Synthesis, biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide, sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold

Reale, Annalisa; Brogi, Simone; Chelini, Alessia; Paolino, Marco; Capua, Angela Di; Giuliani, Germano; Cappelli, Andrea; Giorgi, Gianluca; Chemi, Giulia; Grillo, Alessandro; Valoti, Massimo; Sautebin, Lidia; Rossi, Antonietta; Motta, Concettina La; Mannelli, Lorenzo; Lucarini, Elena; Ghelardini, Carla; Anzini, Maurizio

doi:10.1016/j.bmc.2019.115045

Cited by 22 publications

(15 citation statements)

References 50 publications

(76 reference statements)

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“…This application can generate the most probable ionization state for each input structure at the cellular pH value (7.4 ± 0.5) using Epik tool. Moreover, the OPLS-AA_2005 force field was used for optimization, producing the lowest energy conformer for each ligand [ 34 , 35 ].…”

Section: Methodsmentioning

confidence: 99%

In silico analysis of RNA-dependent RNA polymerase of the SARS-CoV-2 and therapeutic potential of existing antiviral drugs

Mondal

Mukhoty

Kundu

et al. 2021

Computers in Biology and Medicine

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The continued sustained threat of the SARS-CoV-2 virus world-wide, urgently calls for far-reaching effective therapeutic strategies for treating this emerging infection. Accordingly, this study explores mode of action and therapeutic potential of existing antiviral drugs. Multiple sequence alignment and phylogenetic analyses indicate that the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 was mutable and similar to bat coronavirus RaTG13. Successive interactions between RdRp (nsp12 alone or in complex with cofactors nsp7-8) and viral RNA demonstrated that the binding affinity values remained the same, but the sites of interaction of RdRp (highly conserved for homologous sequences from different organisms) were altered in the presence of selected antiviral drugs such as Remdesivir, and Sofosbuvir. The antiviral drug Sofosbuvir reduced the number of hydrogen bonds formed between RdRp and RNA. Remdesivir bound more tightly to viral RNA than viral RdRp alone or the nsp12-7-8 hexadecameric complex, resulting in a significant number of hydrogen bonds being formed in the uracil-rich region. The interaction between nsp12-7-8 complex and RNA was mediated by specific interaction sites of nsp7-8. Therefore, the conserved nature of RdRp interaction sites, and alterations due to drug intervention indicate the therapeutic potential of the selected drugs. In this article, we provide additional focus on the interacting amino acids of the nsp7-8 complex and highlight crucial regions that could be targeted for precluding a correct recognition of subunits involved in the hexadecameric assembly, to rationally design molecules endowed with a significant antiviral profile.

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Section: Methodsmentioning

confidence: 99%

In silico analysis of RNA-dependent RNA polymerase of the SARS-CoV-2 and therapeutic potential of existing antiviral drugs

Mondal

Mukhoty

Kundu

et al. 2021

Computers in Biology and Medicine

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“…Reale et al synthesised and characterised a novel series of 1,5diarylpyrrol-3-sulphur derivatives as COX-2 selective inhibitors endowed with anti-inflammatory/antinociceptive profile. Compound 88 (Figure 16), with IC 50 ¼0.011 mM, showed a significant anti-inflammatory and antinociceptive activity in vivo, thereby providing insights into the development of a novel anti-inflammatory and antinociceptive agent 103 .…”

Section: Pyrrol Derivatives As Anti-inflammatory Agentsmentioning

confidence: 99%

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

Bian

Wu³

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inflammation and disease are closely related. Inflammation can induce various diseases, and diseases can promote inflammatory response, and two possibly induces each other in a bidirectional loop. Inflammation is usually treated using synthetic anti-inflammatory drugs which are associated with several adverse effects hence are not safe for long-term use. Therefore, there is need for anti-inflammatory drugs which are not only effective but also safe. Several researchers have devoted to the research and development of effective anti-inflammatory drugs with little or no side effects. In this review, we studied some small molecules with reported anti-inflammatory activities and hence potential sources of anti-inflammatory agents. The information was retrieved from relevant studies published between January 2019 and May, 2021 for review. This review study was aimed to provide relevant information towards the design and development of effective and safe anti-inflammation agents.

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“…Among the newly published research on selective COX‐2 inhibitors, N ‐acyl hydrazones, as a new class of anti‐inflammatory compounds, have shown great promise in terms of selectivity in COX‐2 binding and anti‐inflammatory activity [9–12] . It is also known that the methyl sulfonyl group enhances selective COX‐2 inhibition [13–20] …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of New N‐Acyl Hydrazones with a Methyl Sulfonyl Moiety as Selective COX‐2 Inhibitors

Osmaniye

Sağlık

Levent

et al. 2021

Chemistry & Biodiversity

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The mechanism of action of nonsteroidal anti‐inflammatory drugs (NSAIDs) is inhibition of specific prostaglandin (PG) synthesis by inhibition of cyclooxygenase (COX) enzymes. The two COX isoenzymes show 60 % similarity. It is known that the nonspecific side effects of conventional NSAIDs are physiologically caused by inhibition of the COX‐1 enzyme. Therefore, the use of COX‐2 selective inhibitors is seen to be a more beneficial approach in reducing these negative effects. However, some of the existing COX‐2 selective inhibitors show cardiovascular side effects. Therefore, studies on the development of new selective COX‐2 inhibitors remain necessary. It is important to develop new COX‐2 inhibitors in the field of medicinal chemistry. Accordingly, novel N‐acyl hydrazone derivatives were synthesized as new COX‐2 inhibitors in this study. The hydrazone structure, also known for its COX activity, is important in terms of many biological activities and was preferred as the main structure in the design of these compounds. A methyl sulfonyl pharmacophore was added to the structure in order to increase the affinity for the polar side pocket present in the COX‐2 enzyme. It is known that methyl sulfonyl groups are suitable for polar side pockets. The synthesis of the compounds (3a–3j) was characterized by spectroscopic methods. Evaluation of in vitro COX‐1/COX‐2 enzyme inhibition was performed by fluorometric method. According to the enzyme inhibition results, the obtained compounds displayed the predicted selectivity for COX‐2 enzyme inhibition. Compound 3j showed important COX‐2 inhibition with a value of IC50=0.143 uM. Interaction modes between the COX‐2 enzyme and compound 3j were investigated by docking studies.

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Synthesis, biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide, sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold

Cited by 22 publications

References 50 publications

In silico analysis of RNA-dependent RNA polymerase of the SARS-CoV-2 and therapeutic potential of existing antiviral drugs

In silico analysis of RNA-dependent RNA polymerase of the SARS-CoV-2 and therapeutic potential of existing antiviral drugs

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

Design, Synthesis and Biological Evaluation of New N‐Acyl Hydrazones with a Methyl Sulfonyl Moiety as Selective COX‐2 Inhibitors

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