- 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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- 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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p. 1183 - 1200
(2020/01/31)
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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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- Synthesis of Novel Bi-Heterocycles as Valuable Anti-Diabetic Agents: 2-({5-((2-Amino-1,3-Thiazol-4-yl)methyl)-1,3,4-Oxadiazol-2-yl}sulfanyl)-N-(Substituted)acetamides
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Abstract: The synthesis of a new series of S-substituted acetamides derivatives of 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol were synthesized and evaluated for enzyme inhibition study along with cytotoxic behavior. Ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate was converted to corresponding acid hydrazide by hydrazine hydrate in ethanol. The reflux of acid hydrazide with carbon disulfide resulted to 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol. Different electrophiles were synthesized by the reaction of respective anilines (one in each reaction) and 2-bromoacetylbromide in an aqueous medium. The targeted bi-heterocyclic compounds were synthesized by stirring nucleophilic 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol with different acetamides electrophiles (one after another), in DMF using LiH as base and activator. The proposed structures of newly synthesized compounds were deduced by spectroscopic techniques such as 1H NMR, 13C NMR, EI MS and elemental analysis. These novel bi-heterocycles were tested for their anti-diabetic potential via the in vitro inhibition of α-glucosidase enzyme. The in silico study of these molecules was also coherent with their enzyme inhibition data. Furthermore, these molecules were analyzed for their cytotoxic behavior against brine shrimps. It was inferred from the results that most of them exhibited very potent inhibitory potential against the studied enzyme and can be utilized as valuable anti-diabetic agent.
- Aziz-ur-Rehman,Khan, Farman Ali,Lodhi, Muhammad Arif,Mirza, Bushra,Muhammad, Athar Abbasi,Ramzan, Muhammad Shahid,Shah, Syed Adnan Ali,Siddiqui, Sabahat Zahra
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p. 590 - 598
(2020/10/02)
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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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- 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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p. 401 - 417
(2018/06/11)
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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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p. 253 - 263
(2018/09/05)
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- Synthesis of acetamide derivatives of 1,2,4-triazole bearing azinane and their binding interactions with bovine serum albumin using spectroscopic techniques
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A new series of acetamide derivatives containing 1,2,4-triazole and azinane moieties has been synthesized and characterized using1 H NMR,13 C NMR, IR, and EI-MS spectroscopic analysis. The intermediate triazole was synthesized through a sequential synthesis of carboxylate and carbohydrazide. The bovine serum albumin (BSA) binding of the newly synthesized 1,2,4-triazole derivatives was evaluated along with thermodynamics, site-selective binding, and synchronous study. The results obtained by BSA binding as well as thermodynamic studies justify that all the compounds show spontaneous interaction with BSA and could be effectively distributed and eliminated from the body. Therefore, the triazole-based analogs might be a useful strategy for designing new drug systems.
- Iqbal, Javed,Ur-Rehman, Aziz,Abbasi, Muhammad Athar,Siddiqui, Sabahat Zahra,Khalid, Hira,Laulloo, Sabina Jhaumeer,Joondan, Nausheen,Taupass, Aniisah Banu,Rasool, Shahid,Shah, Syed Adnan Ali
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p. 1459 - 1478
(2019/01/03)
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- Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives
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Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468 and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active against all cell lines with IC50 values in the 80–250 nM range. In general hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity observed as larger cycloalkyl rings were fused to the pyridine ring.
- Leung, Euphemia,Pilkington, Lisa I.,van Rensburg, Michelle,Jeon, Chae Yeon,Song, Mirae,Arabshahi, Homayon J.,De Zoysa, Gayan Heruka,Sarojini, Vijayalekshmi,Denny, William A.,Reynisson, Jóhannes,Barker, David
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supporting information
p. 1142 - 1154
(2019/05/24)
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- 2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains
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2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.
- Pissinate, Kenia,Villela, Anne Drumond,Rodrigues, Valnês,Giacobbo, Bruno Couto,Grams, Estêv?o Silveira,Abbadi, Bruno Lopes,Trindade, Rogério Valim,Roesler Nery, Laura,Bonan, Carla Denise,Back, Davi Fernando,Campos, Maria Martha,Basso, Luiz Augusto,Santos, Diógenes Santiago,Machado, Pablo
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supporting information
p. 235 - 239
(2016/03/22)
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- Discovery of 3-methyl-N-(1-oxy-3′,4′,5′,6′- tetrahydro-2′H-[2,4′-bipyridine]-1′-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction
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The goal of this study was to identify a structurally distinct D4-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
- Patel, Meena V.,Kolasa, Teodozyj,Mortell, Kathleen,Matulenko, Mark A.,Hakeem, Ahmed A.,Rohde, Jeffrey J.,Nelson, Sherry L.,Cowart, Marlon D.,Nakane, Masaki,Miller, Loan N.,Uchic, Marie E.,Terranova, Marc A.,El-Kouhen, Odile F.,Donnelly-Roberts, Diana L.,Namovic, Marian T.,Hollingsworth, Peter R.,Chang, Renjie,Martino, Brenda R.,Wetter, Jill M.,Marsh, Kennan C.,Martin, Ruth,Darbyshire, John F.,Gintant, Gary,Hsieh, Gin C.,Moreland, Robert B.,Sullivan, James P.,Brioni, Jorge D.,Stewart, Andrew O.
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p. 7450 - 7465
(2007/10/03)
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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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