Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

doi:10.1016/j.bmcl.2011.01.044

Bioorganic & Medicinal Chemistry Letters

Volume 21, Issue 5, 1 March 2011, Pages 1350-1353

https://doi.org/10.1016/j.bmcl.2011.01.044 Get rights and content

Abstract

This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu₅ receptor. ‘Molecular switches’ were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents.

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References and notes (22)

H.Y. Meltzer
Biol. Psychiatry
(1999)
Z. Zhao et al.
Bioorg. Med. Chem. Lett.
(2007)
S. Sharma et al.
Bioorg. Med. Chem. Lett.
(2008)
H. Xiong et al.
Bioorg. Med. Chem. Lett.
(2010)
C.W. Lindsley et al.
Curr. Top. Med. Chem.
(2006)
J.P. Conn et al.
Trends Pharmacol. Sci.
(2009)
D.L. Williams et al.
Curr. Top. Med. Chem.
(2005)
P.J. Conn et al.
Nat. Rev. Durg Disc.
(2009)
J.E. Ayala et al.
J. Neuropsychopharmacol.
(2009)
J.A. O’Brien et al.
Mol. Pharmacol.
(2003)

J.A. O’Brien et al.

J. Pharmacol. Exp. Ther.

(2004)

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Among this group, in this work, we highlighted phthalimides and 1,3-thiazoles. Phthalimide derivatives are assigned to a broad spectrum of pharmacological properties such as anticancer [4,5], analgesic [6], anticonvulsant [7], antituberculosis [8], hypolipidemic and hypoglycemic [9], anti-inflammatory [6,10], antioxidant [11], antimicrobial [8,11], antipsychotic [12] and antiparasitic [13–16]. Literature survey pointed out that the phthalimide ring is suitable for interacting with different biological targets [17,18].
In this work, 22 new compounds were obtained and evaluated for their cytotoxic activity on peripheral blood mononuclear cells (PBMC) and eight different tumor cell lines. All compounds displayed IC₅₀ values above 100 μM when assayed against PBMCs. The cytotoxic assays in tumor cell lines revealed that sub-series of phthalimido-bis-1,3-thiazoles (5a-f) exhibited the best anti-tumor activity profile, presenting viability values below 59 %. As a result, the IC₅₀ value was calculated for compounds 5a-f and 4c, and compounds 5b and 5e were selected for further assays due to their best IC₅₀s. Considering the results presented by the sub-series 5a-f, the importance of the 1,3-thiazole ring in improving the anti-tumor activity was pointed out. Together, the results highlighted the anti-tumor activity of phthalimido-bis-1,3-thiazole derivatives.
Metal and Nonmetal Assisted Synthesis of Six-Membered Heterocycles
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Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase
2018, European Journal of Medicinal Chemistry
Citation Excerpt :
Also, a phthaloyl/phthalimide structural framework could enhance hydrogen bonding and π-π stacking interaction on TcTS active residues due to a carbonyl group and aromatic ring moiety, respectively. Furthermore, phthaloyl/phthalimide derivatives have also received great attention due to their COX-1/2 inhibition [20], anti-inflammatory [21], antihyperlipidemic [22], antitumor/anticancer, anxiolytic, analgesic [23–26], antimicrobial, anticonvulsant, antitubercular [27–29], antipsychotic [30], antiproliferative [31], immunomodulatory [32], antiangiogenic [33], schistosomicidal [34] and anti-protozoa (anti-trypanocidal) activities [35]. All the compounds proposed were analyzed by molecular docking on the active site of TcTS using Auto Dock Vina 4.0.
In the last two decades, trans-sialidase of Trypanosoma cruzi (TcTS) has been an important pharmacological target for developing new anti-Chagas agents. In a continuous effort to discover new potential TcTS inhibitors, 3-amino-3-arylpropionic acid derivatives (series A) and novel phthaloyl derivatives (series B, C and D) were synthesized and molecular docking, TcTS enzyme inhibition and determination of trypanocidal activity were carried out.
From four series obtained, compound D-11 had the highest binding affinity value (−11.1 kcal/mol) compared to reference DANA (−7.8 kcal/mol), a natural ligand for TS enzyme. Furthermore, the 3D and 2D interactions analysis of compound D-11 showed a hydrogen bond, π-π stacking, π-anion, hydrophobic and Van der Waals forces with all important amino acid residues (Arg35, Arg245, Arg314, Tyr119, Trp312, Tyr342, Glu230 and Asp59) on the active site of TcTS. Additionally, D-11 showed the highest TcTS enzyme inhibition (86.9% ± 5) by high-performance ion exchange chromatography (HPAEC). Finally, D-11 showed better trypanocidal activity than the reference drugs nifurtimox and benznidazole with an equal % lysis (63 ± 4 and 65 ± 2 at 10 μg/mL) and LC₅₀ value (52.70 ± 2.70 μM and 46.19 ± 2.36 μM) on NINOA and INC-5 strains, respectively. Therefore, D-11 is a small-molecule with potent TcTS inhibition and a strong trypanocidal effect that could help in the development of new anti-Chagas agents.
In vitro evaluation of cytotoxicity and leishmanicidal activity of phthalimido-thiazole derivatives
2017, European Journal of Pharmaceutical Sciences
Citation Excerpt :
In recent years, many thiazole derivatives have been synthesized and subjected to various biological activities (Ayati et al., 2015). Phthalimide derivatives have also been shown to exhibit a broad range of pharmacological properties: analgesic (Alanazi et al., 2015), anticonvulsant (Obniska et al., 2011), antitubercular (Abdel-aziz et al., 2011; Berk and Akgün, 2012), hypolipidemic (Abdel-aziz et al., 2011), anxiolytic (Alanazi et al., 2015), anti-inflammatory (Alanazi et al., 2015; José et al., 2016), antimicrobial (Berk and Akgün, 2012; Elumalai and Ashraf, 2013; Singh et al., 2015) and antipsychotic (Williams et al., 2011). The process of obtaining phthalimido-triazole derivatives identified as potent antiparasitic agents has been described by various studies.
It is estimated that the worldwide prevalence of leishmaniasis is around 12 million individuals in 80 countries, with 400,000 new cases per year. In the search for new leishmanicidal agents, the hybrid phthalimido-thiazoles have been identified as an important scaffold for drug design and discovery. The present study thus reports the in vitro activity of a series of phthalimido-thiazole derivatives. Cytotoxicity against a strain of L. infantum, Vero cells, J774 macrophages and peritoneal macrophages was evaluated, as well as nitric oxide (NO) production. Activity against amastigote and promastigote forms of L. infantum and microscopic changes in the parasite and intracellular targets of the parasite were achieved. The results show that the compounds arising from hybridization of phthalimide and 1,3-thiazole exhibit promising leishmanicidal activity. Compounds 2j and 2m were the most potent of the series tested and the parasites treated with these compounds exhibited ultrastructural changes, such as cell body shrinkage, loss of cellular membrane integrity, vacuolization of cytoplasm, membrane profiles surrounding organelles and swelling of mitochondria. The data showed that these compounds reduced the survival of intracellular amastigotes and presented low toxicity for mammalian cells. The compounds produced increased NO production compared to untreated cells in non-infected macrophages. Treated promastigote forms showed an increase in the number of cells stained with propidium iodide. The compounds brought about significant changes in mitochondrial membrane potential. According to the present study, phthalimido-thiazole compounds exhibit leishmanicidal activity and could be used to develop novel antileishmaniasis drugs and explore potential molecular targets.
The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis
2016, Pharmacology Biochemistry and Behavior
Citation Excerpt :
ETX (Ethymal 250 mg/4 ml ethosuximide), a blocker of T-type Ca2 + currents in thalamic neurons (Coulter et al., 1989), was obtained from Apotex Europe BV, Leiden. VU0360172 (N-clyclobutyl-6-[2-3(fluorophenyl)ethynyl]pyridine-3-carboxamine), a selective mGlu5 receptor PAM, was obtained from Vanderbilt University Medical Center (Williams et al., 2011). ETX was administered orally through the drinking water.
Ethosuximide (ETX) is the drug of choice for the treatment of patients with absence seizures – taking into account both its efficacy, tolerability and antiepileptogenic properties. However, 47% of subjects failed in ETX-therapy, and most antiepileptic drugs have cognitive side effects. VU0360172, a positive allosteric modulator (PAM) of mGluR5, has been proposed as a new anti-absence drug. Here it is investigated whether anti-epileptogenesis induced by ETX alters the sensitivity of VU0360172, and whether cognition is affected during and after chronic ETX treatment.
EEG's were recorded before and after a challenge with VU0360172 in chronic ETX and in control WAG/Rij rats during and after treatment. Rats were also exposed to a cue discrimination learning task in a Y-maze both during and after treatment. At the end of the experiment, mGlu5 receptors were quantified by Western Blot analysis.
Antiepileptogenesis was successfully induced by ETX and VU0360172 showed a time and dose dependent anti-absence action in the control group. VU0360172 kept its anti-absence action in chronic ETX treated rats both during and after treatment, without time and dose dependency. This anti-absence effect of VU0360172 in both groups matched the lack of differences in mGluR5 expression. Chronic ETX enhanced the number of completed trials, the number of correct choices in the Y-maze and the number of consumed sucrose pallets.
VU0360172 maintains its anti-absence effects after chronic treatment; as such, VU0360172 can also be used as a adjunctive therapy in patients with absence epilepsy. The enhanced motivation and cognitive performance by ETX might be mediated by the antidepressant action of ETX as expressed by an increase in the rewarding properties of sucrose pallets.
Phthalimido-thiazoles as building blocks and their effects on the growth and morphology of Trypanosoma cruzi
2016, European Journal of Medicinal Chemistry
Citation Excerpt :
Many research teams have used this nucleus as a building block to improve compound quality. In fact, phthalimide derivatives have shown a broad spectrum of pharmacological properties, such as analgesic [15], anticonvulsant [16], antitubercular [17,18], hypolipidaemic [18], anxiolytic [15], anti-inflammatory [15], antimicrobial [17,19,20] and antipsychotic [21]. For this reason, our research group has explored the pharmacological properties of phthalimide derivatives.
Chagas disease is a parasitic infection caused by protozoan Trypanosoma cruzi that affects approximately 6–7 million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases; however, its efficacy during the symptomatic chronic phase is controversial. The present work reports the synthesis and anti-T. cruzi activities of a novel series of phthalimido-thiazoles. Some of these compounds showed potent inhibition of the trypomastigote form of the parasite at low cytotoxicity concentrations in spleen cells, and the resulting structure-activity relationships are discussed. We also showed that phthalimido-thiazoles induced ultrastructural alterations on morphology, flagellum shortening, chromatin condensation, mitochondria swelling, reservosomes alterations and endoplasmic reticulum dilation. Together, these data revealed, for the first time, a novel series of phthalimido-thiazoles-structure-based compounds with potential effects against T. cruzi and lead-like characteristics against Chagas disease.

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Published by Elsevier Ltd.

Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

Abstract

Graphical abstract

Biol. Psychiatry

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Curr. Top. Med. Chem.

Trends Pharmacol. Sci.

Curr. Top. Med. Chem.

Nat. Rev. Durg Disc.

J. Neuropsychopharmacol.

Mol. Pharmacol.

J. Pharmacol. Exp. Ther.

Synthesis and SAR of centrally active mGlu₅ positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold