Probing phenylcarbamoylazinane-1,2,4-triazole amides derivatives as lipoxygenase inhibitors along with cytotoxic, ADME and molecular docking studies

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

doi:10.1016/j.bioorg.2020.104525

Cited by 17 publications

(9 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The current findings aim to discover the new and small molecules as potent human aldose reductase inhibitors that may help to synthesize more effective molecules with drug-like properties for the treatment of colon cancer that specifically occurs from the aberrant expression of either protein (Scheme 1) To extend our findings, in current research study, we considered the previously synthesized phenylcarbamoylazinane-1,2,4-triazole amides derivatives (7a-o) with anti-inflammatory activity by our group [27], against two enzymes of aldo-keto reductase, i.e., AKR1B1 and AKR1B10 via in silico studies. Moreover, the previous enzyme inhibition study by our group [27] was performed only using 15-lipoxygenase enzyme, from soybean source, indicating compounds have antiinflammatory potential. The current findings aim to discover the new and small molecules as potent human aldose reductase inhibitors that may help to synthesize more effective molecules with drug-like properties for the treatment of colon cancer that specifically occurs from the aberrant expression of either protein (Scheme 1) To extend our findings, in current research study, we considered the previously synthesized phenylcarbamoylazinane-1,2,4-triazole amides derivatives (7a-o) with anti-inflammatory activity by our group [27], against two enzymes of aldo-keto reductase, i.e., AKR1B1 and AKR1B10 via in silico studies.…”

Section: Introductionmentioning

confidence: 93%

“…The mixture was then allowed to be refluxed for 4-5 h to get different products of phenylcarbamoylazinane-1,2,4-triazole amides derivatives (7a-o). The obtained product was further treated with the EtOH to obtain pure compounds as discussed in earlier work [27].…”

Section: Chemistry Synthesis Of Phenylcarbamoylazinane-124-triazole A...mentioning

confidence: 99%

“…Moreover, the previous enzyme inhibition study by our group [27] was performed only using 15-lipoxygenase enzyme, from soybean source, indicating compounds have antiinflammatory potential. The current findings aim to discover the new and small molecules as potent human aldose reductase inhibitors that may help to synthesize more effective molecules with drug-like properties for the treatment of colon cancer that specifically occurs from the aberrant expression of either protein (Scheme 1) To extend our findings, in current research study, we considered the previously synthesized phenylcarbamoylazinane-1,2,4-triazole amides derivatives (7a-o) with anti-inflammatory activity by our group [27], against two enzymes of aldo-keto reductase, i.e., AKR1B1 and AKR1B10 via in silico studies. The binding interactions of all these derivatives were determined by using two molecular docking programs; one was academic, i.e., AutoDock (version 1.5.6), and one was commercial, i.e., Molecular Operating Environment (MOE Dock version 2015.10).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of Phenylcarbamoylazinane-1,2,4-Triazole Amides Derivatives as the Potential Inhibitors of Aldo-Keto Reductases (AKR1B1 & AKRB10): Potential Lead Molecules for Treatment of Colon Cancer

Ejaz

Sarfraz

et al. 2022

Molecules

Self Cite

View full text Add to dashboard Cite

Both members of the aldo-keto reductases (AKRs) family, AKR1B1 and AKR1B10, are over-expressed in various type of cancer, making them potential targets for inflammation-mediated cancers such as colon, lung, breast, and prostate cancers. This is the first comprehensive study which focused on the identification of phenylcarbamoylazinane-1, 2,4-triazole amides (7a–o) as the inhibitors of aldo-keto reductases (AKR1B1, AKR1B10) via detailed computational analysis. Firstly, the stability and reactivity of compounds were determined by using the Guassian09 programme in which the density functional theory (DFT) calculations were performed by using the B3LYP/SVP level. Among all the derivatives, the 7d, 7e, 7f, 7h, 7j, 7k, and 7m were found chemically reactive. Then the binding interactions of the optimized compounds within the active pocket of the selected targets were carried out by using molecular docking software: AutoDock tools and Molecular operation environment (MOE) software, and during analysis, the Autodock (academic software) results were found to be reproducible, suggesting this software is best over the MOE (commercial software). The results were found in correlation with the DFT results, suggesting 7d as the best inhibitor of AKR1B1 with the energy value of −49.40 kJ/mol and 7f as the best inhibitor of AKR1B10 with the energy value of −52.84 kJ/mol. The other potent compounds also showed comparable binding energies. The best inhibitors of both targets were validated by the molecular dynamics simulation studies where the root mean square value of <2 along with the other physicochemical properties, hydrogen bond interactions, and binding energies were observed. Furthermore, the anticancer potential of the potent compounds was confirmed by cell viability (MTT) assay. The studied compounds fall into the category of drug-like properties and also supported by physicochemical and pharmacological ADMET properties. It can be suggested that the further synthesis of derivatives of 7d and 7f may lead to the potential drug-like molecules for the treatment of colon cancer associated with the aberrant expression of either AKR1B1 or AKR1B10 and other associated malignancies.

show abstract

Section: Introductionmentioning

confidence: 93%

Section: Chemistry Synthesis Of Phenylcarbamoylazinane-124-triazole A...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Phenylcarbamoylazinane-1,2,4-Triazole Amides Derivatives as the Potential Inhibitors of Aldo-Keto Reductases (AKR1B1 & AKRB10): Potential Lead Molecules for Treatment of Colon Cancer

Ejaz

Sarfraz

et al. 2022

Molecules

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, different types of triazoles have been identified as antidepressant, antibacterial, anti-inflammatory, antirheumatic, anticancer, bactericidal, herbicidal, insecticidal, diuretic, and anticonvulsant 41 – 43 . Additionally, they exhibit a strong inhibitory effect on a variety of enzymes, including tumor-associated carbonic anhydrase, ACHE, aromatase, xanthine oxidoreductase, adenosine deaminase, and lipoxygenase 44 (Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of potent inhibitors of NEK7 protein using a comprehensive computational approach

Aziz

Ejaz

Tamam

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

NIMA related Kinases (NEK7) plays an important role in spindle assembly and mitotic division of the cell. Over expression of NEK7 leads to the progression of different cancers and associated malignancies. It is becoming the next wave of targets for the development of selective and potent anti-cancerous agents. The current study is the first comprehensive computational approach to identify potent inhibitors of NEK7 protein. For this purpose, previously identified anti-inflammatory compound i.e., Phenylcarbamoylpiperidine-1,2,4-triazole amide derivatives by our own group were selected for their anti-cancer potential via detailed Computational studies. Initially, the density functional theory (DFT) calculations were carried out using Gaussian 09 software which provided information about the compounds' stability and reactivity. Furthermore, Autodock suite and Molecular Operating Environment (MOE) software’s were used to dock the ligand database into the active pocket of the NEK7 protein. Both software performances were compared in terms of sampling power and scoring power. During the analysis, Autodock results were found to be more reproducible, implying that this software outperforms the MOE. The majority of the compounds, including M7, and M12 showed excellent binding energies and formed stable protein–ligand complexes with docking scores of − 29.66 kJ/mol and − 31.38 kJ/mol, respectively. The results were validated by molecular dynamics simulation studies where the stability and conformational transformation of the best protein–ligand complex were justified on the basis of RMSD and RMSF trajectory analysis. The drug likeness properties and toxicity profile of all compounds were determined by ADMETlab 2.0. Furthermore, the anticancer potential of the potent compounds were confirmed by cell viability (MTT) assay. This study suggested that selected compounds can be further investigated at molecular level and evaluated for cancer treatment and associated malignancies.

show abstract

“… 23 − 25 Recently, we have reported that 1,2,4-triazole derivatives possess azinane and phenylcarbamoyl moieties as 15-LOX inhibitors with excellent to good IC 50 values. 26 In addition to the triazole moiety, several furan-based scaffolds have been identified with remarkable biological activity including nematocidal, insecticidal, antibacterial, antifungal, antiviral, antioxidant, anti-inflammatory, antimicrobial, anthelmintic, and anti-nociceptive properties. 27 , 28 A methoxyphenyl group has been shown to have anticancer effects in these compounds.…”

Section: Introductionmentioning

confidence: 99%

4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds

et al. 2022

Self Cite

View full text Add to dashboard Cite

Lipoxygenases (LOXs) are a class of enzymes that catalyze the production of pro-inflammatory mediators, such as leukotrienes and lipoxins, via an arachidonic acid cascade as soon as they are released from the membrane phospholipids after tissue injury. In continuation of our efforts in search for new LOX inhibitors, a series of chlorophenyl-furfuryl-based 1,2,4-triazole derivatives were prepared and evaluated for their 15-LOX inhibitory activities. A simple precursor, 4-chlorobenzoic acid ( a ), was consecutively transformed into benzoate ( 1 ), hydrazide ( 2 ), semicarbazide ( 3 ), and N -furfuryl 5-(4-chlorobenzyl)-4 H -1,2,4-triazole ( 4 ), which when further merged with electrophiles ( 6a–o ) resulted in end products ( 7a–o ). The structural elucidations of the newly synthesized compounds ( 7a–o ) were carried out by Fourier transform infrared, 1 H-, 13 C NMR spectroscopy, EI-MS, and HR-EI-MS spectrometry. The inhibitive capability of compounds ( 7a–o ) on soybean 15-LOX was performed in vitro using the chemiluminescence method. The compounds 7k , 7o , 7m , 7b, and 7i demonstrated potent activities (IC 50 17.43 ± 0.38, 19.35 ± 0.71, 23.59 ± 0.68, 26.35 ± 0.62, and 27.53 ± 0.82 μM, respectively). These compounds revealed 79.5 to 98.8% cellular viability as measured by the MTT assay at 0.25 mM concentration. The structure-activity relationship (SAR) studies showed that the positions and the nature of substituents bonded to the phenyl ring are important in the determination of 15-LOX inhibitory activities. ADME, in silico, and density functional theory studies supported the evidence as yet another class of triazoles with potential lead properties in search for anti-LOX compounds with a safe gastrointestinal safety profile for various inflammatory diseases. Further work is in progress on the synthesis of more derivatives in search for anti-inflammatory agents.

show abstract

Probing phenylcarbamoylazinane-1,2,4-triazole amides derivatives as lipoxygenase inhibitors along with cytotoxic, ADME and molecular docking studies

Cited by 17 publications

References 22 publications

Discovery of Phenylcarbamoylazinane-1,2,4-Triazole Amides Derivatives as the Potential Inhibitors of Aldo-Keto Reductases (AKR1B1 & AKRB10): Potential Lead Molecules for Treatment of Colon Cancer

Discovery of Phenylcarbamoylazinane-1,2,4-Triazole Amides Derivatives as the Potential Inhibitors of Aldo-Keto Reductases (AKR1B1 & AKRB10): Potential Lead Molecules for Treatment of Colon Cancer

Identification of potent inhibitors of NEK7 protein using a comprehensive computational approach

4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds

Contact Info

Product

Resources

About