In vivo effective dibenzo[b,d]furan-1-yl-thiazoles as novel PDE-4 inhibitors

Gopalan, Balasubramanian; Narayanan, S.; Lavanya, A.; Thirunavukkarasu, Sappanimuthu; Thirunavukkarasu, Saravanan; Sundaram, Shamundeeswari; Natarajan, Saravanakumar; Sivaraman, Naresh; Rajagopal, Sridharan; Nazumudeen, Fakrudeen Ali Ahamed; Saxena, Sanjiv; Vishwakarma, Santosh; Narayanan, Shridhar; Sharma, G. Veera Raghava; Srinivasan, Chidambaram V.; Kilambi, Narasimhan

doi:10.1016/j.bmc.2016.09.011

Cited by 10 publications

(6 citation statements)

References 27 publications

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“…In this context, efficient synthetic strategies towards the construction of challenging hybrid molecule with these two heterocycles pyridine, furan and additional indoles as key components have received great attention. One example is Revamilast 8 , a benzofuropyridine derivative (Figure 2), that has been used for the treatment of inflammatory disorders including rheumatoid arthritis [35] . Another representative 9 was reported to possess pronounced antibacterial activity against mycobacteria.…”

Section: Introductionmentioning

confidence: 99%

Tandem Nenitzescu Reaction/Nucleophilic Aromatic Substitution to Form Novel Pyrido Fused Indole Frameworks

et al. 2021

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5‐Hydroxyindoles are privileged structures that form part of various bioactive compounds. The Nenitzescu reaction of quinones and enamines is one of the most powerful methods to obtain 5‐hydroxyindoles. In this work, we have applied the Nenitzescu reaction to 2‐(2‐chloropyrid‐3‐yl)benzoquinones. Mixtures of regioisomers were obtained that could be separated in the 4‐ and 6‐substituted analogues, and then cyclized separately in a metal‐free base‐catalyzed reaction, affording novel tetracyclic indole derivatives. These are indeed the first examples reported in the literature of the linear pyrido[3′,2′ : 4,5]furo[3,2‐b]indole and angular 1H‐pyrido[2′,3′ : 4,5]furo[2,3‐c]indole systems. The regioselectivity and the yield of the Nenitzescu reaction were found to be dependent on the N‐substituent at the enamine. Furthermore, we analyzed the UV‐Vis and PL spectra of the new systems, and this was supported by DFT calculations, allowing us to compare the properties of angular compared to linearly shaped compounds.

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Section: Introductionmentioning

confidence: 99%

Tandem Nenitzescu Reaction/Nucleophilic Aromatic Substitution to Form Novel Pyrido Fused Indole Frameworks

et al. 2021

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“…A large ring system dibenzo[b,d]furan (DBF) was also chosen as the second novel imidazo [4,5-f] [1,10]phenanthroline derivative. The natural and synthetic DBF derivatives have been reported to have anticancer, [89][90][91][92] antibacterial, [93,94] antiinflammatory, [95,96] antiplatelet, [90,97] hypolipemics, [55] antituberculosis, [98][99][100] antidiabetic, [101] antiviral, analgesics, antimalarial, and herbicidal properties. [102] Several DNA-intercalating Ru(II), Co(III), and a few Ni(II) octahedral complexes generally have one larger planar ligand and two small ligands (1,10-phenanthroline or 2,2'-bypyridine or their derivatives).…”

Section: Introductionmentioning

confidence: 99%

DNA Interactions and Antiproliferative Activity Studies of Octahedral Nickel Complexes of Two Extended Phenanthrolines

et al. 2021

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Two new imidazophenanthroline derivatives, namely 2-(4bromo-(2,1,3)-benzothiadiazol-7-yl)-1H-imidazo [4,5- [1,10]phenanthroline (dbfip) and their octahedral nickel complexes [Ni(phen) 2 (btdip)] 2 + (1) and [Ni(phen) 2 (dbfip)] 2 + (2) have been synthesized and characterized by CHN analysis, ESI-MS, NMR and UV-vis spectra. Their DNA binding abilities were spectrophotometrically, hydrodynamically and electrophoretically studied and found that while btdip binds DNA externally, dbfip binds in the grooves and both of their nickel complexes also bind DNA through grooves giving severe DNA damage in the presence of peroxide. The compounds were screened against four different human cancer cell lines using MTT assay method. The results obtained showed that both ligands are active against DLD-1, and further dbfip is found to be more active than positive control drugs against DLD-1 and HepG2 cell lines. The complex 2 has more antiproliferative effect than 1 against MCF-7 and HepG2 cells. On the other hand, complex 2 was found to have more toxic effect on HepG2 cells than the standard drugs cisplatin and ploxal-S.

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“…Roflumilast (C; Figure 1) was approved by FDA as a PDE4 inhibitor and used for the treatment of chronic obstructive pulmonary disease 26 and was successfully tested in lung cancer and B-cell lymphoma 25 . In contrast, an increase in the level of intracellular cAMP by the inhibition of PDE4 isoenzymes leads to inhibition of the production of tumour necrosis factor-alpha (TNF-a) 28 . TNF-a is a central mediator of inflammation, and thus provides a molecular link between chronic inflammation and the development of malignancies [29][30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

“…In addition, TNF-a is overexpressed in various cancer cells such as liver cancer, kidney cancer, and gallbladder cancer and supports tumour growth and metastasis [29][30][31][32] . The aforementioned results indicated that the inhibition of PDE4 enzyme activity [18][19][20][21][22][23][24][25][26][27] and the suppression of the production of TNF-a [28][29][30][31][32] are an interesting target for the treatment of cancer. Compounds containing 2-cyclopentyloxyanisole analogues are reported to be PDE4 inhibitors with anticancer activities, such as rolipram (B; Figure 1), roflumilast (C; Figure 1), and apremilast (E; Figure 1) 18,22,23 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition

El-Husseiny

El‐Sayed

El‐Azab

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3-14 and their in vitro antitumor activity was evaluated. Compounds 4a, 4b, 6b, 7b, 13, and 14 had the most potent antitumor activity (IC 50 range: 5.13-17.95 lM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a, 4b, 7b, and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-a. Compounds 4a and 13 potently inhibited TNF-a (IC 50 values: 2.01 and 6.72 lM, respectively) compared with celecoxib (IC 50 ¼6.44 lM). Compounds 4b and 13 potently inhibited COX-2 (IC 50 values: 1.08 and 1.88 lM, respectively) comparable to that of celecoxib (IC 50 ¼0.68 lM). Compounds 4a, 7b, and 13 inhibited PDE4B (IC 50 values: 5.62, 5.65, and 3.98 lM, respectively) compared with the reference drug roflumilast (IC 50 ¼1.55 lM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied. HIGHLIGHTS Antitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated. The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-a inhibitors. Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-a inhibition. Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.

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In vivo effective dibenzo[b,d]furan-1-yl-thiazoles as novel PDE-4 inhibitors

Cited by 10 publications

References 27 publications

Tandem Nenitzescu Reaction/Nucleophilic Aromatic Substitution to Form Novel Pyrido Fused Indole Frameworks

Tandem Nenitzescu Reaction/Nucleophilic Aromatic Substitution to Form Novel Pyrido Fused Indole Frameworks

DNA Interactions and Antiproliferative Activity Studies of Octahedral Nickel Complexes of Two Extended Phenanthrolines

Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition

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