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Tevarud designates two poets coincidently writing a same verse in the Ottoman Divan literature. This study aims to analyze the structural similarity of molecules independently designed for inflammation and depression to determine if coincidentally we are building similar molecules for comorbid diseases. For this purpose, a molecule library was first constituted with structures that were developed as anti-inflammatory (AI) and antidepressant (AD) agents these last decades. Then, the similarity of the structures was determined by calculating the Tanimoto and Cosine similarity coefficients for each AD/AI pair. The highest scores were obtained for two theophylline derivatives: AD17 (for which some AI activity was found to be mentioned) and AI42. The study also pointed out the similarity of some AD coumarins with some AI flavonoids interestingly found to be highly similar to some AI coumarins and AD flavonoids, respectively. Thus, our investigation demonstrated that structures independently developed as AD and AI derivatives can present extremely high structural similarity, a finding that can suggest mechanistic interconnection for these comorbid diseases and also guide for the design of novel bioactive compounds.

[Image: see text] Tevarud designates two poets coincidently writing a same verse in the Ottoman Divan literature. This study aims to analyze the structural similarity of molecules independently designed for inflammation and depression to determine if coincidentally we are building similar molecules for comorbid diseases. For this purpose, a molecule library was first constituted with structures that were developed as anti-inflammatory (AI) and antidepressant (AD) agents these last decades. Then, the similarity of the structures was determined by calculating the Tanimoto and Cosine similarity coefficients for each AD/AI pair. The highest scores were obtained for two theophylline derivatives: AD17 (for which some AI activity was found to be mentioned) and AI42. The study also pointed out the similarity of some AD coumarins with some AI flavonoids interestingly found to be highly similar to some AI coumarins and AD flavonoids, respectively. Thus, our investigation demonstrated that structures independently developed as AD and AI derivatives can present extremely high structural similarity, a finding that can suggest mechanistic interconnection for these comorbid diseases and also guide for the design of novel bioactive compounds.

A novel series of 8-substituted coumarin-based compounds, characterized by the presence of alkylpiperazine and arylpiperazine chains, were synthesized and tested for their inhibitory activity against four human carbonic anhydrase (hCA) isoforms. All compounds displayed nanomolar potency against the cancer-related hCA IX and hCA XII, moreover, they were shown to be devoid of any inhibitory activity toward the cytosolic hCA I and hCA II up to 10 &micro, M concentration in the assay system. Therefore, the synthesized coumarin ligands demonstrated to be potent and selective hCA IX/XII inhibitors, and were shown to be as potent as the reference inhibitor acetazolamide against hCA XII, with single-digit nanomolar Ki values. Molecular modeling studies provided a rationale for explaining the selectivity profile of these non-classic hCA inhibitors and their interactions with the enzymes, according to their specific mechanism of action, thus paving the way for future structure-based lead optimization studies.

Coumarins (2H-1-benzopyran-2-one), derivatives that can be isolated from several plants, have been reported for their anticoagulant, antimicrobial, anti-inflammatory, or anticancer activity. Some of these structures are currently approved for the treatment of cardiovascular diseases, as antibiotics or as an anticancer drug. Given the great potential of this structure and the limited number of studies that focus on molecules derived from carbon 8 of the benzopyranone heterocycle, we synthesized in this project 38 coumarin derivatives by substituting carbon 8 of the benzopyran ring with some aromatic and aliphatically substituted piperidines and piperazines. As a few of these structures were already shown to exhibit some carbonic anhydrase (CA) inhibition and as CA enzymes are reported to be closely related to inflammation, the synthesized derivatives were evaluated for their anti-inflammatory activity in vitro. The results indicated that compounds 20 and 31 revealed promising anti-inflammatory activity, as they demonstrated better activity than the reference drugs.

Oxidative stress that corresponds to a significant increase in free radical concentration in cells can cause considerable damage to crucial biological macromolecules if not prevented by cellular defense mechanisms. The low-molecular-weight thiol glutathione (GSH) constitutes one of the main intracellular antioxidants. It is synthesized via cysteine, an amino acid found only in limited amounts in cells because of its neurotoxicity. Thus, to ensure an efficient GSH synthesis in case of an oxidative stress, cysteine should be provided extracellularly. Yet, given its nucleophilic properties and its rapid conversion into cystine, its corresponding disulfide, cysteine presents some toxicity and therefore is usually supplemented in a prodrug approach. Here, some thiazolidine-4-carboxylic acids were synthesized and evaluated for their antioxidant properties via the DDPH and CUPRAC assays. Then, the cysteine releasing capacity of the obtained compounds was investigated in aqueous and organic medium in order to correlate the relevant antioxidant properties of the molecules with their cysteine releasing pattern. As a result, the structures' antioxidative properties were not only attributed to cysteine release but also to the thiazolidine cycle itself.

Growing evidence links inflammation to depression and the combination of antiinflammatory drugs with an antidepressant to treat depressive symptoms is currently suggested. There are only few studies concerning the molecular mechanism underlying this comorbidity, and many of them point out the importance of the tryptophan pathway. There is yet no data that analyzes the structural similarity of the molecules used for the treatment of these comorbid diseases. This review aimed first to classify current antidepressant drugs and Non-steroidal Anti-inflammatory Drugs (NSAIDs) according to their structure. Molecules with two aromatic rings linked with a heteroatom or a carbonyl group (vortioxetine, ketoprofen, diclofenac), or presenting a naphtyl moiety in their structure (duloxetine, agomelatine, naproxen, nabumetone) were found to be structurally related. The antidepressant activity of these NSAIDs and the anti-inflammatory activity of these antidepressants were investigated. The literature search interestingly revealed reports indicating a serotonin-related antidepressant activity of the NSAIDs for structures found to be structurally similar to some antidepressants. Similarly, the antiinflammatory activity of the corresponding antidepressants was found to be correlated to the tryptophan metabolism pathway. These findings suggest a common molecular mechanism involved in both of the diseases and exhibit the importance of the molecular structure for a drug to be a potent antidepressant and/or anti-inflammatory agent.

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