Carboxamides Bearing Sulfonamide Functionality as Potential Novel Phospholipase A<sub>2</sub> Inhibitors

Ibezim, Akachukwu; Onoabedje, Efeturi A.; Adaka, Ifeyinwa C.; Omeje, Kingsley O.; Onoabedje, Ufuoma S.; Bonaventure, C.

doi:10.1002/slct.202003784

Cited by 8 publications

(5 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, the present findings are consistent with those of El-Sayed et al [ 42 ] and Barakat et al [ 43 ] regarding the inhibition by certain quinazoline and pyrimidine derivatives against sPLA2 and cPLA2. Also, the present findings are consistent with those of Ibezim et al [ 44 ] who reported the inhibitory effect of certain sulfonamide derivatives against 3CLpro, sPLA2, and cPLA2. Our results suggest that the combination of quinazoline and sulfamerazine structural features in a single molecule increased the inhibitory activity against 3CLpro, sPLA2, and cPLA2.…”

Section: Discussionsupporting

confidence: 93%

Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors

et al. 2023

View full text Add to dashboard Cite

The current work was conducted to synthesize several novel anti-inflammatory quinazolines having sulfamerazine moieties as new 3CLpro, cPLA2, and sPLA2 inhibitors. The thioureido derivative 3 was formed when compound 2 was treated with sulfamerazine. Also, compound 3 was reacted with NH2-NH2 in ethanol to produce the N-aminoquinazoline derivative. Additionally, derivative 4 was reacted with 4-hydroxy-3-methoxybenzaldehyde, ethyl chloroacetate, and/or diethyl oxalate to produce quinazoline derivatives 5, 6, and 12, respectively. The results of the pharmacological study indicated that the synthesized 4–6 and 12 derivatives showed good 3CLpro, cPLA2, and sPLA2 inhibitory activity. The IC50 values of the target compounds 4–6, and 12 against the SARS-CoV-2 main protease were 2.012, 3.68, 1.18, and 5.47 µM, respectively, whereas those of baicalein and ivermectin were 1.72 and 42.39 µM, respectively. The IC50 values of the target compounds 4–6, and 12 against sPLA2 were 2.84, 2.73, 1.016, and 4.45 µM, respectively, whereas those of baicalein and ivermectin were 0.89 and 109.6 µM, respectively. The IC50 values of the target compounds 4–6, and 12 against cPLA2 were 1.44, 2.08, 0.5, and 2.39 µM, respectively, whereas those of baicalein and ivermectin were 3.88 and 138.0 µM, respectively. Also, incubation of lung cells with LPS plus derivatives 4–6, and 12 caused a significant decrease in levels of sPLA2, cPLA2, IL-8, TNF-α, and NO. The inhibitory activity of the synthesized compounds was more pronounced compared to baicalein and ivermectin. In contrast to ivermectin and baicalein, bioinformatics investigations were carried out to establish the possible binding interactions between the newly synthesized compounds 2–6 and 12 and the active site of 3CLpro. Docking simulations were utilized to identify the binding affinity and binding mode of compounds 2–6 and 12 with the active sites of 3CLpro, sPLA2, and cPLA2 enzymes. Our findings demonstrated that all compounds had outstanding binding affinities, especially with the key amino acids of the target enzymes. These findings imply that compound 6 is a potential lead for the development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 quinazoline derivative-based drugs. Compound 6 was shown to have more antiviral activity than baicalein and against 3CLpro. Furthermore, the IC50 value of ivermectin against the SARS-CoV-2 main protease was revealed to be 42.39 µM, indicating that it has low effectiveness.

show abstract

Section: Discussionsupporting

confidence: 93%

Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors

et al. 2023

View full text Add to dashboard Cite

show abstract

“…The coordinate of P. falciparum falcipain-2 (FP2) along with its cocrystallized inhibitor (E64) were retrieved from the protein databank (pdb code 3BPF) [ 22 ] and the complex was prepared for molecular simulation purposes following standard procedures described [ 23 , 24 ]. Water and non-essential small molecules were deleted and hydrogen atoms were added to the FP2-E64 complex with Protonate 3D Wizard of Molecular Operating Environment (MOE) (Molecular Operating Environment, version 2014).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of anti-malarial potency of new pyrazole-hydrazine coupled to Schiff base derivatives

Ibezim

Ofokansi

Ndukwe

et al. 2022

Malar J

Self Cite

View full text Add to dashboard Cite

Background The search for pharmacologically effective agents among molecules bearing multiple functionalities is commonly practiced. In continuation of the search for new anti-malarial agents, new pyrazole-hydrazine coupled Schiff-base derivatives previously synthesized were screened for anti-malarial property. Methods Here, in vivo prophylactic and curative activities of the compounds were assessed while their binding affinity for falcipain-2, a crucial enzyme in Plasmodium survival, was done using computational techniques. Results The two derivatives (BepINH and BepBeH) respectively led to a significant (p < 0.05) reduction in parasitaemia count (0.76 ± 1.11 and 0.79 ± 1.19) at day 3 post-treatment relative to the negative control (16.37 ± 1.25). For the prophylactic study, it was observed that the highest parasitaemia suppression level of 95.35% and 95.17% for BepINH and BepBeH at 15 mg/kg was slightly comparable to that obtained for ACT-Lonart (99.38%). In addition, their haematological profiles indicate that they are potentially beneficial in suppressing haemolytic damage to RBC, thereby protecting the body against infection-induced anaemia. Docking calculations on the derivatives toward the Plasmodium falciparum falcipain-2 revealed that they favourably interacted with a binding affinity higher than that of a known cocrystallized inhibitor. Conclusion This study confirms the relevance of multi-functional molecules in the search for new and effective anti-plasmodial agent and lay the foundation for further development of these compound series to potent anti-plasmodial agent that interacts with falcipain-2.

show abstract

“…The cocrystallized water molecules and other non-essential particles were removed to retain only the protein-ligand complex. The Protonate 3D procedure implemented in molecular operating environment (MOE) software was used to protonate the complex before energy minimizing it to gradient of 0.001 kcal/mol using the Merck Molecular (MMFF94) force field to eliminate atomic clashes 21 , 22 , 23 .…”

Section: Methodsmentioning

confidence: 99%

Structure-based virtual screening and molecular dynamics simulation studies to discover new SARS-CoV-2 main protease inhibitors

et al. 2021

View full text Add to dashboard Cite

Computational methods were used to filter two datasets (> 8,000 compounds) based on two criteria: higher binding affinity for M PRO than cocrystallized inhibitor and binding interactions with M PRO catalytic dyad (Cys145 and His41). After virtual screening involving ranking and reranking, eleven compounds were identified to satisfy these criteria and analysis of their structures revealed an unparallel common features among them which could be critical for their interactions with M PRO . However, only the topmost scoring compound (AV-203: K i = 0.31 µM) exhibited relatively stable binding interaction during the period of 50 ns MD simulation and thus is a suitable template for drug development.

show abstract

Carboxamides Bearing Sulfonamide Functionality as Potential Novel Phospholipase A₂ Inhibitors

Cited by 8 publications

References 17 publications

Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors

Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors

Evaluation of anti-malarial potency of new pyrazole-hydrazine coupled to Schiff base derivatives

Structure-based virtual screening and molecular dynamics simulation studies to discover new SARS-CoV-2 main protease inhibitors

Contact Info

Product

Resources

About

Carboxamides Bearing Sulfonamide Functionality as Potential Novel Phospholipase A2 Inhibitors

Cited by 8 publications

References 17 publications

Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors

Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors

Evaluation of anti-malarial potency of new pyrazole-hydrazine coupled to Schiff base derivatives

Structure-based virtual screening and molecular dynamics simulation studies to discover new SARS-CoV-2 main protease inhibitors

Contact Info

Product

Resources

About

Carboxamides Bearing Sulfonamide Functionality as Potential Novel Phospholipase A₂ Inhibitors