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• New pyrazolo[3,4-d]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines were designed and synthesized. • In vitro COX-1/COX-2 inhibitory assay. • In vivo formalin paw edema and cotton pellets induced granuloma assays. • Docking experiments rationalized in vitro COX-2 inhibitory activity. • In silico pharmacokinetics and drug-likeness predictions recommended acceptable profiles. New pyrazolo[3,4- d ]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3- a ]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed i n vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

New quinoline compounds comprising pyrazole scaffold through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity. Eight compounds ( 5c , 11b,c , 12c , 14a,b , 20a and 21a ) were found to exhibit promising anti-inflammatory profiles in acute and sub-acute inflammatory models. They were screened for their ulcerogenic activity and none of them showed significant ulcerogenic activity comparable to the reference drug celecoxib and are well tolerated by experimental animals with high safety margin (ALD 50  > 0.3 g/kg). Compounds 5c , 11b,c , 12c , 14a,b , 20a and 21a showed significant in vitro LOX inhibitory activity higher than that of zileuton. In vitro COX-1/COX-2 inhibition study revealed that compounds 12c , 14a,b and 20a showed higher selectivity towards COX-2 than COX-1. Among the tested compounds, 12c , 14a and 14b showed the highest inhibitory activity against COX-2 with an IC 50 values of 0.1, 0.11 and 0.11 μM respectively. The docking experiments attempted to postulate the binding mode for the most active compounds in the binding site of COX-2 enzymes and confirmed the high selectivity binding towards COX-2 enzyme over COX-1. [ABSTRACT FROM AUTHOR]

Non-Structural Protein 6 (NSP6) has a protecting role for SARS-CoV-2 replication by inhibiting the expansion of autophagosomes inside the cell. NSP6 is involved in the endoplasmic reticulum stress response by binding to Sigma receptor 1 (SR1). Nevertheless, NSP6 crystal structure is not solved yet. Therefore, NSP6 is considered a challenging target in Structure-Based Drug Discovery. Herein, we utilized the high quality NSP6 model built by AlphaFold in our study. Targeting a putative NSP6 binding site is believed to inhibit the SR1-NSP6 protein-protein interactions. Three databases were virtually screened, namely FDA-approved drugs (DrugBank), Northern African Natural Products Database (NANPDB) and South African Natural Compounds Database (SANCDB) with a total of 8158 compounds. Further validation for 9 candidates via molecular dynamics simulations for 100 ns recommended potential binders to the NSP6 binding site. The proposed candidates are recommended for biological testing to cease the rapidly growing pandemic. [Display omitted] • Targeting a putative binding site of NSP6 is believed to inhibit SR1-NSP6 protein-protein interactions. • 8158 compounds of DrugBank, NANPDB and SANCDB were virtually screened. • Some candidates from DrugBank and Natural Products exhibited promising binding interactions. • 9 MD simulations for 100 ns revealed high stability of some candidates with NSP6. • The selected natural products showed promising in-silico pharmacokinetics properties. [ABSTRACT FROM AUTHOR]

In the current medical era, there is an urgent necessity to identify new effective drugs to enrich the COVID-19's therapeutic arsenal. The SARS-COV-2 NSP13/helicase enzyme has been identified as a potential target for developing novel COVID-19 inhibitors. In this work, we aimed at endorsing effective natural products with potential inhibitory action towards the NSP13 through the virtual screening of 1012 natural products of botanical and marine origin from the South African Natural Compounds Database (SANCDB). The molecules were docked into the NTPase active site, and the best twelve compounds were chosen for further analysis. Thereafter, a combination of molecular dynamics simulations and MM-GBSA free energy calculations were carried out for a subset of best hits complexed with NSP13 helicase. We believe that the findings of this work will pave the way for additional research and experimental validation of some natural products as viable NSP13 helicase inhibitors. [Display omitted] • SARS-CoV2 helicase protein was targeted for VS. • 1012 compounds of SANCDB were virtually screened. • 12 candidates exhibited promising binding interactions. • 5 MD simulations for 100 ns revealed high stability of selected candidates at NSP6. • Some selected natural products showed promising In-silico pharmacokinetics properties. [ABSTRACT FROM AUTHOR]

New thienopyrimidinone and triazolothienopyrimidinone derivatives have been synthesized. These compounds were subjected to anti-inflammatory and antimicrobial activity screening aiming to identify new candidates that have dual anti-inflammatory and antimicrobial activities. Compounds 5 , 7 and 10a showed minimal ulcerogenic effect and high selectivity towards human recombinant COX-2 over COX-1 enzyme. Their docking outcome correlated with their biological activity and assured the high selectivity binding towards COX-2. In addition, they could act safely up to 80 mg/kg orally or 40 mg/kg parentrally. The antimicrobial screening showed that compound 10a displayed distinctive inhibitory effect on the growth of Escherichia coli comparable to that of ampicillin. Moreover, compounds 5 , 7 , 9 and 12a possessed 50% of the inhibitory activity of ampicillin against E. coli. Thus, compounds 5 , 7 and 10a represent promising dual acting anti-inflammatory and antimicrobial agents. This work provides rewarding template enriching the chemical space for dual anti-inflammatory anti-microbial activities. [ABSTRACT FROM AUTHOR]

• New conjugates of aryl sulfonyl hydrazone and 1,3-diaryl pyrazole were designed and synthesized. • They showed promising inhibition against NDM-1, IMP-1 and AIM-1 MBLs. • They exhibited promising ex vivo antibacterial activity against resistant clinical isolates of K. pneumoniae. • They were able to re-sensitize resistant K. pneumoniae (K5) towards meropenem and cefalexin. • The docking experiments on NDM-1 and IMP-1 rationalized the observed in vitro MBLs inhibition activity. Based on a structure-guided approach, aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles were designed to target metallo-β-lactamases (MBLs), using Klebsiella pneumoniae NDM-1 as a model. The in vitro MBLs inhibition showed remarkable inhibition constant for most of the designed compounds at a low micromolar range (1.5–16.4 µM) against NDM-1 , IMP-1 and AIM-1 MBLs. Furthermore, all compounds showed promising antibacterial activity against (K+, K1-K9) resistant clinical isolates of K. pneumoniae and were able to re-sensitize resistant K. pneumoniae (K5) strain towards meropenem and cefalexin. Besides, in vivo toxicity testing exhibited that the most active compound was non-toxic and well tolerated by the experimental animals orally up to 350 mg/kg and up to 125 mg/kg parenterally. The docking experiments on NDM-1 and IMP-1 rationalized the observed in vitro MBLs inhibition activity. Generally, this work presents a fruitful matrix to extend the chemical space for MBLs inhibition. This aids in tackling drug-resistance issues in antibacterial treatment. [ABSTRACT FROM AUTHOR]

• Hybrids from tetrahydro-1H-pyrazolo[3,4- b quinolines were designed and prepared. • The compounds were tested for their dual activity as AChE / COX-2 inhibitors. • All compounds showed activities comparable to or significantly higher than tacrine. • Most of the compounds showed activities comparable to celecoxib. • All compounds showed a safe hepatic profile via hepatotoxicity testing. New tetrahydro-1 H -pyrazolo[3,4- b quinoline derivatives were designed, synthesized and characterized as dual anticholinestrase and cyclooxygenase-2 inhibitors. The in vitro and in vivo anti-cholinesterase evaluation exhibited promising activities with lower hepatotoxicity for many candidates compared to tacrine as a reference. Furthermore, their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay demonstrated superior activity to celecoxib with higher selectivity indices for some compounds. In addition, some candidates showed extended anti-inflammatory activity by inhibiting COX-2 protein induction. Besides, in silico docking experiments of the active compounds against h AChE rationalized the observed in vitro AChE inhibitory activity. In conclusion, this work provides an extension of the chemical space of tetrahydro-1 H -pyrazolo[3,4- b quinoline chemotype for the anticholinestrase and anti-inflammatory activity. This would aid to minimize the possible neuroinflammation linked to the pathogenesis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]