A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: Synthesis, biological investigation and docking studies

Griglio, Alessia; Torre, Enza; Serafini, M. Teresa; Bianchi, Alice; Schmid, Roberta; Zabetta, G. Coda; Massarotti, Alberto; Sorba, Giovanni; Pirali, Tracey; Fallarini, Silvia

doi:10.1016/j.bmcl.2018.01.032

Cited by 23 publications

(26 citation statements)

References 33 publications

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“…Moreover, it is characterized by a peculiar binding mode that sees the side chain protruding into an additional pocket, named C and located in the most external part of the IDO binding site. Unfortunately, and similarly to what was observed in the case of imidazothiazoles reported by Tojo [10] and compounds 2 and 3 discovered in our laboratory [18], these molecules are not able to significantly permeate the cell and to inhibit IDO1 in a cell-based assay (data not shown).…”

Section: Discussionsupporting

confidence: 78%

“…Overall, the information acquired both in this study and in our previous work [18] provides new insights in the field of IDO1 inhibitors. Indeed, we have demonstrated that pocket C can be exploited in the design of next generations of IDO1 inhibitors.…”

Section: Discussionmentioning

confidence: 58%

“…The first series, published in 2018 [18], was obtained using Passerini three-component and Ugi four-component reactions. The most potent compounds are represented by 2 and 3 (Figure 1) with IC 50 values of 0.20 µM and 0.80 µM, respectively.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors

et al. 2019

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IDO1, a key dioxygenase in tryptophan-kynurenine metabolism, appeared in the last 10 years at the vanguard of druggable targets in cancer therapy due to its well-established role both in immune escape and inflammatory neovascularization. Among the pool of IDO1 inhibitors that have entered clinical trials, none have reached approval. The identification of novel inhibitors endowed with better clinical profile, together with the further comprehension of the interactions with residues in IDO1 active site, are still a need. In this context, we have synthesized a novel class of imidazothiazole derivatives as IDO1 inhibitors and identified three compounds with inhibitory potency in the low micromolar range. This report strengthens the role played by pocket C in the active site of IDO1, providing novel directions in the design of IDO1 inhibitors.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 58%

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Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors

et al. 2019

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“…Since 3-arylisothiazol-4-aminium chloride 2·HCl has been rarely exploited as a nucleophile in multicomponent processes, this substrate was reacted by refluxing glacial acetic acid with an aromatic aldehyde 1 and Meldrum's acid (133) Indoleamine 2,3-dioxygenase 1 (IDO1) has emerged as an attractive target for cancer immunotherapy. In this context, the Passerini reaction was employed to assemble a small library of imidazothiazoles 143 that target IDO1 [151]. The reaction of isocyanides 18 with aqueous formaldehyde (1) and functionalized phenylacetic acids 114 led to imidazothiazoles 143 containing a α-acyloxyamide moiety in the side chain, in moderate to good yields (Scheme 68).…”

Section: Thiazole Derivativesmentioning

confidence: 99%

Synthesis of Biologically Active Molecules through Multicomponent Reactions

et al. 2020

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Focusing on the literature progress since 2002, the present review explores the highly significant role that multicomponent reactions (MCRs) have played as a very important tool for expedite synthesis of a vast number of organic molecules, but also, highlights the fact that many of such molecules are biologically active or at least have been submitted to any biological screen. The selected papers covered in this review must meet two mandatory requirements: (1) the reported products should be obtained via a multicomponent reaction; (2) the reported products should be biologically actives or at least tested for any biological property. Given the diversity of synthetic approaches utilized in MCRs, the highly diverse nature of the biological activities evaluated for the synthesized compounds, and considering their huge structural variability, much of the reported data are organized into concise schemes and tables to facilitate comparison, and to underscore the key points of this review.Molecules 2020, 25, 505 2 of 71 acetylcholinesterase inhibitors, anti-HIV, antimicrobial, antioxidant, anti-mycobacterial and anticancer activities ( Figure 1). It is noteworthy that 64% and 16% of the supporting literature found for this review correspond to heterocyclic structures with anticancer and antimicrobial activities, respectively. Scheme 2. Three-component synthesis of 3,4-dihydropyrimidinones/thiones type 7 under microwave irradiation, for anti-inflammatory activity.Patil et al., reported a one-pot pseudo-five-component synthesis of highly functionalized tetrahydropyridines 9 using Cu(OTf) 2 as catalyst, Scheme 3. In vitro anti-inflammatory activity of the obtained compounds 9 was determined against matrix metalloproteinases (MMPs) as MMP-2 and MMP-9 by using gelatin zymography [29]. Scheme 3. Multicomponent Cu(OTf) 2 catalyzed synthesis of substituted tetrahydropyridines 9 for anti-inflammatory activity.A highly diastereoselective synthesis (exclusively the cis isomer is formed), of chromeno β-lactam hybrids 13/14 was also achieved by an efficient one-pot three-component reaction between either 5,5-dimethylcyclohexane-1,3-dione (10a) or 4-hydroxycoumarin (10b), diverse benzaldehydes 11 and malononitrile (12), in the presence of DABCO under reflux conditions (Scheme 4). Scheme 4. Three-component synthesis of β-lactam hybrids 13/14 for anti-inflammatory activity.The synthesized compounds (13 in 80-95% yield) and (14 in 82-95% yield) were screened for anti-inflammatory activity (as well as for anticancer activity, please see Section 3.13.13. Compound 13b (Ar = 4-ClC 6 H 4 , Ar 1 = 4-MeC 6 H 4 ) was the most active of all the chromeno β-lactam hybrids 13/14 tested, with a 19.8 anti-inflammatory ratio, although, it resulted less active than the reference drug dexamethasone corticosteroid used for the treatment of rheumatoid and skin inflammation [30].

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“…Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular heme-containing enzyme that oxidizes L-tryptophan (L-Trp) to Nformyl-L-kynurenine (NFK), which initiates the rst and ratelimiting step of the kynurenine pathway. [15][16][17][18] Expression of IDO1 mediates the degradation of tryptophan and the accumulation of kynurenine that lead to local immunosuppression. 16,19 Upregulation of IDO1 was observed in several cancer types and could promote tumor cell growth.…”

Section: Introductionmentioning

confidence: 99%

Jejucarbazoles A–C, carbazole glycosides with indoleamine 2,3-dioxygenase 1 inhibitory activity fromStreptomycessp. KCB15JA151

et al. 2021

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A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: Synthesis, biological investigation and docking studies

Cited by 23 publications

References 33 publications

Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors

Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors

Synthesis of Biologically Active Molecules through Multicomponent Reactions

Jejucarbazoles A–C, carbazole glycosides with indoleamine 2,3-dioxygenase 1 inhibitory activity fromStreptomycessp. KCB15JA151

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