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Khalid Mohammed Khan - One of the best experts on this subject based on the ideXlab platform.
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Synthesis, β-glucuronidase inhibition and molecular docking studies of cyano-substituted bisindole hydrazone hybrids
Molecular Diversity, 2020Co-Authors: Obaidurahman Abid, Nor Hadiani Ismail, Syahrul Imran, Khalid Mohammed Khan, Muhammad Taha, Waqas Jamil, Syed Muhammad Kashif, Juliana YusoffAbstract:The β -glucuronidase, a lysosomal enzyme, catalyzes the cleavage of glucuronosyl-O-bonds. Its inhibitors play a significant role in different medicinal therapies as they cause a decrease in carcinogen-induced colonic tumors by reducing the level of toxic substances present in the intestine. Among those inhibitors, bisindole derivatives had displayed promising β -glucuronidase inhibition activity. In the current study, hydrazone derivatives of bisindolymethane ( 1 – 30 ) were synthesized and evaluated for in vitro β -glucuronidase inhibitory activity. Twenty-eight analogs demonstrated better activity (IC_50 = 0.50–46.5 µM) than standard D -Saccharic Acid 1,4-lactone (IC_50 = 48.4 ± 1.25 µM). Compounds with hydroxyl group like 6 (0.60 ± 0.01 µM), 20 (1.50 ± 0.10 µM) and 25 (0.50 ± 0.01 µM) exhibited the most potent inhibitory activity, followed by analogs with fluorine 21 (3.50 ± 0.10 µM) and chlorine 23 (8.20 ± 0.20 µM) substituents. The presence of hydroxyl group at the aromatic side chain was observed as the main contributing factor in the inhibitory potential. From the docking studies, it was predicted that the active compounds can fit properly in the binding groove of the β -glucuronidase and displayed significant binding interactions with essential residues. Graphic abstract
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2,5-Disubstituted thiadiazoles as potent β-glucuronidase inhibitors; Synthesis, in vitro and in silico studies.
Bioorganic Chemistry, 2019Co-Authors: Muhammad Taha, Mohammed Gollapalli, Noor B. Almandil, Umer Rashid, Mohamed Ibrahim, Ashik Mosaddik, Khalid Mohammed KhanAbstract:Abstract Twenty-five thiadiazole derivatives 1–25 were synthesized from methyl 4-methoxybenzoate via hydrazide and thio-hydrazide intermediates, and evaluated for their potential against β-glucuronidase enzyme. Most of the compounds including 1 (IC50 = 26.05 ± 0.60 μM), 2 (IC50 = 42.53 ± 0.80 μM), 4 (IC50 = 38.74 ± 0.70 μM), 5 (IC50 = 9.30 ± 0.29 μM), 6 (IC50 = 6.74 ± 0.26 μM), 7 (IC50 = 18.40 ± 0.66 μM), and 15 (IC50 = 18.10 ± 0.53 μM) exhibited superior activity potential than the standard d -Saccharic Acid-1,4-lactone (IC50 = 48.4 ± 1.25 μM). Molecular docking studies were conducted to correlate the in vitro results and to identify possible mode of interaction with enzyme active site.
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Synthesis, in vitro β-glucuronidase inhibitory potential and molecular docking studies of quinolines
European Journal of Medicinal Chemistry, 2017Co-Authors: Bilquees Bano, Nor Hadiani Ismail, Khalid Mohammed Khan, Muhammad Taha, Abdul Wadood, Arshia, Kanwal, Bibi Fatima, Mehreen Ghufran, Shahnaz PerveenAbstract:Abstract In this study synthesis and β -glucuronidase inhibitory potential of 3/5/8 sulfonamide and 8-sulfonate derivatives of quinoline ( 1–40 ) are discussed. Studies reveal that all the synthetic compounds were found to have good inhibitory activity against β -glucuronidase. Nonetheless, compounds 1 , 2 , 5 , 13 , and 22 – 24 having IC 50 values in the range of 1.60–8.40 μ M showed superior activity than the standard Saccharic Acid 1,4-lactone (IC 50 = 48.4 ± 1.25 μ M). Moreover, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites. Structures of all the synthetic compounds were confirmed through 1 H NMR, EI-MS and HREI-MS spectroscopic techniques.
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Synthesis of indole analogs as potent β-glucuronidase inhibitors.
Bioorganic Chemistry, 2017Co-Authors: Mohd Syukri Baharudin, Nor Hadiani Ismail, Syahrul Imran, Fazal Rahim, Muhammad Taha, Muhammad Tariq Javid, Khalid Mohammed KhanAbstract:Abstract Natural products are the main source of motivation to design and synthesize new molecules for drug development. Designing new molecules against β -glucuronidase inhibitory is utmost essential. In this study indole analogs ( 1–35 ) were synthesized, characterized using various spectroscopic techniques including 1 H NMR and EI-MS and evaluated for their β -glucuronidase inhibitory activity. Most compounds were identified as potent inhibitors for the enzyme with IC 50 values ranging between 0.50 and 53.40 μM, with reference to standard d -Saccharic Acid 1,4-lactone (IC 50 = 48.4 ± 1.25 μM). Structure-activity relationship had been also established. The results obtained from docking studies for the most active compound 10 showed that hydrogen bond donor features as well as hydrogen bonding with (Oe1) of nucleophilic residue Glu540 is believed to be the most importance interaction in the inhibition activity. It was also observed that hydroxyl at fourth position of benzylidene ring acts as a hydrogen bond donor and interacts with hydroxyl (OH) on the side chain of catalysis residue Tyr508. The enzyme-ligand complexed were being stabilized through electrostatic π-anion interaction with Acid-base catalyst Glu451 (3.96 A) and thus preventing Glu451 from functioning as proton donor residue.
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Synthesis and in silico studies of novel sulfonamides having oxadiazole ring: As β-glucuronidase inhibitors.
Bioorganic Chemistry, 2017Co-Authors: Muhammad Taha, Nor Hadiani Ismail, Manikandan Selvaraj, Uzma Salar, Mohd Syukri Baharudin, Khaled Abdullah Ali Al-kadi, Khalid Mohammed KhanAbstract:Abstract Novel sulfonamides having oxadiazole ring were synthesized by multistep reaction and evaluated to check in vitro β -glucuronidase inhibitory activity. Luckily, except compound 13 , all compounds were found to demonstrate good inhibitory activity in the range of IC 50 = 2.40 ± 0.01–58.06 ± 1.60 μM when compared to the standard d -Saccharic Acid 1,4-lactone (IC 50 = 48.4 ± 1.25 μM). Structure activity relationship was also presented. However, in order to ensure the SAR as well as the molecular interactions of compounds with the active site of enzyme, molecular docking studies on most active compounds 19 , 16 , 4 and 6 was carried out. All derivatives were fully characterized by 1 H NMR, 13 C NMR and EI-MS spectroscopic techniques. CHN analysis was also presented.
Muhammad Taha - One of the best experts on this subject based on the ideXlab platform.
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Inhibition potential of phenyl linked benzimidazole-triazolothiadiazole modular hybrids against β-glucuronidase and their interactions thereof.
International journal of biological macromolecules, 2020Co-Authors: Muhammad Taha, Fazal Rahim, Mohammed Gollapalli, Rai Khalid Farooq, El Hassane Anouar, Nizam Uddin, Gulraiz Khan, Naveed Iqbal, Muhammad FarooqAbstract:β-Glucuronidase is responsible for the catalytic deconjugation of β-d-glucuronides. β-Glucuronidase has evolved to be a viable molecular target for numerous therapeutic treatments. It plays a pivotal role in the metabolism of drugs and endogenous substances. Herein, we report the inhibitory potentials of newly developed and modular benzimidazole-triazolothiadiazole hybrids spaced through a phenyl linker (1-26) and their interactions with the β-glucuronidase. All analogues showed IC50 values in the range of 1.30 ± 0.10 to 44.10 ± 0.80 μM, and hence were found to have outstanding inhibitory potential as compare to the standard D-Saccharic Acid 1,4-lactone (IC50 = 48.4 ± 1.25 μM). These modular hybrids were successfully synthesized, rigorously characterized through various spectroscopic techniques. Molecular docking studies further revealed the potential interactions between the inhibitor and active amino Acid site in β-glucuronidase. These findings helped in identifying the potential for new drug candidates. A Plausible structure activity relationship (SAR) were established which suggested that variation in the inhibitory potential was mainly based upon the substituents attached to the phenyl ring.
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Synthesis, β-glucuronidase inhibition and molecular docking studies of cyano-substituted bisindole hydrazone hybrids
Molecular Diversity, 2020Co-Authors: Obaidurahman Abid, Nor Hadiani Ismail, Syahrul Imran, Khalid Mohammed Khan, Muhammad Taha, Waqas Jamil, Syed Muhammad Kashif, Juliana YusoffAbstract:The β -glucuronidase, a lysosomal enzyme, catalyzes the cleavage of glucuronosyl-O-bonds. Its inhibitors play a significant role in different medicinal therapies as they cause a decrease in carcinogen-induced colonic tumors by reducing the level of toxic substances present in the intestine. Among those inhibitors, bisindole derivatives had displayed promising β -glucuronidase inhibition activity. In the current study, hydrazone derivatives of bisindolymethane ( 1 – 30 ) were synthesized and evaluated for in vitro β -glucuronidase inhibitory activity. Twenty-eight analogs demonstrated better activity (IC_50 = 0.50–46.5 µM) than standard D -Saccharic Acid 1,4-lactone (IC_50 = 48.4 ± 1.25 µM). Compounds with hydroxyl group like 6 (0.60 ± 0.01 µM), 20 (1.50 ± 0.10 µM) and 25 (0.50 ± 0.01 µM) exhibited the most potent inhibitory activity, followed by analogs with fluorine 21 (3.50 ± 0.10 µM) and chlorine 23 (8.20 ± 0.20 µM) substituents. The presence of hydroxyl group at the aromatic side chain was observed as the main contributing factor in the inhibitory potential. From the docking studies, it was predicted that the active compounds can fit properly in the binding groove of the β -glucuronidase and displayed significant binding interactions with essential residues. Graphic abstract
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2,5-Disubstituted thiadiazoles as potent β-glucuronidase inhibitors; Synthesis, in vitro and in silico studies.
Bioorganic Chemistry, 2019Co-Authors: Muhammad Taha, Mohammed Gollapalli, Noor B. Almandil, Umer Rashid, Mohamed Ibrahim, Ashik Mosaddik, Khalid Mohammed KhanAbstract:Abstract Twenty-five thiadiazole derivatives 1–25 were synthesized from methyl 4-methoxybenzoate via hydrazide and thio-hydrazide intermediates, and evaluated for their potential against β-glucuronidase enzyme. Most of the compounds including 1 (IC50 = 26.05 ± 0.60 μM), 2 (IC50 = 42.53 ± 0.80 μM), 4 (IC50 = 38.74 ± 0.70 μM), 5 (IC50 = 9.30 ± 0.29 μM), 6 (IC50 = 6.74 ± 0.26 μM), 7 (IC50 = 18.40 ± 0.66 μM), and 15 (IC50 = 18.10 ± 0.53 μM) exhibited superior activity potential than the standard d -Saccharic Acid-1,4-lactone (IC50 = 48.4 ± 1.25 μM). Molecular docking studies were conducted to correlate the in vitro results and to identify possible mode of interaction with enzyme active site.
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Synthesis of oxadiazole-coupled-thiadiazole derivatives as a potent β-glucuronidase inhibitors and their molecular docking study.
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Muhammad Taha, Syahrul Imran, Fazal Rahim, Abdul Wadood, Mohammed A. Alqahtani, Mohammed Gollapalli, Ashik Mosaddik, Nizam Uddin, Munther Alomari, Yasser A. BamaroufAbstract:Abstract A new series of oxadiazole with thiadiazole moiety (6–27) were synthesized, characterized by different spectroscopic techniques and evaluated for β-glucuronidase inhibitory potential. Sixteen analogs such as 6, 7, 8, 9, 10, 12, 13, 14, 17, 18, 20, 23, 24, 25, 26 and 27 showed IC50 values in the range of 0.96 ± 0.01 to 46.46 ± 1.10 μM, and hence were found to have excellent inhibitory potential in comparison to standard d -Saccharic Acid 1,4-lactone (IC50 = 48.4 ± 1.25 μM). Two analogs such as 16 and 19 showed moderate inhibitory potential while analogs 11, 15, 21 and 22 were found inactive. Our study identifies new series of potent β-glucuronidase inhibitors for further investigation. Structure activity relationships were established for all compounds which showed that the activity is varied due to different substituents on benzene ring. The interaction of the compounds with enzyme active site were confirmed with the help of docking studies, which reveals that the electron withdrawing group and hydroxy group make the molecules more favorable for enzyme inhibition.
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Synthesis of Chromen-4-One-Oxadiazole Substituted Analogs as Potent β-Glucuronidase Inhibitors.
Molecules, 2019Co-Authors: Muhammad Taha, Fazal Rahim, Muhammad Naseem Khan, Mohammed A. Alqahtani, Yasser A. Bamarouf, Mohammed Gollapalli, Rai Khalid Farooq, Syed Adnan Ali Shah, Qamar Uddin AhmedAbstract:Chromen-4-one substituted oxadiazole analogs 1–19 have been synthesized, characterized and evaluated for β-glucuronidase inhibition. All analogs exhibited a variable degree of β-glucuronidase inhibitory activity with IC50 values ranging in between 0.8 ± 0.1–42.3 ± 0.8 μM when compared with the standard d-Saccharic Acid 1,4 lactone (IC50 = 48.1 ± 1.2 μM). Structure activity relationship has been established for all compounds. Molecular docking studies were performed to predict the binding interaction of the compounds with the active site of enzyme.
Shahnaz Perveen - One of the best experts on this subject based on the ideXlab platform.
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synthesis of bis indolylmethanes as new potential inhibitors of β glucuronidase and their molecular docking studies
European Journal of Medicinal Chemistry, 2018Co-Authors: Muhammad Taha, Norizan Ahmat, Hayat Ullah, Laode Muhammad Ramadhan Al Muqarrabun, Fazal Rahim, Muhammad Naseem Khan, Shahnaz PerveenAbstract:Abstract Thirty-two (32) bis-indolylmethane-hydrazone hybrids 1–32 were synthesized and characterized by 1HNMR, 13CNNMR and HREI-MS. All compounds were evaluated in vitro for β-glucuronidase inhibitory potential. All analogs showed varying degree of β-glucuronidase inhibitory potential ranging from 0.10 ± 0.01 to 48.50 ± 1.10 μM when compared with the standard drug d -Saccharic Acid-1,4-lactone (IC50 value 48.30 ± 1.20 μM). Derivatives 1–32 showed the highest β-glucuronidase inhibitory potentials which is many folds better than the standard drug d -Saccharic Acid-1,4-lactone. Further molecular docking study validated the experimental results. It was proposed that bis-indolylmethane may interact with some amino Acid residues located within the active site of β-glucuronidase enzyme. This study has culminated in the identification of a new class of potent β-glucuronidase inhibitors.
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Synthesis, in vitro β-glucuronidase inhibitory potential and molecular docking studies of quinolines
European Journal of Medicinal Chemistry, 2017Co-Authors: Bilquees Bano, Nor Hadiani Ismail, Khalid Mohammed Khan, Muhammad Taha, Abdul Wadood, Arshia, Kanwal, Bibi Fatima, Mehreen Ghufran, Shahnaz PerveenAbstract:Abstract In this study synthesis and β -glucuronidase inhibitory potential of 3/5/8 sulfonamide and 8-sulfonate derivatives of quinoline ( 1–40 ) are discussed. Studies reveal that all the synthetic compounds were found to have good inhibitory activity against β -glucuronidase. Nonetheless, compounds 1 , 2 , 5 , 13 , and 22 – 24 having IC 50 values in the range of 1.60–8.40 μ M showed superior activity than the standard Saccharic Acid 1,4-lactone (IC 50 = 48.4 ± 1.25 μ M). Moreover, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites. Structures of all the synthetic compounds were confirmed through 1 H NMR, EI-MS and HREI-MS spectroscopic techniques.
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biology oriented drug synthesis biods in vitro β glucuronidase inhibitory and in silico studies on 2 2 methyl 5 nitro 1h imidazol 1 yl ethyl aryl carboxylate derivatives
European Journal of Medicinal Chemistry, 2017Co-Authors: Uzma Salar, Nor Hadiani Ismail, Khalid Mohammed Khan, Shahnaz Perveen, Muhammad Taha, Mehreen Ghufran, Abdul WadoodAbstract:Abstract Current study is based on the biology-oriented drug synthesis (BIODS) of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl carboxylate derivatives 1–26, by treating metronidazole with different aryl and hetero-aryl carboxylic Acids in the presence of 1,1′-carbonyl diimidazole (CDI) as a coupling agent. Structures of all synthetic derivatives were confirmed with the help of various spectroscopic techniques such as EI-MS, 1H -NMR and 13C NMR. CHN elemental analyses were also found in agreement with the calculated values. Synthetic derivatives were evaluated to check their β-glucuronidase inhibitory activity which revealed that except few derivatives, all demonstrated good inhibition in the range of IC50 = 1.20 ± 0.01–60.30 ± 1.40 μM as compared to the standard d -Saccharic Acid 1,4-lactone (IC50 = 48.38 ± 1.05 μM). Compounds 1, 3, 4, 6, 9–19, and 21–24 were found to be potent analogs and showed superior activity than standard. Limited structure-activity relationship is suggested that the molecules having electron withdrawing groups like NO2, F, Cl, and Br, were displayed better activity than the compounds with electron donating groups such as Me, OMe and BuO. To verify these interpretations, in silico study was also performed, a good correlation was observed between bioactivities and docking studies.
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Synthesis, in vitro β-glucuronidase inhibitory activity and in silico studies of novel (E)-4-Aryl-2-(2-(pyren-1-ylmethylene)hydrazinyl)thiazoles.
Bioorganic Chemistry, 2016Co-Authors: Uzma Salar, Nor Hadiani Ismail, Khalid Mohammed Khan, Shahnaz Perveen, Muhammad Taha, Abdul Wadood, Shazia Syed, Mehreen GhufranAbstract:Abstract Current research is based on the synthesis of novel ( E )-4-aryl-2-(2-(pyren-1-ylmethylene)hydrazinyl)thiazole derivatives ( 3 – 15 ) by adopting two steps route. First step was the condensation between the pyrene-1-carbaldehyde ( 1 ) with the thiosemicarbazide to afford pyrene-1-thiosemicarbazone intermediate ( 2 ). While in second step, cyclization between the intermediate ( 2 ) and phenacyl bromide derivatives or 2-bromo ethyl acetate was carried out. Synthetic derivatives were structurally characterized by spectroscopic techniques such as EI-MS, 1 H NMR and 13 C NMR. Stereochemistry of the iminic double bond was confirmed by NOESY analysis. All pure compounds 2 – 15 were subjected for in vitro β -glucuronidase inhibitory activity. All molecules were exhibited excellent inhibition in the range of IC 50 = 3.10 ± 0.10–40.10 ± 0.90 μM and found to be even more potent than the standard d -Saccharic Acid 1,4-lactone (IC 50 = 48.38 ± 1.05 μM). Molecular docking studies were carried out to verify the structure-activity relationship. A good correlation was perceived between the docking study and biological evaluation of active compounds.
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thiadiazole derivatives as new class of β glucuronidase inhibitors
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Uzma Salar, Nor Hadiani Ismail, Syahrul Imran, Khalid Mohammed Khan, Shahnaz Perveen, Muhammad Taha, Abdul Wadood, Muhammad RiazAbstract:Abstract Thiadiazole derivatives 1 – 24 were synthesized via a single step reaction and screened for in vitro β -glucuronidase inhibitory activity. All the synthetic compounds displayed good inhibitory activity in the range of IC 50 = 2.16 ± 0.01–58.06 ± 1.60 μM as compare to standard d -Saccharic Acid 1,4-lactone (IC 50 = 48.4 ± 1.25 μM). Molecular docking study was conducted in order to establish the structure–activity relationship (SAR) which demonstrated that thiadiazole as well as both aryl moieties (aryl and N -aryl) involved to exhibit the inhibitory potential. All the synthetic compounds were characterized by spectroscopic techniques 1 H, 13 C NMR, and EIMS.
Nor Hadiani Ismail - One of the best experts on this subject based on the ideXlab platform.
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Synthesis, β-glucuronidase inhibition and molecular docking studies of cyano-substituted bisindole hydrazone hybrids
Molecular Diversity, 2020Co-Authors: Obaidurahman Abid, Nor Hadiani Ismail, Syahrul Imran, Khalid Mohammed Khan, Muhammad Taha, Waqas Jamil, Syed Muhammad Kashif, Juliana YusoffAbstract:The β -glucuronidase, a lysosomal enzyme, catalyzes the cleavage of glucuronosyl-O-bonds. Its inhibitors play a significant role in different medicinal therapies as they cause a decrease in carcinogen-induced colonic tumors by reducing the level of toxic substances present in the intestine. Among those inhibitors, bisindole derivatives had displayed promising β -glucuronidase inhibition activity. In the current study, hydrazone derivatives of bisindolymethane ( 1 – 30 ) were synthesized and evaluated for in vitro β -glucuronidase inhibitory activity. Twenty-eight analogs demonstrated better activity (IC_50 = 0.50–46.5 µM) than standard D -Saccharic Acid 1,4-lactone (IC_50 = 48.4 ± 1.25 µM). Compounds with hydroxyl group like 6 (0.60 ± 0.01 µM), 20 (1.50 ± 0.10 µM) and 25 (0.50 ± 0.01 µM) exhibited the most potent inhibitory activity, followed by analogs with fluorine 21 (3.50 ± 0.10 µM) and chlorine 23 (8.20 ± 0.20 µM) substituents. The presence of hydroxyl group at the aromatic side chain was observed as the main contributing factor in the inhibitory potential. From the docking studies, it was predicted that the active compounds can fit properly in the binding groove of the β -glucuronidase and displayed significant binding interactions with essential residues. Graphic abstract
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Synthesis, in vitro β-glucuronidase inhibitory potential and molecular docking studies of quinolines
European Journal of Medicinal Chemistry, 2017Co-Authors: Bilquees Bano, Nor Hadiani Ismail, Khalid Mohammed Khan, Muhammad Taha, Abdul Wadood, Arshia, Kanwal, Bibi Fatima, Mehreen Ghufran, Shahnaz PerveenAbstract:Abstract In this study synthesis and β -glucuronidase inhibitory potential of 3/5/8 sulfonamide and 8-sulfonate derivatives of quinoline ( 1–40 ) are discussed. Studies reveal that all the synthetic compounds were found to have good inhibitory activity against β -glucuronidase. Nonetheless, compounds 1 , 2 , 5 , 13 , and 22 – 24 having IC 50 values in the range of 1.60–8.40 μ M showed superior activity than the standard Saccharic Acid 1,4-lactone (IC 50 = 48.4 ± 1.25 μ M). Moreover, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites. Structures of all the synthetic compounds were confirmed through 1 H NMR, EI-MS and HREI-MS spectroscopic techniques.
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Synthesis of indole analogs as potent β-glucuronidase inhibitors.
Bioorganic Chemistry, 2017Co-Authors: Mohd Syukri Baharudin, Nor Hadiani Ismail, Syahrul Imran, Fazal Rahim, Muhammad Taha, Muhammad Tariq Javid, Khalid Mohammed KhanAbstract:Abstract Natural products are the main source of motivation to design and synthesize new molecules for drug development. Designing new molecules against β -glucuronidase inhibitory is utmost essential. In this study indole analogs ( 1–35 ) were synthesized, characterized using various spectroscopic techniques including 1 H NMR and EI-MS and evaluated for their β -glucuronidase inhibitory activity. Most compounds were identified as potent inhibitors for the enzyme with IC 50 values ranging between 0.50 and 53.40 μM, with reference to standard d -Saccharic Acid 1,4-lactone (IC 50 = 48.4 ± 1.25 μM). Structure-activity relationship had been also established. The results obtained from docking studies for the most active compound 10 showed that hydrogen bond donor features as well as hydrogen bonding with (Oe1) of nucleophilic residue Glu540 is believed to be the most importance interaction in the inhibition activity. It was also observed that hydroxyl at fourth position of benzylidene ring acts as a hydrogen bond donor and interacts with hydroxyl (OH) on the side chain of catalysis residue Tyr508. The enzyme-ligand complexed were being stabilized through electrostatic π-anion interaction with Acid-base catalyst Glu451 (3.96 A) and thus preventing Glu451 from functioning as proton donor residue.
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Synthesis and in silico studies of novel sulfonamides having oxadiazole ring: As β-glucuronidase inhibitors.
Bioorganic Chemistry, 2017Co-Authors: Muhammad Taha, Nor Hadiani Ismail, Manikandan Selvaraj, Uzma Salar, Mohd Syukri Baharudin, Khaled Abdullah Ali Al-kadi, Khalid Mohammed KhanAbstract:Abstract Novel sulfonamides having oxadiazole ring were synthesized by multistep reaction and evaluated to check in vitro β -glucuronidase inhibitory activity. Luckily, except compound 13 , all compounds were found to demonstrate good inhibitory activity in the range of IC 50 = 2.40 ± 0.01–58.06 ± 1.60 μM when compared to the standard d -Saccharic Acid 1,4-lactone (IC 50 = 48.4 ± 1.25 μM). Structure activity relationship was also presented. However, in order to ensure the SAR as well as the molecular interactions of compounds with the active site of enzyme, molecular docking studies on most active compounds 19 , 16 , 4 and 6 was carried out. All derivatives were fully characterized by 1 H NMR, 13 C NMR and EI-MS spectroscopic techniques. CHN analysis was also presented.
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biology oriented drug synthesis biods in vitro β glucuronidase inhibitory and in silico studies on 2 2 methyl 5 nitro 1h imidazol 1 yl ethyl aryl carboxylate derivatives
European Journal of Medicinal Chemistry, 2017Co-Authors: Uzma Salar, Nor Hadiani Ismail, Khalid Mohammed Khan, Shahnaz Perveen, Muhammad Taha, Mehreen Ghufran, Abdul WadoodAbstract:Abstract Current study is based on the biology-oriented drug synthesis (BIODS) of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl carboxylate derivatives 1–26, by treating metronidazole with different aryl and hetero-aryl carboxylic Acids in the presence of 1,1′-carbonyl diimidazole (CDI) as a coupling agent. Structures of all synthetic derivatives were confirmed with the help of various spectroscopic techniques such as EI-MS, 1H -NMR and 13C NMR. CHN elemental analyses were also found in agreement with the calculated values. Synthetic derivatives were evaluated to check their β-glucuronidase inhibitory activity which revealed that except few derivatives, all demonstrated good inhibition in the range of IC50 = 1.20 ± 0.01–60.30 ± 1.40 μM as compared to the standard d -Saccharic Acid 1,4-lactone (IC50 = 48.38 ± 1.05 μM). Compounds 1, 3, 4, 6, 9–19, and 21–24 were found to be potent analogs and showed superior activity than standard. Limited structure-activity relationship is suggested that the molecules having electron withdrawing groups like NO2, F, Cl, and Br, were displayed better activity than the compounds with electron donating groups such as Me, OMe and BuO. To verify these interpretations, in silico study was also performed, a good correlation was observed between bioactivities and docking studies.
Ratan Gachhui - One of the best experts on this subject based on the ideXlab platform.
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d Saccharic Acid 1 4 lactone protects diabetic rat kidney by ameliorating hyperglycemia mediated oxidative stress and renal inflammatory cytokines via nf κb and pkc signaling
Toxicology and Applied Pharmacology, 2013Co-Authors: Semantee Bhattacharya, Prasenjit Manna, Ratan GachhuiAbstract:Abstract Increasing evidence suggests that oxidative stress is involved in the pathogenesis of diabetic nephropathy (DN) and this can be attenuated by antioxidants. d -Saccharic Acid 1,4-lactone (DSL) is known for its detoxifying and antioxidant properties. Our early investigation showed that DSL can ameliorate alloxan (ALX) induced diabetes mellitus and oxidative stress in rats by inhibiting pancreatic β-cell apoptosis. In the present study we, therefore, investigated the protective role of DSL against renal injury in ALX induced diabetic rats. ALX exposure (at a dose of 120 mg/kg body weight, i. p., once) elevated the blood glucose level, serum markers related to renal injury, the production of reactive oxygen species (ROS), and disturbed the intra-cellular antioxidant machineries. Oral administration of DSL (80 mg/kg body weight) restored all these alterations close to normal. In addition, DSL could also normalize the aldose reductase activity which was found to increase in the diabetic rats. Investigating the mechanism of its protective activity, we observed the activation of different isoforms of PKC along with the accumulation of matrix proteins like collagen and fibronectin. The diabetic rats also showed nuclear translocation of NF-κB and increase in the concentration of inflammatory cytokines in the renal tissue. The activation of mitochondria dependent apoptotic pathway was observed in the diabetic rat kidneys. However, treatment of diabetic rats with DSL counteracted all these changes. These findings, for the first time, demonstrated that DSL could ameliorate renal dysfunction in diabetic rats by suppressing the oxidative stress related signalling pathways.
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the prophylactic role of d Saccharic Acid 1 4 lactone against hyperglycemia induced hepatic apoptosis via inhibition of both extrinsic and intrinsic pathways in diabetic rats
Food & Function, 2013Co-Authors: Semantee Bhattacharya, Ratan GachhuiAbstract:Sustained hyperglycemia and increased oxidative stress play major roles in the development of secondary complications in diabetes including liver injury. Dietary supplement of antioxidants is effective in preventing oxidative stress mediated tissue damage in diabetic pathophysiology. D-Saccharic Acid 1,4-lactone (DSL), a derivative of D-glucaric Acid, is present in many dietary plants and is known for its detoxifying and antioxidant properties. Our early investigation showed that DSL can ameliorate alloxan (ALX) induced diabetes mellitus and oxidative stress in rats by inhibiting pancreatic β-cell apoptosis. In the present study we investigated the protective role of DSL against hepatic dysfunction in ALX induced diabetic rats. ALX exposure elevated the blood glucose, serum ALP and ALT levels, the production of reactive oxygen species (ROS), and disturbed the intra-cellular antioxidant machineries. Oral administration of DSL restored all these alterations close to normal. By investigating the mechanism of its protective activity, we observed that DSL prevented hyperglycemia induced hepatic apoptosis by inhibiting both extrinsic and intrinsic pathways. Results showed that in the liver tissue, diabetes promoted a significant increase of TNF-α/TNF-R1 and led to the activation of caspase-8 and t-Bid. In addition, ALX exposure reciprocally regulated Bcl-2 family protein expression, disturbed mitochondrial membrane potential, and subsequently released cytochrome c from mitochondria to cytosol. As a consequence, a significant increase in caspase-3 expression was observed in the liver of diabetic animals. However, treatment of diabetic rats with DSL counteracted these changes, making it a promising approach in lessening diabetes mediated tissue damage.
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d Saccharic Acid 1 4 lactone ameliorates alloxan induced diabetes mellitus and oxidative stress in rats through inhibiting pancreatic beta cells from apoptosis via mitochondrial dependent pathway
Toxicology and Applied Pharmacology, 2011Co-Authors: Semantee Bhattacharya, Prasenjit Manna, Ratan GachhuiAbstract:Oxidative stress plays a vital role in diabetic complications. To suppress the oxidative stress mediated damage in diabetic pathophysiology, a special focus has been given on naturally occurring antioxidants present in normal diet. D-Saccharic Acid 1,4-lactone (DSL), a derivative of D-glucaric Acid, is present in many dietary plants and is known for its detoxifying and antioxidant properties. The aim of the present study was to evaluate the beneficial role of DSL against alloxan (ALX) induced diabetes in the pancreas tissue of Swiss albino rats. A dose-dependent study for DSL (20-120 mg/kg body weight) was carried out to find the effective dose of the compound in ALX-induced diabetic rats. ALX exposure elevated the blood glucose, glycosylated Hb, decreased the plasma insulin and disturbed the intra-cellular antioxidant machineries whereas oral administration of DSL at a dose of 80 mg/kg body weight restored these alterations close to normal. Investigating the mechanism of the protective activity of DSL we observed that it prevented the pancreatic {beta}-cell apoptosis via mitochondria-dependent pathway. Results showed decreased mitochondrial membrane potential, enhanced cytochrome c release in the cytosol and reciprocal regulation of Bcl-2 family proteins in the diabetic rats. These events were also found to be associated with increasedmore » level of Apaf-1, caspase 9, and caspase 3 that ultimately led to pancreatic {beta}-cell apoptosis. DSL treatment, however, counteracted these changes. In conclusion, DSL possesses the capability of ameliorating the oxidative stress in ALX-induced diabetes and thus could be a promising approach in lessening diabetic complications. Highlights: Black-Right-Pointing-Pointer Oxidative stress is suggested as a key event in the pathogenesis of diabetes. Black-Right-Pointing-Pointer D-Saccharic Acid 1,4-lactone (DSL) reduces the alloxan-induced diabetes mellitus. Black-Right-Pointing-Pointer DSL normalizes cellular antioxidant machineries disturbed due to alloxan toxicity. Black-Right-Pointing-Pointer DSL inhibits pancreatic {beta}-cells apoptosis via mitochondria-dependent pathway. Black-Right-Pointing-Pointer DSL could be a promising approach for the treatment of diabetes mellitus.« less
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Protective effect of kombucha tea against tertiary butyl hydroperoxide induced cytotoxicity and cell death in murine hepatocytes.
Indian Journal of Experimental Biology, 2011Co-Authors: Semantee Bhattacharya, Prasenjit Manna, Ratan GachhuiAbstract:: Kombucha (KT), a fermented black tea (BT), is known to have many beneficial properties. In the present study, antioxidant property of KT has been investigated against tertiary butyl hydroperoxide (TBHP) induced cytotoxicity using murine hepatocytes. TBHP, a reactive oxygen species inducer, causes oxidative stress resulting in organ pathophysiology. Exposure to TBHP caused a reduction in cell viability, increased membrane leakage and disturbed the intra-cellular antioxidant machineries in hepatocytes. TBHP exposure disrupted mitochondrial membrane potential and induced apoptosis as evidenced by flow cytometric analyses. KT treatment, however, counteracted the changes in mitochondrial membrane potential and prevented apoptotic cell death of the hepatocytes. BT treatment also reverted TBHP induced hepatotoxicity, however KT was found to be more efficient. This may be due to the formation of antioxidant molecules like D-Saccharic Acid-1,4-lactone (DSL) during fermentation process and are absent in BT. Moreover, the radical scavenging activities of KT were found to be higher than BT. Results of the study showed that KT has the potential to ameliorate TBHP induced oxidative insult and cell death in murine hepatocytes more effectively than BT.
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prophylactic role of d Saccharic Acid 1 4 lactone in tertiary butyl hydroperoxide induced cytotoxicity and cell death of murine hepatocytes via mitochondria dependent pathways
Journal of Biochemical and Molecular Toxicology, 2011Co-Authors: Semantee Bhattacharya, Prasenjit Manna, Srabasti Chatterjee, Jyotirmoy Ghosh, Ratan GachhuiAbstract:D-Saccharic Acid 1,4-lactone (DSL) is a derivative of D-glucaric Acid. It is a beta-glucuronidase inhibitor and possesses anticarcinogenic, detoxifying, and antioxidant properties. In the present study, the protective effects of DSL were investigated against tertiary butyl hydroperoxide (TBHP) induced cytotoxicity and cell death in vitro using murine hepatocytes. Exposure of TBHP caused a reduction in cell viability, enhanced the membrane leakage, and disturbed the intracellular antioxidant machineries in murine hepatocytes. Investigating the signaling mechanism of TBHP-induced cellular pathophysiology and protective action of DSL, we found that TBHP exposure disrupted mitochondrial membrane potential, facilitated cytochrome c release in the cytosol, and led to apoptotic cell death via mitochondria-dependent pathways. DSL counteracted these changes and maintained normalcy in hepatocytes. Combining, results suggest that DSL possesses the ability to ameliorate TBHP-induced oxidative insult, cytotoxicity, and apoptotic cell death probably due to its antioxidant activity and functioning via mitochondria-dependent pathways. © 2011 Wiley Periodicals, Inc. J Biochem Mol Toxicol 25:341–354 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.20393
