Publications by authors named "Sumera Zaib"

70 Publications

CRISPR-Cas9 genome engineering: trends in medicine and health.

Mini Rev Med Chem 2021 Sep 12. Epub 2021 Sep 12.

Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN. United Kingdom.

The ability to engineer biological systems and organisms holds enormous potential for applications across basic science, medicine and biotechnology. Over the past few decades, the development of CRISPR (clustered regularly interspaced short palindromic repeat) has revolutionized the whole genetic engineering process utilizing the principles of Watson-Crick base pairing. CRISPR-Cas9 technology offers the simplest, fastest, most versatile, reliable and precise method of genetic manipulation thus enabling geneticists and medical researchers to edit parts of the genome by removing, adding or altering sections of the DNA sequence. The current review focuses on the applications of CRISPR-Cas9 in the field of medical research. Compared with other gene editing technologies, CRISPR/Cas9 demonstrates numerous advantages for the treatment of various medical conditions including cancer, hepatitis B, cardiovascular diseases or even high cholesterol. Given its promising performance, CRISPR/Cas9 gene editing technology will surely help in the therapy of several disorders while addressing the issues pertaining to the minimization of the off-target effects of gene editing and incomplete matches between sgRNA and genomic DNA by Cas9.
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http://dx.doi.org/10.2174/1389557521666210913112030DOI Listing
September 2021

Design of a novel multiple epitope-based vaccine: An immunoinformatics approach to combat SARS-CoV-2 strains.

J Infect Public Health 2021 Jul 4;14(7):938-946. Epub 2021 May 4.

Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom. Electronic address:

Background: Since the SARS-CoV-2 outbreak in December 2019 in Wuhan, China, the virus has infected more than 153 million individuals across the world due to its human-to-human transmission. The USA is the most affected country having more than 32-million cases till date. Sudden high fever, pneumonia and organ failure have been observed in infected individuals.

Objectives: In the current situation of emerging viral disease, there is no specific vaccine, or any therapeutics available for SARS-CoV-2, thus there is a dire need to design a potential vaccine to combat the virus by developing immunity in the population. The purpose of present study was to develop a potential vaccine by targeting B and T-cell epitopes using bioinformatics approaches.

Methods: B- and T-cell epitopes are predicted from novel M protein-SARS-CoV-2 for the development of a unique multiple epitope vaccine by applying bioinformatics approaches. These epitopes were analyzed and selected for their immunogenicity, antigenicity scores, and toxicity in correspondence to their ability to trigger immune response. In combination to epitopes, best multi-epitope of potential immunogenic property was constructed. The epitopes were joined using EAAAK, AAY and GPGPG linkers.

Results: The constructed vaccine showed good results of worldwide population coverage and promising immune response. This constructed vaccine was subjected to in-silico immune simulations by C-ImmSim. Chimeric protein construct was cloned into PET28a (+) vector for expression study in Escherichia coli using snapgene.

Conclusion: This vaccine design proved effective in various computer-based immune response analysis as well as showed good population coverage. This study is solely dependent on developing M protein-based vaccine, and these in silico findings would be a breakthrough in the development of an effective vaccine to eradicate SARS-CoV-2 globally.
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http://dx.doi.org/10.1016/j.jiph.2021.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093003PMC
July 2021

Inhibition of Angiotensin-I Converting Enzyme by Ginsenosides: Structure-Activity Relationships and Inhibitory Mechanism.

J Agric Food Chem 2021 Jun 20;69(21):6073-6086. Epub 2021 May 20.

Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.

Ginseng ( C. A. Meyer) extract has been reported to inhibit the angiotensin converting enzyme (ACE); however, the possible inhibitory action of most of its constituents (ginsenosides) against ACE remains unknown. Thus, in this study, we investigated ginsenoside derivatives' inhibitory effect on ACE. We assessed the activities of 22 ginsenosides, most of which inhibited ACE significantly. Notably, protopanaxatriol, protopanaxadiol, and ginsenoside Rh2 exhibited the most potent ACE inhibitory potential, with IC values of 1.57, 2.22, and 5.60 μM, respectively. Further, a kinetic study revealed different modes of inhibition against ACE. Molecular docking studies have confirmed that ginsenosides inhibit ACE via many hydrogen bonds and hydrophobic interactions with catalytic residues and zinc ion of C- and N-domain ACE that block the catalytic activity of ACE. In addition, we found that the active ginsenosides stimulated glucose uptake in insulin-resistant C2C12 skeletal muscle cells in a dose-dependent manner. Moreover, the most active ginsenosides' reactive oxygen species (ROS) and peroxynitrite (ONOO) scavenging properties were evaluated, in which IC values ranged from 1.44-43.83 to 2.36-39.56 μM in ONOO and ROS, respectively. The results derived from these computational and in vitro experiments provide additional scientific support for the anecdotal use of ginseng in traditional medicine to treat cardiovascular diseases such as hypertension.
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http://dx.doi.org/10.1021/acs.jafc.1c01231DOI Listing
June 2021

Rhodanine-3-acetamide derivatives as aldose and aldehyde reductase inhibitors to treat diabetic complications: synthesis, biological evaluation, molecular docking and simulation studies.

BMC Chem 2021 Apr 27;15(1):28. Epub 2021 Apr 27.

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

In diabetes, increased accumulation of sorbitol has been associated with diabetic complications through polyol pathway. Aldose reductase (AR) is one of the key factors involved in reduction of glucose to sorbitol, thereby its inhibition is important for the management of diabetic complications. In the present study, a series of seven 4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetamide derivatives 3(a-g) were synthesized by the reaction of 5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2a) and 5-(4-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2b) with different amines. The synthesized compounds 3(a-g) were investigated for their in vitro aldehyde reductase (ALR1) and aldose reductase (ALR2) enzyme inhibitory potential. Compound 3c, 3d, 3e, and 3f showed ALR1 inhibition at lower micromolar concentration whereas all the compounds were more active than the standard inhibitor valproic acid. Most of the compounds were active against ALR2 but compound 3a and 3f showed higher inhibition than the standard drug sulindac. Overall, the most potent compound against aldose reductase was 3f with an inhibitory concentration of 0.12 ± 0.01 µM. In vitro results showed that vanillin derivatives exhibited better activity against both aldehyde reductase and aldose reductase. The molecular docking studies were carried out to investigate the binding affinities of synthesized derivatives with both ALR1 and ALR2. The binding site analysis of potent compounds revealed similar interactions as were found by cognate ligands within the active sites of enzymes.
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http://dx.doi.org/10.1186/s13065-021-00756-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080350PMC
April 2021

Antiproliferative and Pro-Apoptotic Effects of Thiazolo[3,2-b][1,2,4]triazoles in Breast and Cervical Cancer Cells.

Anticancer Agents Med Chem 2021 Jan 25. Epub 2021 Jan 25.

Department of Chemistry, Faculty of Natural Sciences, The University of Haripur, Haripur, KPK-22620. Pakistan.

Background And Objectives: Cancer is one of the leading causes of death in the world affecting millions of people. The commercially available anticancer drugs lack the selectivity and show several undue side effects during the biologically targeted therapy, thus calling for the exploration of wider chemical space to furnish new structural leads with promising anticancer potential. In this endeavor, we synthesized a series of coumarinyl thiazolotriazoles with diverse functional group tolerance and will be tested for their anticancer properties against cancer cell lines (HeLa and MCF-7) and a normal cell line (BHK-21).

Materials And Methods: To overcome such complications, in the current study, we evaluated the cytotoxic effects of coumarinyl thiazolotriazoles hybrids on human breast adenocarcinoma (MCF-7), cervical adenocarcinoma (HeLa) cells and normal cells i.e., baby hamster kidney cells (BHK-21) using MTT (dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) assay. DNA binding studies of compound 6c was performed on Herring-sperm DNA (HS-DNA) and docking studies were also carried out. The mechanistic studies were performed on potent compounds by fluorescent microscopic studies, release of lactate dehydrogenase (LDH) and mitochondrial membrane potential, activation of caspase-9 and -3 and flow cytometric analysis.

Results: As revealed by MTT assay, compound 6m and 6c were identified as the most potent derivative among the tested series with IC50 values of 5.64 and 29.1 μM against HeLa and MCF cells, respectively as compared to cisplatin which gave IC50 values of 11.3 and 6.20 μM, respectively. DNA binding studies of compound 6c showed the binding of compound in DNA with Gibbs free energy of ‒17 KJ/mol and docking studies validated the DNA binding studies. Fluorescent microscopic studies using 4',6-diamidino-2-phenylindole (DAPI) and propidium iodide (PI) staining confirmed the occurrence of apoptosis in HeLa cells treated with the most active compound 6m. Moreover, compound 6m and 6c also triggered the release of lactate dehydrogenase (LDH) in treated HeLa and MCF-7 cells while a luminescence assay displayed a remarkable increase in the activity of caspase-9 and -3. Moreover, flow cytometric results revealed that compound 6m caused G0/G1 arrest in the treated HeLa cells.

Conclusion: Our results suggested that the compound possesses chemotherapeutic properties against breast cancer and cervical adenocarcinoma cells, thus warranting further research to test the anticancer efficacy of this compound at clinical level.
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http://dx.doi.org/10.2174/1871520621666210126092303DOI Listing
January 2021

Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach.

Molecules 2021 Jan 27;26(3). Epub 2021 Jan 27.

Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer's heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target -heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, H- and C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC values less than 20 μM. -(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC values of 9.68 and 11.59 μM, respectively. Various informative structure-activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.
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http://dx.doi.org/10.3390/molecules26030656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866225PMC
January 2021

Machine Intelligence Techniques for the Identification and Diagnosis of COVID-19.

Curr Med Chem 2021 ;28(26):5268-5283

Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester- M1 7DN, United Kingdom.

COVID-19, an infectious disease caused by a newly discovered enveloped virus (SARS-CoV-2), was first reported in Wuhan, China, in December 2019 and affected the whole world. The infected individual may develop symptoms such as high fever, cough, myalgia, lymphopenia, respiratory distress syndrome etc., or remain completely asymptomatic after the incubation period of two to fourteen days. As the virus is transmitted by inhaling infectious respiratory droplets that are produced by sneezing or coughing, so early and rapid diagnosis of the disease can prevent infection and transmission. In the current pandemic situation, the medical industry is looking for new technologies to monitor and control the spread of COVID-19. In this context, the current review article highlights the Artificial Intelligence methods that are playing an effective role in rapid, accurate and early diagnosis of the disease via pattern recognition, machine learning, expert system and fuzzy logic by improving cognitive behavior and reducing human error. Auto-encoder deep learning method, α-satellite, ACEMod and heterogeneous graph auto- encoder are AI approaches that determine the transfer rate of virus and are helpful in shaping public health and planning. In addition, CT scan, X-ray, MRI, and RT-PCR are some of the techniques that are being employed in the identification of COVID-19. We hope using AI techniques; the world can emerge from COVID-19 pandemic while mitigating social and economic crisis.
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http://dx.doi.org/10.2174/0929867328666210106143307DOI Listing
September 2021

Alkynoates as Versatile and Powerful Chemical Tools for the Rapid Assembly of Diverse Heterocycles under Transition-Metal Catalysis: Recent Developments and Challenges.

Top Curr Chem (Cham) 2021 Jan 5;379(1). Epub 2021 Jan 5.

Department of Biochemistry, Faculty of Life Sciences, University of Central Punjab, Lahore, 54590, Pakistan.

Heterocycles, heteroaromatics and spirocyclic entities are ubiquitous components of a wide plethora of synthetic drugs, biologically active natural products, marketed pharmaceuticals and agrochemical targets. Recognizing their high proportion in drugs and rich pharmacological potential, these invaluable structural motifs have garnered significant interest, thus enabling the development of efficient catalytic methodologies providing access to architecturally complex and diverse molecules with high atom-economy and low cost. These chemical processes not only allow the formation of diverse heterocycles but also utilize a range of flexible and easily accessible building units in a single operation to discover diversity-oriented synthetic approaches. Alkynoates are significantly important, diverse and powerful building blocks in organic chemistry due to their unique and inherent properties such as the electronic bias on carbon-carbon triple bonds posed by electron-withdrawing groups or the metallic coordination site provided by carbonyl groups. The present review highlights the comprehensive picture of the utility of alkynoates (2007-2019) for the synthesis of various heterocycles (> 50 types) using transition-metal catalysts (Ru, Rh, Pd, Ir, Ag, Au, Pt, Cu, Mn, Fe) in various forms. The valuable function of versatile alkynoates (bearing multifunctional groups) as simple and useful starting materials is explored, thus cyclizing with an array of coupling partners to deliver a broad range of oxygen-, nitrogen-, sulfur-containing heterocycles alongside fused-, and spiro-heterocyclic compounds. In addition, these examples will also focus the scope and reaction limitations, as well as mechanistic investigations into the synthesis of these heterocycles. The biological significance will also be discussed, citing relevant examples of drug molecules highlighting each class of heterocycles. This review summarizes the recent developments in the synthetic methods for the synthesis of various heterocycles using alkynoates as readily available starting materials under transition-metal catalysis.
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http://dx.doi.org/10.1007/s41061-020-00316-4DOI Listing
January 2021

Utilization of the common functional groups in bioactive molecules: Exploring dual inhibitory potential and computational analysis of keto esters against α-glucosidase and carbonic anhydrase-II enzymes.

Int J Biol Macromol 2021 Jan 27;167:233-244. Epub 2020 Nov 27.

Department of Chemistry, Faculty of Natural Sciences, The University of Haripur, Haripur, KPK 22620, Pakistan. Electronic address:

Diabetes mellitus, a progressive chronic disease, characterized by the abnormal carbohydrate metabolism is associated with severe health complications including long term dysfunction or failure of several organs, cardiovascular and micro-angiopathic problems (neuropathy, nephropathy, retinopathy). Despite the existence of diverse chemical structural libraries of α-glucosidase inhibitors, the limited diabetic treatment due to the adverse side effects such as abdominal distention, flatulence, diarrhoea, and liver damage associated with these inhibitors encourage the medicinal research community to design and develop new and potent inhibitors of α-glucosidase with better pharmacokinetic properties. In this perspective, we demonstrate the successful integration of common functional groups (ketone & ester) in one combined pharmacophore which is favorable for the formation of hydrogen bonds and other weaker interactions with the target proteins. These keto ester derivatives were screened for their α-glucosidase inhibition potential and the in vitro results revealed compound 3c as the highly active inhibitor with an IC value of 12.4 ± 0.16 μM compared to acarbose (IC = 942 ± 0.74 μM). This inhibition potency was ~76-fold higher than acarbose. Other potent compounds were 3f (IC = 28.0 ± 0.28 μM), 3h (IC = 33.9 ± 0.09 μM), 3g (IC = 34.1 ± 0.04 μM), and 3d (IC = 76.5 ± 2.0 μM). In addition, the emerging use of carbonic anhydrase inhibitors for the treatment of diabetic retinopathy (a leading cause of vision loss) prompted us to screen the keto ester derivatives for the inhibition of carbonic anhydrase-II. Compound 3b was found significantly active against carbonic anhydrase-II with an IC of 16.5 ± 0.92 μM (acetazolamide; IC = 18.2 ± 1.23 μM). Compound 3a also exhibited comparable potency with an IC value of 18.9 ± 1.08 μM. Several structure-activity relationship analyses depicted the influence of the substitution pattern on both the aromatic rings. Molecular docking analysis revealed the formation of several H-bonding interactions through the ester carbonyl and the nitro oxygens of 3c with the side chains of His348, Arg212 and His279 in the active pocket of α-glucosidase whereas 3b interacted with His95, -OH of Thr197, Thr198 and WAT462 in the active site of carbonic anhydrase-II. Furthermore, evaluation of ADME properties suggests the safer pharmacological profile of the tested derivatives.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.11.170DOI Listing
January 2021

Synthetic and medicinal chemistry of phthalazines: Recent developments, opportunities and challenges.

Bioorg Chem 2020 12 24;105:104425. Epub 2020 Oct 24.

Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom. Electronic address:

Fused diaza-heterocycles constitute the core structure of numerous bioactive natural products and effective therapeutic drugs. Among them, phthalazines have been recognized as remarkable structural leads in medicinal chemistry due to their wide application in pharmaceutical and agrochemical industries. Accessing such challenging pharmaceutical agents/drug candidates with high chemical complexity through synthetically efficient approaches remains an attractive goal in the contemporary medicinal chemistry and drug discovery arena. In this review, we focus on the recent developments in the synthetic routes towards the generation of phthalazine-based active pharmaceutical ingredients and their biological potential against various targets. The general reaction scope of these innovative and easily accessible strategies was emphasized focusing on the functional group tolerance, substrate and coupling partner compatibility/limitation, the choice of catalyst, and product diversification. These processes were also accompanied by the mechanistic insights where deemed appropriate to demonstrate meaningful information. Moreover, the rapid examination of the structure-activity relationship analyses around the phthalazine core enabled by the pharmacophore replacement/integration revealed the generation of robust, efficient, and more selective compounds with pronounced biological effects. A large variety of in silico methods and ADME profiling tools were also employed to provide a global appraisal of the pharmacokinetics profile of diaza-heterocycles. Thus, the discovery of new structural leads offers the promise of improving treatments for various tropical diseases such as tuberculosis, leishmaniasis, malaria, Chagas disease, among many others including various cancers, atherosclerosis, HIV, inflammatory, and cardiovascular diseases. We hope this review would serve as an informative collection of structurally diverse molecules enabling the generation of mature, high-quality, and innovative routes to support the drug discovery endeavors.
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http://dx.doi.org/10.1016/j.bioorg.2020.104425DOI Listing
December 2020

Evaluation of sulfonate and sulfamate derivatives possessing benzofuran or benzothiophene nucleus as inhibitors of nucleotide pyrophosphatases/phosphodiesterases and anticancer agents.

Bioorg Chem 2020 11 24;104:104305. Epub 2020 Sep 24.

Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt. Electronic address:

Ectonucleotidases are a broad family of ectoenzymes that play a crucial role in purinergic cell signaling. Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) belong to this group and are important drug targets. In particular, NPP1 and NPP3 are known to be druggable targets for treatment of impaired calcification disorders (including pathological aortic calcification) and cancer, respectively. In this study, we investigated a series of sulfonate and sulfamate derivatives of benzofuran and benzothiophene as potent and selective inhibitors of NPP1 and NPP3. Compounds 1c, 1g, 1n, and 1s are the most active NPP1 inhibitors (IC values in the range 0.12-0.95 µM). Moreover, compounds 1e, 1f, 1j, and 1l are the most potent inhibitors of NPP3 (IC ranges from 0.12 to 0.95 µM). Compound 1d, 1f and 1t are highly selective inhibitors of NPP1 over NPP3, whereas compounds 1m and 1s are found to be highly selective towards NPP3 over NPP1. Structure-activity relationship (SAR) study has been discussed in detailed. With the aid of molecular docking studies, a common binding mode of these compounds and suramin (the standard inhibitor) was revealed, where the sulfonate group acts as a cation-binding moiety that comes in close contact with the zinc ion of the active site. Moreover, cytotoxic evaluation against MCF-7 and HT-29 cancer cell lines revealed that compound 1r is the most cytotoxic towards MCF-7 cell line with IC value of 0.19 µM. Compound 1r is more potent and selective against cancer cells than normal cells (WI-38) as compared to doxorubicin.
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http://dx.doi.org/10.1016/j.bioorg.2020.104305DOI Listing
November 2020

Mechanistic insight of DACH1 receptor in the development of carcinoma insurgence through MD simulation studies.

J Biomol Struct Dyn 2020 Sep 14:1-10. Epub 2020 Sep 14.

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

Proteins are key player in the prognosis and therapeutics of carcinomas through the interactions of downstream signalling cascades. Current work insight the structural and mutational analysis of DACH1 in association with carcinogenesis. The homology modelling was employed to predict mutant and wild protein models and their reliability and accuracy was verified through multiple online approaches. Furthermore, MD simulation technique was employed to check the mutation effects on the stability of DACH1 through root mean square deviation and fluctuation graphs. Our results proposed that DACH1 mutation (C188Y) may cause lethal effects and can disturb the DACH1 structure. The observed mutational results showed that C188Y may cause some lethal effect in human body. Based on aforementioned computational assessments, it has concluded that DACH1 could be used as good therapeutic target in the prognosis and therapeutic of carcinoma insurgence.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1818624DOI Listing
September 2020

Indane-1,3-diones: As Potential and Selective α-glucosidase Inhibitors, their Synthesis, in vitro and in silico Studies.

Med Chem 2021 ;17(8):887-902

PCSIR Laboratories Complex, Karachi, Shahra-e-Dr. Salimuzzaman Siddiqui, Karachi-75280, Pakistan.

Background: Diabetes mellitus is one of the most chronic metabolic disorders. Since past few years, our research group had synthesized and evaluated libraries of heterocyclic compounds against α and β-glucosidase enzymes and found encouraging results. The current study comprises of evaluation of indane-1,3-dione as antidiabetic agents based on our previously reported results obtained from closely related moiety isatin and its derivatives.

Objective: A library of twenty three indane-1,3-dione derivatives (1-23) was synthesized and evaluated for α and β-glucosidase inhibitions. Moreover, in silico docking studies were carried out to investigate the putative binding mode of selected compounds with the target enzyme.

Methods: The indane-1,3-dione derivatives (1-23) were synthesized by Knoevenagel condensation of different substituted benzaldehydes with indane-1,3-dione under basic condition. The structures of synthetic molecules were deduced by using different spectroscopic techniques, including H-, C-NMR, EI-MS, and CHN analysis. Compounds (1-23) were evaluated for α and β-glucosidase inhibitions by adopting the literature protocols.

Result: Off twenty three, eleven compounds displayed good to moderate activity against α- glucosidase enzyme, nonetheless, all compounds exhibited less than 50% inhibition against β- glucosidase enzyme. Compounds 1, 14, and 23 displayed good activity against α-glucosidase enzyme with IC values of 2.80 ± 0.11, 0.76 ± 0.01, and 2.17 ± 0.18 μM, respectively. The results have shown that these compounds have selectively inhibited the α-glucosidase enzyme. The in silico docking studies also supported the above results and showed different types of interactions of synthetic molecules with the active site of enzyme.

Conclusion: The compounds 1, 14, and 23 have shown good inhibition against α-glucosidase and may potentially serve as lead for the development of new therapeutic representatives.
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http://dx.doi.org/10.2174/1573406416666200826102051DOI Listing
January 2021

Synthesis, characterization, alkaline phosphatase inhibition assay and molecular modeling studies of 1-benzylidene-2-(4-tert- butylthiazol-2-yl) hydrazines.

J Biomol Struct Dyn 2021 Oct 11;39(16):6140-6153. Epub 2020 Aug 11.

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

Alkaline phosphatases are homodimeric protein enzymes which removes phosphates from several types of molecules. These catalyze the hydrolysis of monoesters in phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are a privileged class of heterocyclic compounds which may potentially serve as effective phosphatase inhibitors. In this regard, the present research paper reports the facile synthesis and characterization of substituted 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines with excellent yields. The synthesized compounds were tested for inhibitory potential against alkaline phosphatases. The compound 1-(4-Hydroxy, 3-methoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine ( was found to be the most potent inhibitor of human tissue non-alkaline phosphatase in this group of molecules with an IC value of 1.09 ± 0.18 µM. The compound 1-(3,4-dimethoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine exhibited selectivity and potency for human intestinal alkaline phosphatase with an IC value of 0.71 ± 0.02 µM. In addition, structure activity relationship and molecular docking studies were performed to evaluate their binding modes with the target site of alkaline phosphatase. The docking analysis revealed that the most active inhibitors showed the important interactions within the binding pockets of human intestinal alkaline phosphatase and human tissue non-alkaline phosphatase and may be responsible for the inhibitory activity of the compound towards the enzymes. Therefore, the screened thiazole derivatives provided an outstanding platform for further development of alkaline phosphatase inhibitors.
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http://dx.doi.org/10.1080/07391102.2020.1802336DOI Listing
October 2021

Structure-based virtual screening of dipeptidyl peptidase 4 inhibitors and their in vitro analysis.

Comput Biol Chem 2021 Apr 25;91:107326. Epub 2020 Jun 25.

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

Type 2 diabetes mellitus (T2DM) is one of the most widely prevalent metabolic disorders with no cure to date thus remains the most challenging task in the current drug discovery. Therefore, the only strategy to control diabetes prevalence is to develop novel efficacious therapeutics. Dipeptidyl Peptidase 4 (DPP-4) inhibitors are currently used as anti-diabetic drugs for the inhibition of incretins. This study aims to construct the chemical feature based on pharmacophore models for dipeptidyl peptidase IV. The structure-based pharmacophore modeling has been employed to evaluate new inhibitors of DPP-4. A four-featured pharmacophore model was developed from crystal structure of DPP-4 enzyme with 4-(2-aminoethyl) benzenesulfonyl fluoride in its active site via pharmacophore constructing tool of Molecular Operating Environment (MOE) consisting F1 Hyd (hydrophobic region), F2 Hyd|Cat|Don (hydrophobic cationic and donor region), F3 Acc (acceptor region) and F4 Hyd (hydrophobic region). The generated pharmacophore model was used for virtual screening of in-house compound library (the available compounds which were used for initial screening to get the few compounds for the current studies). The resultant selected compounds, after virtual screening were further validated using in vitro assay. Furthermore, structure-activity relationship was carried out for the compounds possessing significant inhibition potential after docking studies. The binding free energy of analogs was evaluated via molecular mechanics generalized Born surface area (MM-GBSA) and Poisson-Boltzmann surface area (MM-PBSA) methods using AMBER 16 as a molecular dynamics (MD) simulation package. Based on potential findings, we report that selected candidates are more likely to be used as DPP-4 inhibitors or as starting leads for the development of novel and potent DPP-4 inhibitors.
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http://dx.doi.org/10.1016/j.compbiolchem.2020.107326DOI Listing
April 2021

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

New Hybrid Scaffolds Based on Carbazole-Chalcones as Potent Anticancer Agents.

Anticancer Agents Med Chem 2021 ;21(9):1082-1091

Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.

Background And Objectives: Despite various technological advances for the treatment of cancer, the identification of new chemical entities with potent anticancer effects remain an indispensable requirement of the time due to multi-drug resistance exhibited by previously developed anticancer drugs. Particularly, the hybrid drugs incorporating two individual bioactive pharmacophores present medicinally important structural leads, thus improving the pharmacodynamic profile of the drug molecules. The antiproliferative and pro-apoptotic activity of the carbazole-chalcone hybrids on human breast and cervical cancer cells will be examined.

Materials And Methods: To overcome such complications, in the current study, we evaluated the cytotoxic effects of carbazole-chalcone hybrids on human breast adenocarcinoma (MCF-7), cervical adenocarcinoma (HeLa) cells and normal cells, i.e., Baby Hamster Kidney cells (BHK-21) using MTT (dimethyl-2-thiazolyl-2,5- diphenyl-2H-tetrazolium bromide) assay. The mechanistic studies were performed on potent compound 4g by fluorescent microscopic studies, release of Lactate Dehydrogenase (LDH) and mitochondrial membrane potential, activation of caspase-9 and -3 and flow cytometric analysis.

Results: As revealed by MTT assay, compound 4g was identified as the most potent derivative among the tested series with IC values of 5.64 and 29.15μM against HeLa and MCF-7 cells, respectively. The results were compared with cisplatin. Fluorescent microscopic studies using 4',6-diamidino-2-phenylindole (DAPI) and Propidium Iodide (PI) staining confirmed the occurrence of apoptosis in HeLa cells treated with the most active compound 4g. Moreover, compound 4g also triggered the release of Lactate Dehydrogenase (LDH) in treated HeLa and MCF-7 cells while a fluorescence assay displayed a remarkable increase in the activity of caspase-9 and -3. Moreover, flow cytometric results revealed that compound 4g caused G/G arrest in the treated HeLa cells.

Conclusion: Our results demonstrated that the compound 4g possesses chemotherapeutic properties against breast cancer and cervical adenocarcinoma cells, thus warranting further research to test the anticancer potential of this compound at preclinical and clinical level.
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http://dx.doi.org/10.2174/1871520620666200721110732DOI Listing
January 2021

Poncirin, an orally active flavonoid exerts antidiabetic complications and improves glucose uptake activating PI3K/Akt signaling pathway in insulin resistant C2C12 cells with anti-glycation capacities.

Bioorg Chem 2020 09 30;102:104061. Epub 2020 Jun 30.

Department of Korean Medicine, Graduate School, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address:

Poncirin, a natural flavanone glycoside present abundantly in many citrus fruits, contains an extensive range of biological activities. However, the antidiabetic mechanism of poncirin is unexplored yet. In this study, we examined the anti-diabetic prospective of poncirin by evaluating its ability to inhibit protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant AR (HRAR), rat lens aldose reductase (RLAR), and advanced glycation end-product (AGE) formation (IC = 7.76 ± 0.21, 21.31 ± 1.26, 3.56 ± 0.33, 11.91 ± 0.21, and 3.23 ± 0.09 µM, respectively). Kinetics data and docking studies showed the lowest binding energy and highestaffinityforthemixed and competitivetypeof inhibitorsof poncirin. Moreover, the molecular mechanisms underlying the antidiabetic outcomes of poncirin in insulin resistant C2C12 skeletal muscle cells were explored, which significantly increased glucose uptake and decreased the expression of PTP1B in C2C12 cells. Consequently, poncirin increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. Moreover, poncirin (0.5-50 µM) remarkably inhibited the formation of fluorescent AGE, nonfluorescent CML, fructosamine, and β-cross amyloid structures in glucose-fructose-induced BSA glycation during 4 weeks of study. Poncirin also notably prevented protein oxidation demonstrated with decreasing the protein carbonyl and the consumption of protein thiol in the dose-dependent manner. The results clearly expressed the promising activity of poncirin for the therapy of diabetes and its related complications.
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http://dx.doi.org/10.1016/j.bioorg.2020.104061DOI Listing
September 2020

Bisthioureas of pimelic acid and 4-methylsalicylic acid derivatives as selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP) and intestinal alkaline phosphatase (IAP): Synthesis and molecular docking studies.

Bioorg Chem 2020 08 3;101:103996. Epub 2020 Jun 3.

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

Alkaline phosphatases (ALPs) are membrane bound metalloenzymes, distributed all over the body. Recent studies have revealed that by targeting ALPs can lead towards the treatment of many deadliest diseases including cardiac, cancerous and brain diseases. Thioureas and their derivatives are of considerable significance and are privileged scaffolds in medicinal chemistry. They show a wide range of pharmacological activities such as antibacterial, antiparasitic, anti-inflammatory and antioxidants etc. On the other hand, salicylic acid and its derivatives are known for its broad spectrum of activities. The work presented comprises of synthesis of N-acyl-N'-aryl substituted bisthioureas of pimelic acid (1-7) and 3,5-dimethyl pyrazole (11), 1-aroyl-3-aryl thiourea (12) and 1,3,4-oxadiazole (13) derivatives of 4-methyl salicylic acid. Structures of all the synthesized compounds were characterized by FT-IR and H NMR spectroscopic analysis. Synthesized compounds were evaluated for their alkaline phosphatases inhibition potential and exhibited high potency as well as selectivity towards h-TNAP and h-IAP. Compound 7 and 12 which were the bisthiourea derivative of pimmelic acid and thiourea derivative of 4-methyl salicylic acid, respectively, showed excellent selectivity against h-TNAP and h-IAP, respectively.
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http://dx.doi.org/10.1016/j.bioorg.2020.103996DOI Listing
August 2020

An efficient synthetic approach toward a sporadic heterocyclic scaffold: 1,3-Oxathiol-2-ylidenes; alkaline phosphatase inhibition and molecular docking studies.

Bioorg Med Chem Lett 2020 07 4;30(13):127238. Epub 2020 May 4.

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

We developed a simple and robust method for synthesis of 1,3-oxathiol-2-ylidene benzamides (4a-m) a sporadic class of heterocycles, by reacting freshly prepared aroyl isothiocyanates, with ethyl 2-chloroacetoacetate in presence of N-methylimidazole in dry acetonitrile. The synthesized compounds were explored for their inhibition against alkaline phosphatases and HeLa cancer cell lines. The results suggest that almost all the compounds possess good % inhibition against both enzymes, with compound 4m showing dual inhibition while 4g and 4i as potent and selective inhibitors of TNAP and c-IAP respectively. Structure activity relationship for the active members of series has been carried out based on molecular docking studies. The result of SAR shows the involvement of active inhibitors in H-bonding at various sites with different amino acid residues in addition to secondary metal ion interactions with Zn ions inside the active pocket of the enzyme. The π-π interactions between the 1,3-oxathiole ring and imidazole ring of His321 and His 317 further defines the dual mode of inhibition by compound 4m. These compounds also possess inhibition potential against cervical cell lines in the range of 2.42-69.03% with the maximum inhibition shown by the unsubstituted member 4a compared to the reference drug cisplatin.
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http://dx.doi.org/10.1016/j.bmcl.2020.127238DOI Listing
July 2020

Exploiting oxadiazole-sulfonamide hybrids as new structural leads to combat diabetic complications via aldose reductase inhibition.

Bioorg Chem 2020 06 14;99:103852. Epub 2020 Apr 14.

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

A series of oxadiazole-sulfonamide hybrids was synthesized through multistep reaction and for the formation of targeted thioethers 6(a-l), a much facile route was adopted through which S-alkylation was successfully carried out at room temperature. These novel thioethers 6(a-l) were later screened against aldehyde reductase (ALR1) and aldose reductase (ALR2). Beside the enzyme inhibition studies, the compounds were also tested against cervical cancer cell lines (HeLa). The results suggested the significant inhibition pattern towards ALR2, while few compounds were active against ALR1. The synthesized derivatives have shown weak to moderate cytotoxicity. The most potent inhibitors (6b, 6e, 6f and 6l) were selected for molecular docking studies and the binding interactions were reported.
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http://dx.doi.org/10.1016/j.bioorg.2020.103852DOI Listing
June 2020

Synthesis, biological evaluation, and docking studies of new pyrazole-based thiourea and sulfonamide derivatives as inhibitors of nucleotide pyrophosphatase/phosphodiesterase.

Bioorg Chem 2020 06 21;99:103783. Epub 2020 Mar 21.

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

A series of six compounds (1a-f) possessing pyridine-pyrazole-benzenethiourea or pyridine-pyrazole-benzenesulfonamide scaffold were synthesized. The target compounds were screened to evaluate their inhibitory effect on human nucleotide pyrophosphatase/phosphodiesterase 1 and -3 (ENPP1 and ENPP3) isoenzymes. Compounds 1c-e were the most potent inhibitors of ENPP1 with sub-micromolar IC values (0.69, 0.18, and 0.40 µM, respectively. Moreover, compound 1b was the most potent inhibitor of ENPP3 (IC = 0.21 µM). They were much more potent than the reference standard inhibitor, suramin (IC values against ENPP1 and -3 were 7.77 and 0.89 µM, respectively). Furthermore, all the six compounds were investigated for cytotoxic effect against cancerous cell lines (HeLa, MCF-7, and 1321N1) and normal cell line (BHK-21). Compound 1e was active against all the three cancer cell lines, however, showed preferential cytotoxicity against MCF-7 (IC = 16.05 µM), which is comparable to the potency of cisplatin. All the tested compounds exhibited low or negligible cytotoxic effect against the normal cells. They have the merit of superior selectivity towards cancer cells than normal cells compared to cisplatin. The relative selectivity and potency of the inhibitors was justified by molecular docking studies. All the docked structures showed considerable binding interactions with amino acids residues of active sites of ENPP isoenzymes.
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http://dx.doi.org/10.1016/j.bioorg.2020.103783DOI Listing
June 2020

Recent advances with alkaline phosphatase isoenzymes and their inhibitors.

Arch Pharm (Weinheim) 2020 May 4;353(5):e2000011. Epub 2020 Mar 4.

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

Alkaline phosphatases are found in different living species and play crucial roles in various significant functions, such as hydrolyzing a variable spectrum of phosphate-containing physiological compounds, contributing to DNA synthesis, bone calcification, and attenuation of inflammation. They are homodimeric enzymes; each subunit contains one magnesium ion and two zinc ions crucial for the catalytic activity of the enzyme. Alkaline phosphatases exist in four distinct isoenzymes (placental, intestinal, germ cell, and tissue nonspecific alkaline phosphatases), which are expressed by four different genes; each one of them has distinguished functions. Any disturbance in the gene expression of alkaline phosphatase eventually induces serious disease conditions. Thus, the need to explore new lead inhibitors has increased recently. In this literature review, we aim to investigate the role of alkaline phosphatase in different diseases and physiological conditions and to study the structure-activity relationships of recently reported inhibitors. We focused on the lead compounds reported in the last 5 years (between 2015 and 2019).
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http://dx.doi.org/10.1002/ardp.202000011DOI Listing
May 2020

Anticancer evaluation of a manganese complex on HeLa and MCF-7 cancer cells: design, deterministic solvothermal synthesis approach, Hirshfeld analysis, DNA binding, intracellular reactive oxygen species production, electrochemical characterization and density functional theory.

J Biomol Struct Dyn 2021 Feb 6;39(3):1068-1081. Epub 2020 Mar 6.

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

Herein, a deterministic solvothermal strategy was employed to synthesize an efficient anticancer agent '-dichlorobis(1,10-phenanthroline)manganese(II)' (Mn(phen)Cl). A single-crystal X-ray diffraction analysis revealed that Mn(phen)Cl crystallizes in a triclinic system with the space group . Cyclic voltammetric studies of Mn(phen)Cl indicated that the electrode process occurs only due to complex formation and has a diffusion-controlled mechanism. Density functional theory estimations showed that the Mn(phen)Cl is quite stable and exists in sextet spin state (five unpaired electrons) as the most stable form and hence, Mn(phen)Cl is a high spin complex. Mn(phen)Cl demonstrated significant anticancer potential against HeLa and MCF-7 cancer cells and less toxic behaviour towards normal BHK-21 cells. Fluorescence imaging confirmed that the production of reactive oxygen species (ROS) in HeLa cells by Mn(phen)Cl induces oxidized fluorescence of dichlorofluorescein which emitted fluorescence at 530 nm after excitation at 488 nm. The microscopic investigation of apoptotic effect of Mn(phen)Cl using propidium iodide and 4',6-diamidino-2-phenylindole staining indicated that nuclear condensation, cell detachment and shrinkage occur after treatment with IC values of Mn(phen)Cl. Furthermore, an assessment of caspase-9 and caspase-3 activity after exposure to Mn(phen)Cl in HeLa cells indicated that at IC values of Mn(phen)Cl, 1.5 fold and 4.8 fold increase in caspase-9 and caspase-3 activity, respectively, occurs. The measurement of mitochondrial membrane potential of a cationic dye (JC-1) showed a decrease in mitochondrial membrane potential in both HeLa and MCF-7 cells depicting that compound might have adopted intrinsic pathway of apoptosis. Ability of Mn(phen)Cl to interact with HS-DNA demonstrates hyperchromicity with slight blue shift from 269 nm to 265 nm showing a non-covalent interaction with Gibbs free energy of Δ = -14.62 kJ/mol. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1726818DOI Listing
February 2021

Synthesis, characterization, and anticancer activity of Schiff bases.

J Biomol Struct Dyn 2020 Jul 28;38(11):3246-3259. Epub 2019 Aug 28.

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

Five Schiff bases, 2-((3-chlorophenylimino)methyl)-5-(diethylamino)phenol (L1), 2-((2,4-dichlorophenylimino)methyl)-5-(diethylamino)phenol (L2), 5-(diethylamino)-2-((3,5-dimethylphenylimino)methyl)phenol (L3), 2-((2-chloro-4-methylphenylimino)methyl)-5-(diethylamino)phenol (L4), and 5-(diethylamino)-2-((2,6-diethylphenylimino)methyl)phenol (L5) were synthesized and characterized by elemental analysis, FT-IR, H and C NMR spectroscopy. Three of the compounds (L1, L2, and L4) were analyzed by single crystal X-ray diffraction: L1 and L2 crystallized in orthorhombic P222 and Pca2 space group, respectively, while L4 crystallized in monoclinic P2/c space group. Theoretical investigations were performed for all the synthesized compounds to evaluate the structural details. Drug-DNA interaction studies results from UV-Vis spectroscopy and electrochemistry complement that the compounds bind to DNA through electrostatic interactions. The cytotoxicity of the synthesized compounds was studied against cancer cell lines (HeLa and MCF-7) and a normal cell line (BHK-21) by means of an MTT assay compared to carboplatin, featuring IC values in the micromolar range. The pro-apoptotic mechanism for the active compound L5 was evaluated by fluorescence microscopy, cell cycle analysis, caspase-9 and -3 activity, reactive oxygen species production, and DNA binding studies that further strengthen the results of that L5 is a potent drug against cancer.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1654924DOI Listing
July 2020

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

Synthesis, biological evaluation, and docking studies of new raloxifene sulfonate or sulfamate derivatives as inhibitors of nucleotide pyrophosphatase/phosphodiesterase.

Eur J Med Chem 2019 Nov 25;181:111560. Epub 2019 Jul 25.

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

A new series of raloxifene sulfonate/sulfamate derivatives were designed and synthesized. The target compounds were tested for inhibitory effect against nucleotide pyrophosphatase/phosphodiesterase-1 and -3 (NPP1 and NPP3) enzymes. Furthermore, all the ten target compounds were subjected to cytotoxic studies on various cancer cell lines, and the most potent derivatives were explored for their potency against these cancer cell lines as well as F180 fibroblasts to investigate the selectivity indexes. Compound 1f exerted the highest potency against HT-29 colon cancer cell line (IC = 1.4 μM) with 8.43-fold selectivity towards HT-29 than F180 fibroblasts. Compound 1f exerted sub-micromolar IC values against NPP1 and NPP3 (IC = 0.29 μM and 0.71 μM, respectively). The most potent inhibitors were docked in developed homology model of NPP1 and crystal structure of NPP3. All the docked analogues manifested remarkable interactions within the active pocket of NPP1 and NPP3.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.063DOI Listing
November 2019

Sulfonate and sulfamate derivatives possessing benzofuran or benzothiophene nucleus as potent carbonic anhydrase II/IX/XII inhibitors.

Bioorg Med Chem 2019 09 13;27(17):3889-3901. Epub 2019 Jul 13.

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

In the current work, we report the discovery of new sulfonate and sulfamate derivatives of benzofuran- and benzothiophene as potent inhibitors of human carbonic anhydrases (hCAs) II, IX and XII. A set of derivatives, 1a-t, having different substituents on the fused benzofuran and benzothiophene rings (R = alkyl, cyclohexyl, aryl, NH, NHMe, or NMe) was designed and synthesized. Most of the derivatives exhibited higher potency than acetazolamide as inhibitors of the purified hCAII, IX and XII isoforms. The most potent inhibitors for hCAII, hCAIX and hCAXII were 1g, 1b and 1d with an IC ± SEM values of 0.14 ± 0.03, 0.13 ± 0.03 and 0.17 ± 0.06 µM, respectively. In addition, compounds 1d and 1n exerted preferential inhibitory effect against hCAXII isozyme with good potencies. Some selected compounds were docked within the active pocket of these isozymes and binding of the molecules revealed that sulfonate and sulfamate rings were located towards the active cavity and compounds coordinated to zinc ions.
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http://dx.doi.org/10.1016/j.bmc.2019.07.026DOI Listing
September 2019

Investigation of potent inhibitors of cholinesterase based on thiourea and pyrazoline derivatives: Synthesis, inhibition assay and molecular modeling studies.

Bioorg Chem 2019 09 4;90:103036. Epub 2019 Jun 4.

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

Owing to the desperate need of new drugs development to treat Alzheimer's ailment the synthesis of 1-aroyl-3-(5-(4-chlorophenyl)-1,2,4-triazole-3-thioneaminylthioureas (2-6) starting from (4-amino-5-(4-chlorophenyl)-4H-1,2,4-triazole-3-thiol) (1) and synthesis of 1-(3-(4-aminophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-isobutylphenyl)propan-1-one (7-9) starting from 2-(4-isobutylphenyl)propanehydrazide (a) with the cyclization with substituted chalcones (c-e) was carried out. To check the biological potential of the synthesized compounds, all were subjected to acetylcholinesterase (AChE) and butrylcholinesterase (BChE) inhibition assays. The most potent and selective inhibitor for the acetylcholinesterase was compound 7 having an inhibitory concentration of 123 ± 51 nM, whereas, compound 6 was found as selective inhibitor of butyrylcholinesterase (BChE) with an IC value of 201 ± 80 nM. However, the compounds 1 and 2 were found as dual inhibitors i.e. active against both acetylcholinesterase as well as butyrylcholinesterase.
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http://dx.doi.org/10.1016/j.bioorg.2019.103036DOI Listing
September 2019

Highly Potent and Selective Ectonucleoside Triphosphate Diphosphohydrolase (ENTPDase1, 2, 3 and 8) Inhibitors Having 2-substituted-7- trifluoromethyl-thiadiazolopyrimidones Scaffold.

Med Chem 2020 ;16(5):689-702

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

Background: The ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) terminate nucleotide signaling via the hydrolysis of extracellular nucleoside-5'-triphosphate and nucleoside- 5'-diphosphate, to nucleoside-5'-monophosphate and composed of eight Ca2+/Mg2+ dependent ectonucleotidases (NTPDase1-8). Extracellular nucleotides are involved in a variety of physiological mechanisms. However, they are rapidly inactivated by ectonucleotidases that are involved in the sequential removal of phosphate group from nucleotides with the release of inorganic phosphate and their respective nucleoside. Ectonucleoside triphosphate diphosphohydrolases (NTPDases) represent the key enzymes responsible for nucleotides hydrolysis and their overexpression has been related to certain pathological conditions. Therefore, the inhibitors of NTPDases are of particular importance in order to investigate their potential to treat various diseases e.g., cancer, ischemia and other disorders of the cardiovascular and immune system.

Methods: Keeping in view the importance of NTPDase inhibitors, a series of thiadiazolopyrimidones were evaluated for their potential inhibitory activity towards NTPDases by the malachite green assay.

Results: The results suggested that some of the compounds were found as non-selective inhibitors of isozyme of NTPDases, however, most of the compounds act as potent and selective inhibitors. In case of substituted amino derivatives (4c-m), the compounds 4m (IC50 = 1.13 ± 0.09 μM) and 4g (IC50 = 1.72 ± 0.08 μM) were found to be the most potent inhibitors of h-NTPDase1 and 2, respectively. Whereas, compound 4d showed the best inhibitory potential for both h-NTPDase3 (IC50 = 1.25 ± 0.06 μM) and h-NTPDase8 (0.21 ± 0.02 μM). Among 5a-t derivatives, compounds 5e (IC50 = 2.52 ± 0.15 μM), 5p (IC50 = 3.17 ± 0.05 μM), 5n (IC50 = 1.22 ± 0.06 μM) and 5b (IC50 = 0.35 ± 0.001 μM) were found to be the most potent inhibitors of h-NTPDase1, 2, 3 and 8, respectively. Interestingly, the inhibitory concentration values of above-mentioned inhibitors were several folds greater than suramin, a reference control. In order to determine the binding interactions, molecular docking studies of the most potent inhibitors were conducted into the homology models of NTPDases and the putative binding analysis further confirmed that selective and potent compounds bind deep inside the active pocket of the respective enzymes.

Conclusion: The docking analysis proposed that the inhibitory activity correlates with the hydrogen bonds inside the binding pocket. Thus, these derivatives are of interest and may further be investigated for their importance in medicinal chemistry.
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http://dx.doi.org/10.2174/1573406415666190614095821DOI Listing
April 2021
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