucosidase is one of the important approaches in designing antidiabetic drugs for its role in decrease of the carbohydrates digestion to avoid post-prandial increase in blood sugar levels in diabetic patients. In the present study we designed a novel series of 2-acetylbenzofuran hydrazones (L1-L7) and their metal (II) complexes Cu (II), Co (II), Zn (II) and Mn (II) (8-29) and screened for inhibitory activity against the yeast α-glucosidase. The synthesis of hydrazones incorporated the use of I as a catalyst which resulted in excellent yield of 94%. The ligand L3, showed good activity (IC = 47.51 ± 0.86 µM) while its metal complex (10) showed potent activity (IC = 1.15 ± 0.001 µM) compared to reference acarbose IC = 378.25 ± 0.12 µM. Similarly, the Cu (II) complexes with ligands L5 and L6 showed excellent α-glucosidase inhibition (IC = 0.15 ± 0.003 12 and 0.21 ± 0.002 µM for 13, respectively) whereas, the metal complexes of Co (II), Mn (II), and Zn (II) showed moderate to poor inhibitory activities against α-glucosidase. The The findings are supported by the ligands and enzyme interactions through molecular docking studies. In conclusion, it is indicated that metal complexes of 2-acetylbenzofuran hydrazones have good potential for research leading to antidiabetic therapies.
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http://dx.doi.org/10.1016/j.bioorg.2020.104082DOI Listing
September 2020

Synthesis, characterization, in vitro tissue-nonspecific alkaline phosphatase (TNAP) and intestinal alkaline phosphatase (IAP) inhibition studies and computational evaluation of novel thiazole derivatives.

Bioorg Chem 2020 09 12;102:104088. Epub 2020 Jul 12.

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

Alkaline phosphatases (APs) are a class of homodimeric enzymes which physiologically possess the dephosphorylation ability. APs catalyzes the hydrolysis of monoesters into phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are nitrogen and sulfur containing aromatic heterocycles considered as effective APs inhibitors. In this context, the current research paper presents the successful synthesis, spectroscopic characterization and in vitro alkaline phosphatase inhibitory potential of new thiazole derivatives. The structure activity relationship and molecular docking studies were performed to find out the binding modes of the screened compounds with the target site of tissue non-specific alkaline phosphatase (h-TNAP) as well as intestinal alkaline phosphatase (h-IAP). Compound 5e was found to be potent inhibitor of h-TNAP with IC value of 0.17 ± 0.01 µM. Additionally, compounds 5a and 5i were found to be highly selective toward h-TNAP with IC values of 0.25 ± 0.01 µM and 0.21 ± 0.02 µM, respectively. In case of h-IAP compound 5f was the most potent inhibitor with IC value of 1.33 ± 0.10 µM. The most active compounds were resort to molecular docking studies on h-TNAP and h-IAP to explore the possible binding interactions of enzyme-ligand complexes. Molecular dynamic simulations were carried out to investigate the overall stability of protein in apo and holo state.
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http://dx.doi.org/10.1016/j.bioorg.2020.104088DOI Listing
September 2020

Development of sulfonamide-based Schiff bases targeting urease inhibition: Synthesis, characterization, inhibitory activity assessment, molecular docking and ADME studies.

Bioorg Chem 2020 09 30;102:104057. Epub 2020 Jun 30.

Department of Chemistry, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address:

A series of Sulfonamide-based Schiff bases (E)-4-(benzylideneamino)-N-(6-methoxypyridazin-3-yl) benzenesulfonamide (3a-r) targeting Urease Inhibition was synthesized from sulphamethoxy pyridazine and substituted aldehydes. The prepared compounds were characterized by various spectroscopic techniques including FTIR, HNMR, CNMR, and spectrometric HRMS analysis. The most active agent (3g) bearing halogens and OH groups gave IC value of 2.20 µM for urease inhibition against the standard Thiourea (IC = 20.03 ± 2.06) and the overall trend within the series was 3g > 3n > 3p > 3j > 3q > 3h, 3o > 3l, 3r > 3k, 3m > 3a > 3d > 3e > 3f. Structure-activity relationship study established that the nature as well as the position of varying groups attached to aryl group had crucial roles in defining the urease inhibition activity. Additionally, in silico investigation was carried out which demonstrated that the compounds exhibit polar and apolar contacts with the crucial residues in the binding site of urease. The ADME analysis suggested all the synthesized compounds to be non-toxic, and likely to undergo passive gastrointestinal absorption. Taken together, the study suggests that the synthesized Sulfonamide-based Schiff bases derivatives may serve as potential hits as urease inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2020.104057DOI Listing
September 2020

Synthesis, bioactivity and binding energy calculations of novel 3-ethoxysalicylaldehyde based thiosemicarbazone derivatives.

Bioorg Chem 2020 07 12;100:103924. Epub 2020 May 12.

Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia.

In recent decade, the entrance of α-N-heterocyclic thiosemicarbazones derivates (Triapne, COTI-2 and DpC) in clinical trials for cancer and HIV-1 has vastly increased the interests of medicinal chemists towards this class of organic compounds. In the given study, a series of eighteen new (3a-r) 3-ethoxy salicylaldehyde-based thiosemicarbazones (TSC), bearing aryl and cycloalkyl substituents, were synthesized and assayed for their pharmacological potential against carbonic anhydrases (hCA I and hCA II), cholinesterases (AChE and BChE) and α-glycosidase. The hCA I isoform was inhibited by these novel 3-ethoxysalicylaldehyde thiosemicarbazone derivatives (3a-r) in low nanomolar levels, the Ki of which differed between 144.18 ± 26.74 and 454.92 ± 48.32 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Ks varying from 110.54 ± 14.05 to 444.12 ± 36.08 nM. Also, these novel derivatives (3a-r) effectively inhibited AChE, with Ki values in the range of 385.38 ± 45.03 to 983.04 ± 104.64 nM. For BChE was obtained with Ki values in the range of 400.21 ± 35.68 to 1003.02 ± 154.27 nM. For α-glycosidase the most effective Ki values of 3l, 3n, and 3q were with Ki values of 12.85 ± 1.05, 16.03 ± 2.84, and 19.16 ± 2.66 nM, respectively. Moreover, the synthesized TCSs were simulated using force field methods whereas the binding energies of the selected compounds were estimated using MM-GBSA method. The findings indicate the present novel 3-ethoxy salicylaldehyde-based thiosemicarbazones to be excellent hits for pharmaceutical applications.
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http://dx.doi.org/10.1016/j.bioorg.2020.103924DOI Listing
July 2020

Synthesis, characterization and molecular docking of some novel hydrazonothiazolines as urease inhibitors.

Bioorg Chem 2020 01 26;94:103404. Epub 2019 Oct 26.

Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address:

A series of new hydrazonothiazolines (3a-v) was obtained in good to excellent yields (79-96%) via cyclization of the appropriate thiosemicarbazones with phenacyl bromide. The targeted compounds were characterized by advanced spectroscopic techniques, such as FTIR, HNMR, CNMR and ESI-MS. The structure of compounds 3n and 3v was unambiguously confirmed by single crystal X-ray analysis. All compounds displayed enhanced inhibitory activity against urease enzyme with IC values in range of 1.73 ± 1.57-27.3 ± 0.655 μM when compared to standard thiourea (IC = 20.8 ± 0.75 µM). The structure-activity relationship studies demonstrated that the activity of this series is due the central thiazole ring that interacts with nickel atoms in the active site of urease enzyme. Moreover, molecular docking studies were carried out to investigate the binding mode of all active compounds and an inactive (3u) with the active site of the urease enzyme. The docking results are in complete agreement with the experimental finding.
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http://dx.doi.org/10.1016/j.bioorg.2019.103404DOI Listing
January 2020

Exploring antidiabetic potential of adamantyl-thiosemicarbazones via aldose reductase (ALR2) inhibition.

Bioorg Chem 2019 11 4;92:103244. Epub 2019 Sep 4.

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

The role of aldose reductase (ALR2) in diabetes mellitus is well-established. Our interest in finding ALR2 inhibitors led us to explore the inhibitory potential of new thiosemicarbazones. In this study, we have synthesized adamantyl-thiosemicarbazones and screened them as aldehyde reductase (ALR1) and aldose reductase (ALR2) inhibitors. The compounds bearing phenyl 3a, 2-methylphenyl 3g and 2,6-dimethylphenyl 3m have been identified as most potent ALR2 inhibitors with IC values of 3.99 ± 0.38, 3.55 ± 0.26 and 1.37 ± 0.92 µM, respectively, compared with sorbinil (IC = 3.14 ± 0.02 μM). The compounds 3a, 3g, and 3m also inhibit ALR1 with IC value of 7.75 ± 0.28, 7.26 ± 0.39 and 7.04 ± 2.23 µM, respectively. Molecular docking was also performed for putative binding of potent inhibitors with target enzyme ALR2. The most potent 2,6-dimethylphenyl bearing thiosemicarbazone 3m (IC = 1.37 ± 0.92 µM for ALR2) and other two compound 3a and 3g could potentially lead for the development of new therapeutic agents.
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http://dx.doi.org/10.1016/j.bioorg.2019.103244DOI Listing
November 2019

Synthesis and characterization of new thiosemicarbazones, as potent urease inhibitors: In vitro and in silico studies.

Bioorg Chem 2019 06 6;87:155-162. Epub 2019 Mar 6.

Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman. Electronic address:

A new series of N-substituted thiosemicarbazones (3a-u) bearing 2-naphthyl and dihydrobenzofuranyl scaffolds were synthesized in good to excellent yields (78-95%). The synthesized compounds were characterized by advanced spectroscopic techniques, such as FTIR, HNMR, CNMR and ESI-MS and evaluated as urease inhibitors. The structure of compound 3m was unambiguously confirmed by single crystal X-ray analysis. All compounds showed remarkable activities against urease enzyme with IC values in range of 1.4-36.1 µM. The majority of the synthesized compounds showed higher activity than the standard compound thiourea. Molecular docking was performed to study the mode of interaction of these compounds and their structure-activity relationship. These studies revealed that the compounds bind at the active site and interacts with the nickel atom present in the binding site. The molecular docking demonstrated excellent co-relations with the experimental findings.
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http://dx.doi.org/10.1016/j.bioorg.2019.03.008DOI Listing
June 2019

Benzoxazinone-thiosemicarbazones as antidiabetic leads via aldose reductase inhibition: Synthesis, biological screening and molecular docking study.

Bioorg Chem 2019 06 11;87:857-866. Epub 2018 Dec 11.

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

Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC values of 0.52 ± 0.04 and 0.19 ± 0.03 μM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC value of 3.14 ± 0.02 μM).
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http://dx.doi.org/10.1016/j.bioorg.2018.12.006DOI Listing
June 2019

Xanthenone-based hydrazones as potent α-glucosidase inhibitors: Synthesis, solid state self-assembly and in silico studies.

Bioorg Chem 2019 03 30;84:372-383. Epub 2018 Nov 30.

Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address:

Xanthenone based hydrazone derivatives (5a-n) have been synthesized as potential α-glucosidase inhibitors. All synthesized compounds (5a-n) are characterized by their FTIR, H NMR, C NMR and HRMS, and in case of 5g also by X-ray crystallographic technique. The compounds unveiled a varying degree of α-glucosidase inhibitory activity when compared with standard acarbose (IC = 375.38 ± 0.12 µM). Amongst the series, compound 5l (IC = 62.25 ± 0.11 µM) bearing a trifluoromethyl phenyl group is found to be the most active compound. Molecular modelling is performed to establish the binding pattern of the more active compound 5l, which revealed the significance of substitution pattern. The pharmacological properties of molecules are also calculated by MedChem Designer which determines the ADME (absorption, distribution, metabolism, excretion) properties of molecules. The solid state self-assembly of compound 5g is discussed to show the conformation and role of iminoamide moiety in the molecular packing.
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http://dx.doi.org/10.1016/j.bioorg.2018.11.053DOI Listing
March 2019

Novel acridine-based thiosemicarbazones as 'turn-on' chemosensors for selective recognition of fluoride anion: a spectroscopic and theoretical study.

R Soc Open Sci 2018 Jul 4;5(7):180646. Epub 2018 Jul 4.

H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.

New thiosemicarbazide-linked acridines were prepared and investigated as chemosensors for the detection of biologically and environmentally important anions. The compounds were found selective for fluoride (F) with no affinity for other anions, i.e. OAc, Br, I, HSO, SO, PO, ClO, ClO, CN and SCN. Further, upon the gradual addition of a fluoride anion (F) source (tetrabutylammonium fluoride), a well-defined change in colour of the solution of probes was observed. The anion-sensing process was studied in detail via UV-visible absorption, fluorescence and H-NMR experiments. Moreover, during the synthesis of acridine probes nickel fluoride (NiF), a rarely explored transition metal fluoride salt, was used as the catalyst. Theoretical studies via density functional theory were also carried out to further investigate the sensing and anion (F) selectivity pattern of these probes.
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http://dx.doi.org/10.1098/rsos.180646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083729PMC
July 2018

Gauging and Tuning Cross-Linking Kinetics of Catechol-PEG Adhesives via Catecholamine Functionalization.

Biomacromolecules 2015 Dec 1;16(12):3811-8. Epub 2015 Dec 1.

Max- Planck Institut für Polymerforschung , Ackermannweg 10, 55128 Mainz, Germany.

The curing time of an adhesive material is determined by the polymerization and cross-linking kinetics of the adhesive formulation and needs to be optimized for the particular application. Here, we explore the possibility of tuning the polymerization kinetics and final mechanical properties of tissue-adhesive PEG gels formed by polymerization of end-functionalized star-PEGs with catecholamines with varying substituents. We show strong differences in cross-linking time and cohesiveness of the final gels among the catecholamine-PEG variants. Installation of an electron-withdrawing but π-electron donating chloro substituent on the catechol ring resulted in faster and more efficient cross-linking, while opposite effects were observed with the strongly electron-withdrawing nitro group. Chain substitution slowed down the kinetics and hindered cross-linking due either to chain breakdown (β-OH group, in norepinephrine) or intramolecular cyclization (α-carboxyl group, in DOPA). Interesting perspectives derive from use of mixtures of catecholamine-PEG precursors offering further opportunities for fine-tuning of the curing parameters. These are interesting properties for the application of catecholamine-PEG gels as tissue glues or biomaterials for cell encapsulation.
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http://dx.doi.org/10.1021/acs.biomac.5b01126DOI Listing
December 2015

Synthesis, biological evaluation and molecular docking of N-phenyl thiosemicarbazones as urease inhibitors.

Bioorg Chem 2015 Aug 22;61:51-7. Epub 2015 Jun 22.

Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address:

Urease is an important enzyme which breaks urea into ammonia and carbon dioxide during metabolic processes. However, an elevated activity of urease causes various complications of clinical importance. The inhibition of urease activity with small molecules as inhibitors is an effective strategy for therapeutic intervention. Herein, we have synthesized a series of 19 benzofurane linked N-phenyl semithiocarbazones (3a-3s). All the compounds were screened for enzyme inhibitor activity against Jack bean urease. The synthesized N-phenyl thiosemicarbazones had varying activity levels with IC50 values between 0.077 ± 0.001 and 24.04 ± 0.14 μM compared to standard inhibitor, thiourea (IC50 = 21 ± 0.11 μM). The activities of these compounds may be due to their close resemblance of thiourea. A docking study with Jack bean urease (PDB ID: 4H9M) revealed possible binding modes of N-phenyl thiosemicarbazones.
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http://dx.doi.org/10.1016/j.bioorg.2015.06.004DOI Listing
August 2015

Light-triggered in vivo activation of adhesive peptides regulates cell adhesion, inflammation and vascularization of biomaterials.

Nat Mater 2015 Mar 15;14(3):352-60. Epub 2014 Dec 15.

1] Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA [2] Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.

Materials engineered to elicit targeted cellular responses in regenerative medicine must display bioligands with precise spatial and temporal control. Although materials with temporally regulated presentation of bioadhesive ligands using external triggers, such as light and electric fields, have recently been realized for cells in culture, the impact of in vivo temporal ligand presentation on cell-material responses is unknown. Here, we present a general strategy to temporally and spatially control the in vivo presentation of bioligands using cell-adhesive peptides with a protecting group that can be easily removed via transdermal light exposure to render the peptide fully active. We demonstrate that non-invasive, transdermal time-regulated activation of cell-adhesive RGD peptide on implanted biomaterials regulates in vivo cell adhesion, inflammation, fibrous encapsulation, and vascularization of the material. This work shows that triggered in vivo presentation of bioligands can be harnessed to direct tissue reparative responses associated with implanted biomaterials.
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http://dx.doi.org/10.1038/nmat4157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336636PMC
March 2015

Antibacterial strategies from the sea: polymer-bound cl-catechols for prevention of biofilm formation.

Adv Mater 2013 Jan 9;25(4):529-33. Epub 2012 Nov 9.

Max-Planck-Institut für Polymerforschung, Ackermannweg 10, 55128 Mainz, Germany.

Inspired by the amino acid 2-chloro-4,5-dihydroxyphenylalanine (Cl-DOPA), present in the composition of the proteinaceous glue of the sandcastle worm Phragmatopoma californica, a simple strategy is presented to confer antifouling properties to polymer surfaces using (but not releasing) a bioinspired biocide. Cl-Dopamine is used to functionalize polymer materials and hydrogel films easily, to prevent biofilm formation on them.
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http://dx.doi.org/10.1002/adma.201203362DOI Listing
January 2013

Bioinspired underwater bonding and debonding on demand.

Angew Chem Int Ed Engl 2012 Apr 27;51(18):4332-5. Epub 2012 Mar 27.

Max-Planck-Institut für Polymerforschung, Ackermannweg 10, 55128 Mainz, Germany.

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http://dx.doi.org/10.1002/anie.201108629DOI Listing
April 2012
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