Molecular Variations Based on Isosteric Replacements

Ciapetti, Paola; Giethlen, Bruno

doi:10.1016/b978-0-12-417205-0.00008-0

Cited by 15 publications

(12 citation statements)

References 224 publications

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“…Since fluorine is a bioisostere for hydrogen, methyl analogues (R = CH 3 ) were included to directly contrast any electronic effects displayed by trifluoromethyl analogues. [25] Methylsulfanyl (R = SCH 3 ), methylsulfinyl (R = S(O)CH3), and methylsulfonyl (R = S(O2)CH 3 ) analogues were selected based on both previous SAR which noted the importance of the sulfinyl group in 1 [20] and the goal of evaluating the effect of electron-deficient groups (e.g. sulfinyl, sulfonyl).…”

Section: Introductionmentioning

confidence: 99%

Differentiating Antiproliferative and Chemopreventive Modes of Activity for Electron‐Deficient Aryl Isothiocyanates against Human MCF‐7 Cells

et al. 2018

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The consumption of Brassica vegetables provides beneficial effects through organic isothiocyanates (ITCs), products of the enzymatic hydrolysis of glucosinolate secondary metabolites. The ITC l-sulforaphane (l-SFN) is the principle agent in broccoli that demonstrates several modes of anticancer action. While the anticancer properties of ITCs like l-SFN have been extensively studied and l-SFN has been the subject of multiple human clinical trials, the scope of this work has largely been limited to those derivatives found in nature. Previous studies have demonstrated that structural changes in an ITC can lead to marked differences in a compound's potency to 1) inhibit the growth of cancer cells, and 2) alter cellular transcriptional profiles. This study describes the preparation of a library of non-natural aryl ITCs and the development of a bifurcated screening approach to evaluate the dose- and time-dependence on antiproliferative and chemopreventive properties against human MCF-7 breast cancer cells. Antiproliferative effects were evaluated using a commercial MTS cell viability assay. Chemopreventive properties were evaluated using an antioxidant response element (ARE)-promoted luciferase reporter assay. The results of this study have led to the identification of 1) several key structure-activity relationships and 2) lead ITCs for continued development.

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Section: Introductionmentioning

confidence: 99%

Differentiating Antiproliferative and Chemopreventive Modes of Activity for Electron‐Deficient Aryl Isothiocyanates against Human MCF‐7 Cells

et al. 2018

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“…Core or scaffold hopping is a technique frequently used by medicinal chemists to discover novel compounds by mutating the molecule core or scaffold starting from known active molecules. 22 Core hopping gives medicinal chemists an opportunity to pursue drug design in a different chemical space to improve potency, to improve adsorption, distribution, metabolism, excretion and toxicity liabilities of a given scaffold, to circumvent intellectual property rights associated with a parent scaffold or to speed up the lead optimization process. 22 Our primary goal was to improve the potency of virtual screening hits 1 and 2.…”

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confidence: 99%

“…22 Core hopping gives medicinal chemists an opportunity to pursue drug design in a different chemical space to improve potency, to improve adsorption, distribution, metabolism, excretion and toxicity liabilities of a given scaffold, to circumvent intellectual property rights associated with a parent scaffold or to speed up the lead optimization process. 22 Our primary goal was to improve the potency of virtual screening hits 1 and 2. For the initial optimization of 2 with corehoping strategy, we selected analogs which were commercially available, affordable and had an a-thioketone to act as a softelectrophile prior to initiating extensive synthetic efforts.…”

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confidence: 99%

Design, synthesis and biological evaluation of novel benzothiazole and triazole analogs as falcipain inhibitors

Shah

Gut

et al. 2011

Med. Chem. Commun.

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We describe the design, combinatorial library synthesis and biological evaluation of compounds with benzothiazole and triazole cores as inhibitors of falcipain, cysteine proteases of the malaria parasite Plasmodium falciparum. These classes were originally discovered by structure-based virtual screening of a focused cysteine protease inhibitor library. Fifteen structural analogs of both series showed moderate inhibition of falcipain-2. Two compounds, 41 and 42, were predicted by docking studies to interact with polar residues buried in the S2 pockets of falcipain-2 and -3, and these compounds inhibited both enzymes. Compound 41 also demonstrated activity against chloroquine-resistant cultured P. falciparum parasites at the lower micromolar concentration. Evaluation of 41 and 42 against mammalian cysteine proteases of papain family suggest these polar residues of the S2 pocket may not be important for the design of selective inhibitors against falcipain.

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“…The GluA2-LBD (L504Y/ N775S) flip-like isoform from rat was prepared as previously described. 16 The purified protein (final concentration 4 mg/mL) was mixed with L-glutamate (final concentration 5 mM) and 12b (added in excess as soluble compound to ensure a saturated concentration) in 10 mM Hepes at pH 7, 20 mM NaCl, and 1 mM EDTA. For crystallization, the hanging-drop vapor diffusion method was used, and crystallization plates were set up at 6 °C.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…13,14 In the present paper, we disclose the results of our studies on a new series of AMPAR PAMs designed using the classical isosteric replacement concept. 15,16 We have here focused our efforts on the replacement of the two nitrogen atoms of the thiadiazine ring by carbon atoms, leading to the preparation of thiochroman 1,1-dioxides. The idea beyond this approach was to explore a scaffold closely related to the 3,4-dihydro-2Hbenzothiadiazine 1,1-dioxide core, with a higher expected lipophilicity (clogP) that could be responsible for a better distribution into the CNS.…”

Section: ■ Introductionmentioning

confidence: 99%

Development of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Etsè

Dorosz

Christensen

et al. 2021

ACS Chem. Neurosci.

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On the basis of the activity of 1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors, thiochroman 1,1-dioxides were designed applying the isosteric replacement concept. The new compounds expressed strong modulatory activity on AMPA receptors in vitro, although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (12a, 12b, 12e) was examined in vivo after oral administration, showing that these compounds freely cross the blood–brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallization of the racemic compound 12b in complex with the ligand-binding domain of GluA2 (L504Y/N775S). Interestingly, both enantiomers of 12b were found to interact with the GluA2 dimer interface, almost identically to its benzothiadiazine analogue, BPAM344 (4). The interactions of the two enantiomers in the cocrystal were further analyzed (mapping Hirshfeld surfaces and 2D fingerprint) and compared to those of 4. Taken together, these data explain the lower affinity on AMPA receptors of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides.

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Molecular Variations Based on Isosteric Replacements

Cited by 15 publications

References 224 publications

Differentiating Antiproliferative and Chemopreventive Modes of Activity for Electron‐Deficient Aryl Isothiocyanates against Human MCF‐7 Cells

Differentiating Antiproliferative and Chemopreventive Modes of Activity for Electron‐Deficient Aryl Isothiocyanates against Human MCF‐7 Cells

Design, synthesis and biological evaluation of novel benzothiazole and triazole analogs as falcipain inhibitors

Development of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

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