- Synthesis, biological evaluation, and in silico study of some unique multifunctional 1,2,4-triazole acetamides
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The imperative demand for antibacterial agents and enzyme inhibitors prompted us to synthesize some new compounds, 6a–6k, bearing multifunctional moieties. The target acetamides were derived from 4-phenyl-5-(1-tosylpiperidin-4-yl)-4H-1,2,4-triazole-3-thiol (3). The structural analysis was carried out using modern spectroscopic techniques including IR, NMR, and EIMS spectral analysis. The antibacterial activity was screened against five bacterial strains including three gram-negative and two gram-positive ones. Enzyme inhibition was carried out against lipoxygenase enzyme and results were supported by in silico study. The synthesized compounds were proved to be potent antibacterial agents and enzyme inhibitors.
- Sattar, Almas,Ur Rehman, Aziz,Abbasi, Muhammad Athar,Siddiqui, Sabahat Zahra,Rasool, Shahid,Khalid, Hira,Lodhi, Muhammad Arif,Khan, Farman Ali
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- Structural basis of binding and justification for the urease inhibitory activity of acetamide hybrids of N-substituted 1,3,4-oxadiazoles and piperidines
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In present, we have performed the Michaelis–Menten kinetics studies of urease inhibitors (6a–o), having basic skeleton of acetamide hybrids of N-substituted 1,3,4-oxadiazoles and piperidines. From the Lineweaver-Burk plot, Dixon plot and their secondary replots, it has been confirmed that all the compounds have inhibited the enzyme competitively with Ki values of in range from 3.11 ± 0.2 to 5.20 ± 0.7 μM. Compound 6a was found to have lowest Ki among the series, while compounds 6d, 6e, 6gand 6i were found subsequently the excellent Ki values after 6a. Molecular docking has supported their types of inhibitions and structure activity-relationship. Most frequently, the nitro group oxygen atoms were found in contact with nickel ions of the active site. Moreover, all the compounds were subjected to toxicity tests and were found nontoxic against human neutrophils and plants, respectively.
- Abbasi, Muhammad Athar,Afridi, Sahib Gul,Khan, Ajmal,Khan, Asifullah,Khan, Farman Ali,Lodhi, Muhammad Arif,Rehman, Aziz Ur
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- New indole based hybrid oxadiazole scaffolds with N-substituted acetamides: As potent anti-diabetic agents
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Current study is based on the sequential conversion of indolyl butanoic acid (1) into ethyl indolyl butanoate (2), indolyl butanohydrazide (3), and 1,3,4-oxadiazole-2-thiol analogs (4) by adopting chemical transformations. In a parallel series of reaction
- Nazir, Majid,Abbasi, Muhammad Athar,Aziz-ur-Rehman,Siddiqui, Sabahat Zahra,Khan, Khalid Mohammed,Kanwal,Salar, Uzma,Shahid, Muhammad,Ashraf, Muhammad,Arif Lodhi, Muhammad,Ali Khan, Farman
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- Convergent synthesis, free radical scavenging, Lineweaver-Burk plot exploration, hemolysis and in silico study of novel indole-phenyltriazole hybrid bearing acetamides as potent urease inhibitors
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In the current paper, through a convergent multi-step approach, a library of novel indole-phenyltriazole hybrids containing an amide moiety (9a-k) was synthesized. The structural verification of all synthesized molecules was accomplished by CHN and spectral analyses data. These synthesized bi-heterocyclic derivatives (9a-k) were evaluated for their anti-ulcer potential by inhibitory action against Jack bean urease enzyme and subsequently their structure-activity relationship was perceived. Moreover, these compounds were inspected for cytotoxic profile by hemolytic activity and it was professed that nearly all the synthesized compounds showed low cytotoxicity. In addition, free radical scavenging activity and kinetic analysis were also carried out for these compounds to understand their mode of inhibition. So, it was summated that these derivatives might lead to further research gateways for obtaining better and safe anti-ulcer agents.
- Abbasi, Muhammad A.,Ali Shah, Syed A.,Hassan, Mubashir,Khan, Wajiha,Nazir, Majid,Raza, Hussain,Rehman, Aziz-ur,Seo, Sung Y.,Shahid, Muhammad,Siddiqui, Sabahat Z.
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- A novel method for the synthesis of 1,2,4-triazole-derived heterocyclic compounds: enzyme inhibition and molecular docking studies
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Two series of new N-aryl/aralkyl derivatives (9a–q) of 2-(4-ethyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetamide and N-aryl/aralkyl derivatives (10a–q) of 2-(4-phenyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetamide were synthesized. The methods included successive conversions of thiophen-2-acetic acid (a) into its respective ester, hydrazide and N-aryl/aralkyl 1,3,4-triazole. The target compounds (9a–q; 10a–q) were obtained by the reaction of N-aryl/aralkyl 1,3,4-triazole (5, 6) with various electrophiles, (8a–q), in N,N-dimethyl formamide (DMF) and sodium hydroxide at room temperature. The characterization of these compounds was done by FTIR, 1H-, 13C-NMR, EI-MS and HR-EI-MS spectral data. All compounds were evaluated for their enzyme inhibitory potentials against electric eel acetylcholinesterase, AChE (10f, 10d; IC50 values 32.26 ± 0.12, 45.72 ± 0.11?μM, respectively), equine butyrylcholinesterase, BChE (9d, 9l, 9b, 10d, 10h; IC50 values 12.52 ± 0.19, 12.52 ± 0.19, 21.72 ± 0.18, 23.62 ± 0.22, 24.52 ± 0.21?μM, respectively), jack bean urease (10i, 10n, 9e; IC50 values 7.27 ± 0.05, 7.35 ± 0.04, 8.79 ± 0.05?μM, respectively) and yeast α-glucosidase enzymes (9o, 10i; IC50 values 62.94 ± 0.19, and 69.46 ± 0.15?μM, respectively). The molecular docking studies supported these findings. This study provides cheaper bioactive triazole amides as promising future lead molecules.
- Riaz, Naheed,Iftikhar, Muhammad,Saleem, Muhammad,Aziz-ur-Rehman,Ahmed, Ishtiaq,Ashraf, Muhammad,Shahnawaz,Rehman, Jameel,al-Rashida, Mariya
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- Probing phenylcarbamoylazinane-1,2,4-triazole amides derivatives as lipoxygenase inhibitors along with cytotoxic, ADME and molecular docking studies
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Hunting small molecules as anti-inflammatory agents/drugs is an expanding and successful approach to treat several inflammatory diseases such as cancer, asthma, arthritis, and psoriasis. Besides other methods, inflammatory diseases can be treated by lipoxygenase inhibitors, which have a profound influence on the development and progression of inflammation. In the present study, a series of new N-alkyl/aralky/aryl derivatives (7a-o) of 2-(4-phenyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide was synthesized and screened for their inhibitory potential against the enzyme 15-lipoxygenase. The simple precursor ethyl piperidine-4-carboxylate (a) was successively converted into phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and N-phenylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4), then in combination with electrophiles (6a-o) through further multistep synthesis, final products (7a-o) were generated. All the synthesized compounds were characterized by FTIR, 1H, 13C NMR spectroscopy, EIMS, and HREIMS spectrometry. Almost all the synthesized compounds showed excellent inhibitory potential against the tested enzyme. Compounds 7c, 7f, 7d, and 7g displayed potent inhibitory potential (IC50 9.25 ± 0.26 to 21.82 ± 0.35 μM), followed by the compounds 7n, 7h, 7e, 7a, 7b, 7l, and 7o with IC50 values in the range of 24.56 ± 0.45 to 46.91 ± 0.57 μM. Compounds 7c, 7f, 7d exhibited 71.5 to 83.5% cellular viability by MTT assay compared with standard curcumin (76.9%) when assayed at 0.125 mM concentration. In silico ADME studies supported the drug-likeness of most of the molecules. In vitro inhibition studies were substantiated by molecular docking wherein the phenyl group attached to the triazole ring was making a π-δ interaction with Leu607. This work reveals the possibility of a synthetic approach of compounds in relation to lipoxygenase inhibition as potential lead compounds in drug discovery.
- Muzaffar, Saima,Shahid, Wardah,Riaz, Naheed,Saleem, Muhammad,Ashraf, Muhammad,Aziz-ur-Rehman,Bashir, Bushra,Kaleem, Ayesha,al-Rashida, Mariya,Baral, Bikash,Bhattarai, Keshab,Gross, Harald
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- Identification of phenylcarbamoylazinane-1,3,4-oxadiazole amides as lipoxygenase inhibitors with expression analysis and in silico studies
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In search for new anti-inflammatory agents that inhibit the enzymes of arachidonic acid pathway as the drug targets, the present article describes the screening of 1,3,4-oxadiazole analogues against lipoxygenase (LOX) enzyme. The work is based on the synthesis of new N-alkyl/aralky/aryl derivatives (6a-o) of 2-(4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,3,4-oxadiazol-3-ylthio)acetamide which were obtained by the reaction of 1,3,4-oxadiazole (3) with various electrophiles (5a-o), in KOH. The synthesized analogues showed potent to moderate inhibitory activity against the soybean 15-LOX enzyme; especially 6g, 6b, 6a and 6l displayed the potent inhibitory potential with IC50 values 7.15 ± 0.26, 9.32 ± 0.42, 15.83 ± 0.45 & 18.37 ± 0.53 μM, respectively, while excellent to moderate inhibitory profiles with IC50 values in the range of 26.13–98.21 μM were observed from the compounds 6k, 6m, 6j, 6o, 6h, 6f, 6n and 6c. Most of the active compounds exhibited considerable cell viability against blood mononuclear cells (MNCs) at 0.25 mM by MTT assay except 6f, 6h, 6k and 6m which showed around 50% cell viability. Flow cytometry studies of the selected compounds 6a, 6j and 6n revealed that these caused 79.5–88.51% early apoptotic changes in MNCs compared with 4.26% for control quercetin at their respective IC50 values. The relative expression of 5-LOX gene was monitored in MNCs after treatment with these three molecules and all down-regulated the enzyme activity. In silico ADME and molecular docking studies further supported these studies of oxadiazole derivatives and considered it as potential ‘lead’ compounds in drug discovery and development.
- Amjad, Hira,Ashraf, Muhammad,Aziz-ur-Rehman,Bashir, Bushra,Bhattarai, Keshab,Imran, Muhammad,Muzaffar, Saima,Riaz, Naheed,Saleem, Muhammad,Shahid, Wardah
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- Synthesis, anticancer, and computational studies of 1, 3, 4-oxadiazole-purine derivatives
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Theophylline-7-acetic acid (acefylline) (3) and its derivatives are pharmacologically active compounds and generally recognized as bronchodilators for the treatment of respiratory diseases like acute asthma for over 70 years. In this article, synthesis of
- Faisal, Shahla,Kamal, Shagufta,Parveen, Bushra,Rasool, Nasir,Rasul, Azhar,Raza, Zohaib,Shahzadi, Irum,Zahid, Faisal M.,Zahoor, Ameer F.,Zia-ur-Rehman, Muhammad
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p. 2782 - 2794
(2020/04/16)
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- Synthesis and structure-activity relationship of tyrosinase inhibiting novel bi-heterocyclic acetamides: Mechanistic insights through enzyme inhibition, kinetics and computational studies
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The present research was designed for the selective synthesis of novel bi-heterocyclic acetamides, 9a-n, and their tyrosinase inhibition to overwhelm the problem of melanogenesis. The structures of newly synthesized compounds were confirmed by spectral techniques such as 1H NMR, 13C NMR, and EI-MS along with elemental analysis. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against tyrosinase and all these molecules were recognized as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which explored that compound, 9h, inhibited tyrosinase competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0027 μM. The computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal/mol). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules can be pondered as nontoxic medicinal scaffolds for skin pigmentation and related disorders.
- Butt, Abdul Rehman Sadiq,Abbasi, Muhammad Athar,Aziz-ur-Rehman,Siddiqui, Sabahat Zahra,Raza, Hussain,Hassan, Mubashir,Shah, Syed Adnan Ali,Shahid, Muhammad,Seo, Sung-Yum
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p. 459 - 472
(2019/02/19)
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- Design, Synthesis, Antimicrobial Evaluation, and Laccase Catalysis Effect of Novel Benzofuran–Oxadiazole and Benzofuran–Triazole Hybrids
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Novel structural hybrids of benzofuran–oxadiazole and benzofuran–triazole have been synthesized and evaluated for their potential against Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. The excellent antibiotic activity was shown by compou
- Faiz, Sadia,Zahoor, Ameer Fawad,Ajmal, Muhammad,Kamal, Shagufta,Ahmad, Sajjad,Abdelgawad, Abdelrahman M.,Elnaggar, Mehrez E.
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p. 2839 - 2852
(2019/11/03)
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- Synthesis, characterization and biological activity of some new S-substituted derivatives of 5-(2-chlorophenyl)-1,3,4-oxadiazol-2-thiol
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Molecules with multi-functional groups are being synthesized to acquire more potent molecules. Two series of S-substituted derivatives of 5-(2-chlorophenyl)-1,3,4-Oxadiazol-2-thiol (4) were synthesized and also evaluated for their biological activities. The 2-chlorobenzoic acid (1) was stepped up to ethyl 2-chlorobenzoate (2), 2-chlorobenzohydrazide (3) and 5-(2-chlorophenyl)-1,3,4- Oxadiazol-2-thiol (4). The molecule 4 was made to react with N-substituted-2-bromoacetamide, 6a-f, to yield N-substituted-2-((5-(2-chlorophenyl)-1,3,4-Oxadiazol-2-yl)sulfanyl)acetamide, 7a-f. Simultaneously, the compound 4 was converted to 2-(5-(2-chlorophenyl)-1,3,4-Oxadiazol-2- ylthio)acetohydrazide (9) which on reaction with different aldehydes, 10a-g, resulted N'-substituted- 2-(5-(2-chlorophenyl)-1,3,4-Oxadiazol-2-ylthio)acetohydrazide, 11a-g. The proposed structures of the molecules were supported by spectral analysis and the series 7a-f was found to be better antibacterial agents and lipoxygenase enzyme inhibitors as compared to 11a-g.
- Aziz-Ur-Rehman,Rasool, Shahid,Abbasi, M. Athar,Siddiqui, Sabahat Z.,Sattar, Almas,Khan, Khalid Mohammed,Ahmad, Irshad,Afzal, Saira
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p. 776 - 786
(2016/01/12)
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- A small molecule inhibits protein disulfide isomerase and triggers the chemosensitization of cancer cells
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Resistance to chemotherapeutic agents represents a major challenge in cancer research. One approach to this problem is combination therapy, the application of a toxic chemotherapeutic drug together with a sensitizing compound that addresses the vulnerability of cancer cells to induce apoptosis. Here we report the discovery of a new compound class (T8) that sensitizes various cancer cells towards etoposide treatment at subtoxic concentrations. Proteomic analysis revealed protein disulfide isomerase (PDI) as the target of the T8 class. In-depth chemical and biological studies such as the synthesis of optimized compounds, molecular docking analyses, cellular imaging, and apoptosis assays confirmed the unique mode of action through reversible PDI inhibition. In the battle against the chemoresistance of cancer cells a screening approach has identified a novel compound class that sensitizes cancer cells in combination with etoposide. Proteomic target discovery revealed the reversible inhibition of protein disulfide isomerase as the molecular mechanism, which was further supported by cellular imaging studies and docking and biochemical assays in various cancer model systems.
- Eirich, Jürgen,Braig, Simone,Schyschka, Liliana,Servatius, Phil,Hoffmann, Judith,Hecht, Sabrina,Fulda, Simone,Zahler, Stefan,Antes, Iris,Kazmaier, Uli,Sieber, Stephan A.,Vollmar, Angelika M.
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supporting information
p. 12960 - 12965
(2016/02/18)
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- N-substituted derivatives of 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl-2- sulfanyl acetamide as valuable bioactive compounds
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In the described research work, a new series of N-substituted derivatives of 5-(4- chlorophenyl)-1,3,4-Oxadiazol-2-yl-2-sulfanyl acetamide has been synthesized. The synthesis was carried out by converting 4-chlorobenzoic acid (1) into ethyl 4-chlorobenzoate (2), 4- chlorobenzohydrazide (3) and then 5-(4-chlorophenyl)-1,3,4-Oxadiazol-2-thiol (4) respectively. The target molecules 6a-o were synthesized by reacting compound 4 with different N-alkyl/aryl substituted 2-bromoacetamide (5a-o) in equimolar ratios of using DMF and sodium hydride (NaH). The structure of all the synthesized compounds was confirmed by spectral data like EI-MS, IR and 1H-NMR. The compounds were also analysed for antimicrobial & hemolytic activity and most of them were found active against the selected microbial species at variable extent relative to reference standards. But 6f and 6o were the active against the selected panel of microbes and former was most potent one. This series revealed less toxicity and may consider for further biological screening and application trial except 6g and 6j, exhibiting high cytotoxicity.
- Rehman, Aziz-Ur,Gul, Samreen,Abbasi, Muhammad Athar,Nafeesa, Khadija,Siddiqa, Asia,Khan, Khalid Mohammed,Shahid, Muhammad,Subhani, Zinayyera
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p. 503 - 511
(2014/08/05)
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- Carbamates as HIV anti-viral agents
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The present invention relates to carbamate derivatives having RNase H, polymerase and/or HIV reverse transcriptase modulatory, and particularly, inhibitory activity. Included in the invention are the carbamate derivatives, compositions containing the deri
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Page/Page column 9
(2008/06/13)
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- Propionic acid derivatives
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The present application relates to novel potent PPAR-alpha-activating compounds for treating, for example, coronary heart disease, and to their preparation.
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- Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) selectivity
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When the dialkylacetamide side chain of the ETA-selective antagonist ABT-627 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ETB over ETA. By optimizing the aniline substitution pattern, as well as the alkoxy group on the 2-aryl substituent, it is possible to prepare antagonists with subnanomolar affinity for ETB and with selectivities in excess of 4000-fold. A number of these compounds also show promising pharmacokinetic profiles; a useful balance of properties is found in A-192621 (38). Pharmacology studies with A-192621 serve to reveal the role of the ETB receptor in modulating blood pressure; the observed hypertensive response to persistent ETB blockade is consistent with previous postulates and indicates that ETB-selective antagonists may not be suitable as agents for long-term systemic therapy.
- Von Geldern, Thomas W.,Tasker, Andrew S.,Sorensen, Bryan K.,Winn, Martin,Szczepankiewicz, Bruce G.,Dixon, Douglas B.,Chiou, William J.,Wang, Liming,Wessale, Jerry L.,Adler, Andy,Marsh, Kennan C.,Nguyen, Bach,Opgenorth, Terry J.
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p. 3668 - 3678
(2007/10/03)
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