RSC Medicinal Chemistry Blog

New, effective and selective COX-2 inhibitors that prevent inflammation have been reported in MedChemComm, in a new HOT article.

Cyclo-oxygenases are enzymes responsible for production of key inflammation-promoting molecules. Most drugs that target COX are non-selective and inhibit both COX-2, present in inflamed tissues, and COX-1, which has important regulatory functions in normal tissues. This can lead to gastro-intestinal side-effects such as ulcers.

Dr Marwa El-Gazzar’s group at the National Centre for Radiation Research and Technology in Cairo synthesized new derivatives of celecoxib, a recently discovered COX-2 selective inhibitor. They tested their effect on COX-2 in vitro to study their structure-activity relationship. Several of the compounds – many of which had sulfonamide moieties – were as effective as celecoxib at inhibiting COX-2, while having no effect on COX-1. These compounds were also the most effective at reducing paw oedema in rat models of inflammation, and had significant analgesic effects – importantly, they were non-toxic and did not cause ulceration.

The designed 1,3,4-thiadiazole derivatives and their proposed orientation into the selectivity site of COX-2.

The group also performed a molecular docking study to gain insight into the compounds’ inhibition mechanism. The compounds were found to strongly bind to the COX-2 active site, making them more effective. They could also enter a small pocket found only in COX-2 to bind to specific residues there – this gave them their selectivity.

The promising results for the reported compounds, as well as the mechanistic insights gained, could prove invaluable in developing new, selective drugs that can successfully treat inflammation without adverse side effects.


Read the full article here:

Synthesis of novel thiadiazole derivatives as selective COX-2 inhibitors
Fatma A. Ragab, Helmi I. Heiba, Marwa G. El-Gazzar,* Sahar M. Abou-Seri, Walaa A. El-Sabbagh and Reham M. El-Hazek
Med. Chem. Commun., 2016, Advance Article
DOI:  10.1039/C6MD00367B

Susannah May is a guest web writer for the RSC Journal blogs. She currently works in the Publishing Department of the Royal Society of Chemistry, and has a keen interest in biology and biomedicine, and the frontiers of their intersection with chemistry. She can be found on Twitter using @SusannahCIMay.

The following MedChemComm articles have all been recommened by the reviewers of the articles as being particularly interesting or particularly significant research. These have all been made free to access until 12th December 2014. The order they appear in the list holds no special meaning or ranking.

Imidazole derivatives show anticancer potential by inducing apoptosis and cellular senescence
Gangavaram V. M. Sharma, Adepu Ramesh, Ashita Singh, Gourishetty Srikanth, Vankudoth Jayaram, Divya Duscharla, Jung Ho Jun, Ramesh Ummanni and Sanjay V. Malhotra  
DOI: 10.1039/C4MD00277F, Concise Article

Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor
Katherine S. England, Anthony Tumber, Tobias Krojer, Giuseppe Scozzafava, Stanley S. Ng, Michelle Daniel, Aleksandra Szykowska, KaHing Che, Frank von Delft, Nicola A. Burgess-Brown, Akane Kawamura, Christopher J. Schofield and Paul E. Brennan  
DOI: 10.1039/C4MD00291A, Concise Article
From themed collection Epigenetics

Computationally motivated synthesis and enzyme kinetic evaluation of N-(β-D-glucopyranosyl)-1,2,4-triazolecarboxamides as glycogen phosphorylase inhibitors
Jaida Begum, Gergely Varga, Tibor Docsa, Pál Gergely, Joseph M. Hayes, László Juhász and László Somsák  
DOI: 10.1039/C4MD00335G, Concise Article

Synthesis and biological evaluation of a series of aryl triazoles as firefly luciferase inhibitors
Haixiu Bai, Peng Zhu, Wenxiao Wu, Jing Li, Zhao Ma, Wei Zhang, Yanna Cheng, Lupei Du and Minyong Li  
DOI: 10.1039/C4MD00368C, Concise Article

Rational design of protein–protein interaction inhibitors
Didier Rognan  
DOI: 10.1039/C4MD00328D, Review Article

The following are HOT articles, as recommened by the reviewers of the articles. These have all been made free to access until 24th October:

Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain
Apirat Chaikuad, Andrew M. Petros, Oleg Fedorov, Jing Xu and Stefan Knapp
Med. Chem. Commun., DOI: 10.1039/C4MD00237G, Concise Article
From themed collection Epigenetics

Gold compounds as aquaporin inhibitors: new opportunities for therapy and imaging
Andreia de Almeida, Graça Soveral and Angela Casini
Med. Chem. Commun., DOI: 10.1039/C4MD00265B, Review Article

A novel surface-coated nanocarrier for efficient encapsulation and delivery of camptothecin to cells
Rie Wakabayashi, Ryutaro Ishiyama, Noriho Kamiya and Masahiro Goto
Med. Chem. Commun., DOI: 10.1039/C4MD00179F, Concise Article
From themed collection In celebration of Seiji Shinkai’s 70^th Birthday

Peptide HIV fusion inhibitors: modifications and conjugations
Wei Liu, Jianjun Tan, Mohammadreza Mohammadzad Mehryar, Zhiping Teng and Yi Zeng
Med. Chem. Commun., 2014, Advance Article
DOI: 10.1039/C4MD00214H, Review Article

3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors
Craig J. Kutz, Steven L. Holshouser, Ethan A. Marrow and Patrick M. Woster
Med. Chem. Commun., 2014, Advance Article
DOI: 10.1039/C4MD00283K, Concise Article
From themed collection Epigenetics

Check out the following HOT articles, these have been made free to access for a limited time:

Recognition of diazirine-modified O-GlcNAc by human O-GlcNAcase
Andrea C. Rodriguez and Jennifer J. Kohler
Med. Chem. Commun., 2014,5, 1227-1234
DOI: 10.1039/C4MD00164H

Free to access until 21st August 2014

Evaluation of functional groups as acetyl-lysine mimetics for BET bromodomain inhibition
Phillip P. Sharp, Jean-Marc Garnier, David C. S. Huang and Christopher J. Burns
Med. Chem. Commun., 2014, Advance Article
DOI: 10.1039/C4MD00182F

Free to access until 21st August 2014

Beyond substrate analogues: new inhibitor chemotypes for glycosyltransferases
Lauren Tedaldi and Gerd K. Wagner
Med. Chem. Commun., 2014,5, 1106-1125
DOI: 10.1039/C4MD00086B

Free to access until 21st August 2014

Emerging classes of armed antibody therapeutics against cancer
Christian Hess, Dario Venetz and Dario Neri  
Med. Chem. Commun., 2014,5, 408-431
DOI: 10.1039/C3MD00360D

Free to access until 25th April

Cysteine-reactive chemical probes based on a modular 4-aminopiperidine scaffold
Shalise M. Couvertier and Eranthie Weerapana
Med. Chem. Commun., 2014,5, 358-362
DOI: 10.1039/C3MD00289F

Free to access until 25th April

Design, synthesis, and preliminary ex vivo and in vivo evaluation of cationic magnetic resonance contrast agent for rabbit articular cartilage imaging
Takayoshi Irie, Kazuhiro Oda, Akihiko Shiino, Mitsuhiko Kubo, Shigehiro Morikawa, Noboru Urushiyama, Shuji Aonuma, Takahide Kimura, Toshiro Inubushi, Toshitaka Oohashi and Naoki Komatsu  
Med. Chem. Commun., 2013, DOI: 10.1039/C3MD00229B

Free to access until 13th December

Small-molecule Inhibitors of SREBP Activation – Potential for New Treatment of Metabolic Disorders
Mizuki Watanabe and Motonari Uesugi  
Med. Chem. Commun., 2013, DOI: 10.1039/C3MD00177F

Free to access until 13th December