4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation

Medapi, Brahmam; Suryadevara, Priyanka; Renuka, Janupally; Sridevi, Jonnalagadda Padma; Yogeeswari, Perumal; Sriram, Dharmarajan

doi:10.1016/j.ejmech.2015.06.032

Cited by 43 publications

(42 citation statements)

References 20 publications

(4 reference statements)

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“…Aminoquinoline moiety is present in many biologically active compounds. Compounds bearing this sub-structure are described with anti-tuberculosis, 1 anti-leishmania 2 or antiinflammatory 3 , or antiviral (Ebola 4 ) activity or against Parkinson's disease 5 although an anti-malarial therapeutic indication is most well-known. The most used compounds of this family are chloroquine (CQ) and amodiaquine (AQ) ( Figure 1).…”

Section: -mentioning

confidence: 99%

“…The residue was purified by flash chromatography (DCM/MeOH(NH3), 10:0 to 9.5:0.5 (v/v)) to give compound 15b as a colourless oil (yield: 48 %). 1 = C33H49N6O3. Purity: C4 column: tr = 16.7 min, purity = 90 %; C18 column: tr = 18.7 min, purity = 92 %.…”

Section: 1 4 2 -([ 2 -(M O R P H O L I N -4 -Y L M Et H Yl )Pmentioning

confidence: 99%

“…The residue was purified by column chromatography (DCM/MeOH(NH3) 9.5:0.5 to 9.3:0.7 (v/v)) to give compound 16a as a colourless oil (yield: 26%). 1…”

Section: 1 1 3 -B I S (([ 2 -(P I P Er I D I N -1 -Yl )Et Hmentioning

confidence: 99%

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New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

Gay

Renault

Coevoet

et al. 2018

Bioorganic & Medicinal Chemistry

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The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer's disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aβ), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques. We showed that AQ and analogs have similar effects although having a higher cytotoxicity. Herein, two new series of compounds were synthesized by replacing 7chloroquinolin-4-amine moiety of AQ by 2-aminomethylaniline and 2aminomethylphenyle moieties. Their structure activity relationship was based on their ability to modulate APP metabolism, Aβ release, and their cytotoxicity similarly to CQ. Two compounds 15a, 16a showed interesting and potent effect on the redirection of APP metabolism toward a decrease of Aβ peptide release (in the same range compared to AQ), and a 3 to 10-fold increased stability of APP carboxy terminal fragments (CTFα and AICD) without obvious cellular toxicity at 100µM.

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Section: -mentioning

confidence: 99%

Section: 1 4 2 -([ 2 -(M O R P H O L I N -4 -Y L M Et H Yl )Pmentioning

confidence: 99%

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New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

Gay

Renault

Coevoet

et al. 2018

Bioorganic & Medicinal Chemistry

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“…A set of 248 compounds belonging to the class of DNA GyrB inhibitors along with inhibitory activity (IC 50 ) were collected from the literature. To develop the pharmacophore model and subsequently validate the model, the molecular data set was randomly distributed into training and test set compounds, respectively.…”

Section: Methodsmentioning

confidence: 99%

Identification of promising DNA GyrB inhibitors for Tuberculosis using pharmacophore‐based virtual screening, molecular docking and molecular dynamics studies

Islam

Pillay

2017

Chem Biol Drug Des

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In this study, we searched for potential DNA GyrB inhibitors using pharmacophore-based virtual screening followed by molecular docking and molecular dynamics simulation approaches. For this purpose, a set of 248 DNA GyrB inhibitors was collected from the literature and a well-validated pharmacophore model was generated. The best pharmacophore model explained that two each of hydrogen bond acceptors and hydrophobicity regions were critical for inhibition of DNA GyrB. Good statistical results of the pharmacophore model indicated that the model was robust in nature. Virtual screening of molecular databases revealed three molecules as potential antimycobacterial agents. The final screened promising compounds were evaluated in molecular docking and molecular dynamics simulation studies. In the molecular dynamics studies, RMSD and RMSF values undoubtedly explained that the screened compounds formed stable complexes with DNA GyrB. Therefore, it can be concluded that the compounds identified may have potential for the treatment of TB.

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“…Compounds 2a-c were cyclized thermally in diphenyl ether to the corresponding 4-oxo-1,4-dihydroquinolines 3a-c. Under the anhydrous condition, quinolines 3a-c were chlorinated via heating with excess of POCl 3 to provide the key intermediates 4a-c, as reported previously (Al-Sanea et al 2019;Medapi et al 2015;Rivilli et al 2018). The target compounds 5a-i were achieved through microwave-assisted nucleophilic substitution reaction of 3-amino-N-methylbenzenesulfonamide, 3aminobenzenesulfonamide and N-(3-phenyl)methanesulfonamide with the appropriate key intermediate 4a-c in ethanol (Al-Sanea et al 2019).…”

Section: Chemistrymentioning

confidence: 99%

Peer Review #1 of "Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold (v0.1)"

2020

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Background. CDK8/CycC complex has kinase activity towards the carboxyterminal domain of RNA polymerase II, and contributes to the regulation of transcription via association with the mediator complex. Different human malignancies, mainly colorectal and gastric cancers, were produced as a result of overexpression of CDK8/CycC in the mediator complex. Therefore, CDK8/CycC complex represents as a cancer oncogene and it has become a potential target for developing CDK8/CycC modulators. Methods. A series of nine 4-phenylaminoquinoline scaffold-based compounds 5a-i were synthesized, and biological evaluation of this series was performed as potential inhibitors of CDK8/CycC complex. Results. The scaffold substituent effects on the intrinsic inhibitory activity toward CDK8/CycC complex are addressed trying to present a novel outlook of CDK8/CycC Complex inhibitors with 4phenylaminoquinoline scaffold in cancer therapy. The secondary benzenesulfonamide analogues proved to be the most potent compounds in suppressing CDK8/CycC enzyme, whereas, their primary benzenesulfonamide analogues showed inferior activity. Moreover, the benzene reversed sulfonamide analogues were totally inactive. Discussion. The titled scaffold showed promising inhibitory activity data and there is a crucial role of un/substituted sulfonamido group for CDK8/CycC complex inhibitory activity. Compound 5d showed submicromolar potency against CDK8/CycC (IC 50 = 0.639 μM) and it can be used for further investigations and to design another larger library of phenylaminoquinoline scaffold-based analogues in order to establish detailed SARs.

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4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation

Cited by 43 publications

References 20 publications

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

Identification of promising DNA GyrB inhibitors for Tuberculosis using pharmacophore‐based virtual screening, molecular docking and molecular dynamics studies

Peer Review #1 of "Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold (v0.1)"

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