Publications by authors named "Muhammad Tariq Shehzad"

9 Publications

  • Page 1 of 1

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

Bioorg Chem 2021 Oct 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
October 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

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

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

Improved physicochemical characteristics of artemisinin using succinic acid.

Acta Pol Pharm 2014 May-Jun;71(3):451-62

Artemisinin (ARMN) is a potent antimalarial drug, which is effective against multidrug resistant strains of Plasmodium falciparum and produces rapid recovery even in patients with cerebral malaria. Being poorly soluble in water, artemisinin is incompletely absorbed after oral intake due to poor dissolution characteristics in the intestinal fluids. To enhance these properties, solid dispersions of artemisinin with succinic acid (SUC) were prepared using drug-carrier ratios 1 : 1, 1 : 4, 1 : 6, 1 : 8 and 1 : 10 by solvent evaporation and freeze drying methods. These solid dispersions were characterized by differential scanning calorimetery (DSC), Fourier transform infrared spectroscopy (FTIR), x-ray diffraction patterns (XRD), phase solubility and dissolution kinetics evaluated by applying zero order, first order, Higuchi, and Korsmeyer-Peppas models. Physical mixtures produced significantly higher aqueous solubility and rate of dissolution as compared to artemisinin alone. The dissolution profiles of all formulations followed Higuchi model and exhibited diffusion-controlled release of drug. Solvent evaporation method (SLVPs) exhibited improved solubility and freeze dried solid dispersions (FDSDs) produced highest solubility but stability constant was opposite. ARMN and SUC both were found completely crystalline as shown by their XRD patterns. Physical mixtures (PMs) showed reduced intensity in their XRD patterns while solid dispersions by SLVPs exhibited twice reduced intensity and much displaced angles, whereas FDSDs showed synergistic effects in some of ARMN and SUC peaks. DSC thermograms of FDSDs at drug-carrier ratios 1 : 1-1 : 4 showed lower melting temperature and enthalpy change (deltaH) values than respective SLVPs, whereas at higher ratios, a reverse was true. SLVPs showed displaced methyl stretching bands at lower drug-carrier ratios and exhibited O-H stretching characteristic bands of SUC at higher drug-carrier ratios. In addition, carbonyl group and C-O stretching vibrations characteristic of SUC (1307 cm(-1)) appeared prominently compared to PMs, whereas C-O stretching characteristic bands of ARMN disappeared at higher ratios. FDSDs exhibited distinct nature of bonding compared to respective SLVPs and PMs.
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October 2014

Improved physicochemical characteristics of artemisinin-nicotinamide solid dispersions by solvent evaporation and freeze dried methods.

Pak J Pharm Sci 2012 Apr;25(2):447-56

Department of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan.

Artemisinin (ARMN) is a drug of choice against drug-resistant malaria especially due to Plasmodium falciparum. Being poorly soluble in water, its solid dispersions with nicotinamide (NA) were prepared at various drug-carrier ratios (1:1, 1:4, 1:6, 1:8, 1:10) by solvent evaporation and freeze drying methods. These solid dispersions were characterized by differential scanning calorimetery (DSC), fourier transform infrared spectroscopy (FTIR), X-ray diffraction patterns (XRD), phase solubility and dissolution studies. Artemisinin and nicotinamide both were found completely crystalline as shown by their XRD patterns. Physical mixtures (PMs) showed decreased intensity in their XRD patterns while solid dispersions by solvent evaporation method (SLVPs) exhibited displaced angles and decreased intensity whereas freeze dried solid dispersions (FDSDs) showed least number of peaks having low intensity and maximum displaced angles. DSC thermograms of drug-carrier ratios at 1:1-1:4 showed lower melting temperature than artemisinin and nicotinamide in all preparations. Endothermic temperature of artemisinin in PMs and SLVPs increased with rise of nicotinamide content upto 1:6 ratio followed by decline. All samples showed crystallization temperature below the artemisinin except drug-carrier ratio 1:6 of PMs while δH value was minimum at this ratio. FDSDs produced lowest endothermic temperature than corresponding PMs and SLVPs. SLVPs exhibited band shifting in both functional and fingerprint region compared to respective PMs as exhibited by their FTIR spectra. FDSDs and SLVPs showed different nature of bonding among artemisinin and nicotinamide. FDSDs produced strongest CONH(2) bonding followed by SLVPs and PMs respectively. PMs produced significantly higher aqueous solubility and rate of dissolution as compared to artemisinin alone. SLVPs exhibited improved solubility and dissolution profile corresponding to PMs. FDSDs showed highest release rate and aqueous solubility followed by SLVPs and PMs at all ratios. PMs and SLVPs showed their highest dissolution profile at 1:6 drug-carrier ratio followed by gradual decrease while FDSDs progressed in dissolution rate with increase of nicotinamide content successively upto maximum at 1:10 ratio.
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April 2012
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