New resveratrol analogs as improved biologically active structures: Design, synthesis and computational modeling

Mlakić, Milena; Odak, Ilijana; Barić, Danijela; Talić, Stanislava; Šagud, Ivana; Štefanić, Zoran; Molčanov, Krešimir; Lasić, Zlata; Kovačević, Borislav; Škorić, Irena

doi:10.1016/j.bioorg.2023.106965

Cited by 5 publications

(14 citation statements)

References 38 publications

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“…The first fractions gave corresponding cis-isomers in small amounts for 1, 3-5, and the last fractions trans-isomers 1-5. All isolated cisand trans-isomers were published in our previous investigation [1]. [1]: 13 mg, 5% isolated; white powder; R f (PE/E (18%)) = 0.24; 1 H NMR (CDCl 3 , 600 MHz) δ/ppm: 7.22-7.18 (m, 3H), 7.06 (d, J = 3.9 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 7.00 (dd, J = 5.4, 3.3 Hz, 1H), 6.94 (t, J = 2.1 Hz, 1H), 6.86 (d, J = 15.9 Hz, 1H), 6.72 (dd, J = 7.9, 2.5 Hz, 1H), 4.78 (s, 3H); 13 On pure isomers 1-5, direct photochemical preparative illuminations were carried out without the use of catalysts at wavelengths of 313 nm and 365 nm in the Rayonet RPR 100 photoreactor, using 10 halogen lamps for all experiments.…”

Section: Synthesis Of the Resveratrol Derivatives 1-5mentioning

confidence: 99%

“…All isolated cisand trans-isomers were published in our previous investigation [1]. [1]: 13 mg, 5% isolated; white powder; R f (PE/E (18%)) = 0.24; 1 H NMR (CDCl 3 , 600 MHz) δ/ppm: 7.22-7.18 (m, 3H), 7.06 (d, J = 3.9 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 7.00 (dd, J = 5.4, 3.3 Hz, 1H), 6.94 (t, J = 2.1 Hz, 1H), 6.86 (d, J = 15.9 Hz, 1H), 6.72 (dd, J = 7.9, 2.5 Hz, 1H), 4.78 (s, 3H); 13 On pure isomers 1-5, direct photochemical preparative illuminations were carried out without the use of catalysts at wavelengths of 313 nm and 365 nm in the Rayonet RPR 100 photoreactor, using 10 halogen lamps for all experiments. The irradiations were carried out in 30 min with about 0.001 mol/dm 3 working concentrations of the studied compounds 1-5, without stirring purges air/oxygen before irradiation, after which the products were determined using HPLC and NMR spectroscopy.…”

Section: Synthesis Of the Resveratrol Derivatives 1-5mentioning

confidence: 99%

“…In our previous research [ 1 ], new analogs of the well-known bioactive molecule resveratrol were synthesized to investigate their potential biological activity. The configurational isomers of those derivatives underwent evaluation for antioxidant activity (AOA) using DPPH and CUPRAC assay, and their potential to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) was also measured.…”

Section: Introductionmentioning

confidence: 99%

“…)[1]: 495 mg, 82% isolated; white powder, m. p. 126-127 • C; R f (PE/DCM (50%)) = 0.33; UV (ACN) λ max /nm (ε/dm 3 mol −1 cm −1 ) 335 (27,412); 1 H NMR (CDCl 3 , 600 MHz) δ/ppm: 7.46 (dd, J = 7.7, 1.6 Hz, 1H), 7.28 (dt, J = 16.1, 0.8 Hz, 1H), 7.20-7.16 (m, 2H), 7.15-7.10 (m, 1H), 7.07 (dt, J = 3.7, 0.9 Hz, 1H), 6.99 (dd, J = 5.1, 3.5 Hz, 1H), 6.93 (td, J = 7.5, 1.2 Hz, 1H), 6.78 (dd, J = 8.1, 1.2 Hz, 1H), 4.97 (s, 1H);13 C NMR (CDCl 3 , 150 MHz) δ/ppm: 152.9, 143.3, 128.6, 127.6, 127.2, 126.0, 124.4, 124.3, 123.3, 122.7, 121.2, 115.9; MS (ESI) (m/z) (%, fragment): 202 (25), 105 (100).…”

mentioning

confidence: 99%

“…E)-2-(2-(5-methylthiophen-2-yl)vinyl)phenol (4)[1]: 95 mg, 40% isolated; yellow powder; m. p. 88-92 • C; R f (PE/E (20%)) = 0.54; UV (ACN) λ max /nm (ε/dm 3 mol −1 cm −1 ) 339 (26,378), 240(10,925), 208(19,311); 1 H NMR (CDCl 3 , 600 MHz) δ/ppm: 7.44 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 16.6 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 7.01 (d, J = 16.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 2.9 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 6.64-6.64 (m, 1H), 4.93 (s, 1H), 2.48 (s, 3H);13 C NMR (CDCl 3 , 150 MHz) δ/ppm: 152.8, 141.2, 139.3, 128.3, 127.1, 126.3, 125.7, 124.5 123.8, 121.4, 121.2, 115.9, 115.6; MS (ESI) (m/z) (%, fragment): 217 (100); HRMS (m/z) for C 13 H 12 OS: [M + H] + calculated = 216.0609, [M + H] + measured = 216.0607. (E)-5-methoxy-2-(2-(5-methythiophen-2-yl)vinyl)phenol (5) [1]: 5 mg, 6% isolated; yellow powder; m.p.…”

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confidence: 99%

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Photochemical Transformations of Diverse Biologically Active Resveratrol Analogs in Batch and Flow Reactors

Mlakić,

Perinić,

Vušak

et al. 2023

Molecules

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Previous biological tests have shown that some resveratrol analogs exhibited significant antioxidative and cholinesterase inhibitory potential, as evidenced by lower IC50 values compared to the established standards, resveratrol and galantamine, respectively. Photochemical transformations were made in parallel on these compounds in the presence of porphyrin photocatalysts in batch and microreactor, showing the significant advantage of flow photochemistry concerning productivity, selectivity, and yields. In this research, the products of photocatalysis and direct irradiation (photolysis) of resveratrol analogs were compared to elucidate how the types and ratios of the products depend on the excitation energy, to reveal the effects of the substituent on the photoinduced reactions and to rationalize experimentally and computationally the nature and ratio of the obtained products. Thus, two main paths were computed in agreement with the experimental results: isomerization with the participation of triplet state intermediates to yield the experimentally detected cis-isomers and subsequent cyclization following a pathway not available for the trans-isomers. The investigation of five model compounds confirmed the advantages of the flow photoreactor in the photochemical reactions of heterocyclic resveratrol analogs.

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Section: Synthesis Of the Resveratrol Derivatives 1-5mentioning

confidence: 99%

Section: Synthesis Of the Resveratrol Derivatives 1-5mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Photochemical Transformations of Diverse Biologically Active Resveratrol Analogs in Batch and Flow Reactors

Mlakić,

Perinić,

Vušak

et al. 2023

Molecules

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New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

Mlakić,

Čadež,

Šinko

et al. 2024

Preprint

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New furan, thiophene and triazole oximes were synthesized through several-step reaction paths to investigate their potential for development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Acute OP poisoning is still a challenge in treating patients despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, are blocked by the OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to cholinergic crisis. Oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper we described the synthesis of 63 heterostilbene derivatives out of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents – sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in micromolar range, we identified several oximes as BChE or AChE selective inhibitors with a potential for drug development. Moreover, even oximes were poor reactivators of AChE, four heterocyclic derivatives reactivated the cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had comparable reactivation efficacy to the standard oxime HI-6. In silico analysis and molecular docking studies connected the kinetic data to the structural features of these oximes, and confirmed their productive interactions with the active site of the cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases like Alzheimer’s and Parkinson’s.

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New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

Mlakić,

Čadež,

Šinko

et al. 2024

Biomolecules

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New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents–sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

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New resveratrol analogs as improved biologically active structures: Design, synthesis and computational modeling

Cited by 5 publications

References 38 publications

Photochemical Transformations of Diverse Biologically Active Resveratrol Analogs in Batch and Flow Reactors

Photochemical Transformations of Diverse Biologically Active Resveratrol Analogs in Batch and Flow Reactors

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

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