ChemInform Abstract: Synthesis and Antileukemic Activity of 1‐((Quinolizidinylalkyl)amino)‐4/7‐R‐thioxanthen‐9‐ones.

Canu, Caterina; Iusco, G.; Boido, Vito; Sparatore, Fabio; Sparatore, Anna

doi:10.1002/chin.199026207

Cited by 2 publications

(9 citation statements)

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“…Twenty of the evaluated compounds have already been described by some of us (1-3, 6-11, 16, 17; [29] 23-28, 31-33 [30] ) and assayed as antileukemic [29,30] and antimicrobiala gents. [31] Compound 30 wasp reviously described by Elslager et al [32] The fifteen novel compounds (4, 5, 12-15, 18-22, 29, 34-36) were prepared with the same methods used for the preparation of the known compounds, with minor modifications.…”

Section: Resultsmentioning

confidence: 99%

“…[29,30] Thus, this issue deserves furtheri nvestigations in order to establish the value of the present compounds as potential agentsfor the treatment of AD. [29,30] Thus, this issue deserves furtheri nvestigations in order to establish the value of the present compounds as potential agentsfor the treatment of AD.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, based on the results of the testing for antileukemic activity, [29,30] only al ow-to-moderate level of in vivo toxicityi se xpected for the presentc ompounds. To achieve ap reliminarya ssessment of the neurotoxicity of the studied compounds,c ytotoxicity assays were carriedo ut against the human neuroblastoma cell line SH-SY5Y, commonly used in neurobiological studies.…”

Section: Cytotoxicity Assaysmentioning

confidence: 91%

“…In contrast, when AChE inhibition (IC 50 = 0.011-5.8 mm)l argely prevailed over BChE inhibition (affinity ratio:1 0-1000), as observed for naphthoquinones (23)(24)(25)(26)(27)(28)(29)(30), Ab aggregation was poorly inhibited or not affected at all. Twoc ompounds (5 and 22)e ndowed with dual ChE inhibition, and specifically with sub-micromolar IC 50 forB ChE inhibition, were poorly active against Ab aggregation (46 %a nd 55 %i nhibition, respectively, at 100 mm), indicating that other factors play ar olei nd etermining this biological activity.H owever,i ti si mportant to emphasize that some of the presently studied compounds inhibited the ChEs and Ab aggregation with relatively closep otencies, which is ab asic requisite for the potentiald evelopment of therapeutic agentse xhibitingm ultitarget activity.T hus, the most relevant inhibitors compared favorably with the reference compounds donepezil and quercetin, which are among the most potent compounds for the inhibition of ChEs and Ab aggregation, respectively.D onepezil, am ore potent AChE inhibitor than BChE, is practically devoid of inhibitory activity on direct Ab aggregation, whereas aw eak inhibition resulted from its binding at the PASo fA ChE (22 %i nhibition at 100 mm).…”

Section: Structure-activity Relationships Of Ches and Ab Aggregation mentioning

confidence: 94%

“…The introductiono f ac hlorine atom to the naphthoquinone derivatives (26)(27)(28)(29) clearly enhanced the potency of ChE inhibition, while its effect on Ab aggregation was rather modest. The introductiono f ac hlorine atom to the naphthoquinone derivatives (26)(27)(28)(29) clearly enhanced the potency of ChE inhibition, while its effect on Ab aggregation was rather modest.…”

Section: Structure-activity Relationships Of Ches and Ab Aggregation mentioning

confidence: 99%

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Multitarget Therapeutic Leads for Alzheimer’s Disease: Quinolizidinyl Derivatives of Bi‐ and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β‐Amyloid (Aβ) Aggregation

et al. 2015

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Multitarget therapeutic leads for Alzheimer's disease were designed on the models of compounds capable of maintaining or restoring cell protein homeostasis and of inhibiting β-amyloid (Aβ) oligomerization. Thirty-seven thioxanthen-9-one, xanthen-9-one, naphto- and anthraquinone derivatives were tested for the direct inhibition of Aβ(1-40) aggregation and for the inhibition of electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBChE). These compounds are characterized by basic side chains, mainly quinolizidinylalkyl moieties, linked to various bi- and tri-cyclic (hetero)aromatic systems. With very few exceptions, these compounds displayed inhibitory activity on both AChE and BChE and on the spontaneous aggregation of β-amyloid. In most cases, IC50 values were in the low micromolar and sub-micromolar range, but some compounds even reached nanomolar potency. The time course of amyloid aggregation in the presence of the most active derivative (IC50 =0.84 μM) revealed that these compounds might act as destabilizers of mature fibrils rather than mere inhibitors of fibrillization. Many compounds inhibited one or both cholinesterases and Aβ aggregation with similar potency, a fundamental requisite for the possible development of therapeutics exhibiting a multitarget mechanism of action. The described compounds thus represent interesting leads for the development of multitarget AD therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cytotoxicity Assaysmentioning

confidence: 91%

Section: Structure-activity Relationships Of Ches and Ab Aggregation mentioning

confidence: 94%

Section: Structure-activity Relationships Of Ches and Ab Aggregation mentioning

confidence: 99%

See 3 more Smart Citations

Multitarget Therapeutic Leads for Alzheimer’s Disease: Quinolizidinyl Derivatives of Bi‐ and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β‐Amyloid (Aβ) Aggregation

et al. 2015

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Quinolizidine-Derived Lucanthone and Amitriptyline Analogues Endowed with Potent Antileishmanial Activity

et al. 2020

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Leishmaniases are neglected diseases that are endemic in many tropical and sub-tropical Countries. Therapy is based on different classes of drugs which are burdened by severe side effects, occurrence of resistance and high costs, thereby creating the need for more efficacious, safer and inexpensive drugs. Herein, sixteen 9-thioxanthenone derivatives (lucanthone analogues) and four compounds embodying the diarylethene substructure of amitriptyline (amitriptyline analogues) were tested in vitro for activity against Leishmania tropica and L. infantum promastigotes. All compounds were characterized by the presence of a bulky quinolizidinylalkyl moiety. All compounds displayed activity against both species of Leishmania with IC50 values in the low micromolar range, resulting in several fold more potency than miltefosine, comparable to that of lucanthone, and endowed with substantially lower cytotoxicity to Vero-76 cells, for the best of them. Thus, 4-amino-1-(quinolizidinylethyl)aminothioxanthen-9-one (14) and 9-(quinolizidinylmethylidene)fluorene (17), with selectivity index (SI) in the range 16–24, represent promising leads for the development of improved antileishmanial agents. These two compounds also exhibited comparable activity against intramacrophagic amastigotes of L. infantum. Docking studies have suggested that the inhibition of trypanothione reductase (TryR) may be at the basis (eventually besides other mechanisms) of the observed antileishmanial activity. Therefore, these investigated derivatives may deserve further structural improvements and more in-depth biological studies of their mechanisms of action in order to develop more efficient antiparasitic agents.

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ChemInform Abstract: Synthesis and Antileukemic Activity of 1‐((Quinolizidinylalkyl)amino)‐4/7‐R‐thioxanthen‐9‐ones.

Abstract: Cyclocondensation of thiosalicylic acid (I) with p‐chlorotoluene (II) in sulfuric acid gives a mixture of the thioxanthen‐9‐ones (III) and (IV).

Cited by 2 publications

References 0 publications

Multitarget Therapeutic Leads for Alzheimer’s Disease: Quinolizidinyl Derivatives of Bi‐ and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β‐Amyloid (Aβ) Aggregation

Multitarget Therapeutic Leads for Alzheimer’s Disease: Quinolizidinyl Derivatives of Bi‐ and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β‐Amyloid (Aβ) Aggregation

Quinolizidine-Derived Lucanthone and Amitriptyline Analogues Endowed with Potent Antileishmanial Activity

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