A search for antiinflammatory therapies: Synthesis, in silico investigation of the mode of action, and in vitro analyses of new quinazolin‐2,4‐dione derivatives targeting phosphodiesterase‐4 enzyme

Abstract

Inflammation is the response of the body's immune system to harmful stimuli. The expression of phosphodiesterase 4 enzyme (PDE4) was demonstrated in many inflammatory cells. Thus, it was considered an attractive therapeutic target for combating inflammatory disorders. In the present study, a novel class of quinazolin‐2,4‐dione analogues 1‐17a,b was synthesized. Structures of the newly synthesized compounds were characterized by means of spectral and elemental analysis. Additionally, molecular docking studies for the new synthetic compounds were performed using PyRx—virtual screening tool to demonstrate the possible binding pattern mode of interactions within the active site region of the PDE4 enzyme. The antiinflammatory activity of the synthesized compounds was also in vitro examined using inhibition of protein denaturation, anti‐proteinase effect, and membrane stabilization assay. The in silico docking studies revealed that the newly synthesized compounds were well accommodated by the active site region of the target protein through a network of noncovalent interactions such as hydrogen bonds and pi‐stacking, which contributed to the enhancement of affinity and stability between the compounds and the target protein. They exhibited better docking scores when compared with reference drugs diclofenac and coumarin. In addition, in vitro testing revealed that the compounds had moderate to good antiinflammatory effects. The biological study agreed with in silico approach, which revealed that the compounds had promising antiinflammatory activity. Hence, our detailed results can facilitate the rational drug design targeting PDE4 enzyme.

Synthesis, Molecular Docking Analysis and in Vitro Biological Evaluation of Some New Heterocyclic Scaffolds-Based Indole Moiety as Possible Antimicrobial Agents

“…In an effort to elucidate the plausible mechanism by which these new synthesized chromenol, dihydroquinoline, and thiopyran compounds could exhibit their antimicrobial activity, in the present study, in silico molecular docking studies ( Abdelmonsef et al, 2021 ; Abo-Bakr et al, 2021 ) on bacterial target enzyme UDP-N-acetylmuramatel-alanine ligase (MurC) (PDB ID: 2F00) and Human lanosterol 14α-demethylase (PDB ID: 6UEZ) were performed to demonstrate the mechanism of antibacterial and antifungal activity, and to get insights regarding the binding affinity and the intermolecular interactions of the newly synthesized compounds with the active sites of the target enzymes ( Abdelmonsef et al, 2016 ; HA and SP, 2016 ; Dasari et al, 2017 ; Rondla et al, 2017 ; Haredi Abdelmonsef, 2019 ; Abdelmonsef and Mosallam, 2020 ; El-Maghraby and Abdelmonsef, 2020 ; El-Naggar et al, 2020 ; Haredi Abdelmonsef et al, 2020 ; Noser et al, 2020 ; Rashdan et al, 2020 ; El-Saghier et al, 2021 ; Sobhi et al, 2021 ). Ampicillin was used as a standard drug for in silico screening of the newly synthesized compounds.…”

Investigation of Novel Mucorales Fungal Inhibitors: Synthesis, In‐Silico Study and Anti‐Fungal Potency of Novel Class of Coumarin‐6‐Sulfonamides‐Thiazole and Thiadiazole Hybrids

“…[18][19][20] Over the past few years, compounds containing thiazole and/or thiadiazole scaffold are attractive to medicinal chemistry due to their unique chemical properties and diversity of the biological activities. [20][21][22][23][24][25] Therefore, they have therapeutic effects against several diseases such as antimalarial, antimicrobial, antiproliferative agents and anti-inflammatory [26][27][28][29][30] besides their significant with various fungicidal activities . [31,32] In addition, many scientific reported have also demonstrated that the sulfonamide moiety itself possess interesting pharmacological activities and therapeutic functions.…”

Novel Thiadiazole-Based Molecules as Promising Inhibitors of Black Fungi and Pathogenic Bacteria: In Vitro Antimicrobial Evaluation and Molecular Docking Studies

“…The N atom has a unique nature that gives flexibility to the biological targets. Accordingly, N -heterocyclic compounds have many therapeutic uses as scaffolds for new drug candidates [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. In the medicinal chemistry, pyrazine, pyrazoline, indazole, and thiazole derivatives, for example, could offer a broad spectrum of therapeutic and pharmacological applications [ 31 ].…”