Development of PRPK Directed Phthalimides

Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide (Pom) bind to cereblon (CRBN) and trigger proteasomal degradation of neo-substrates IKZF1/3 leading to multiple myeloma (MM) cell apoptosis. Pomalidomide (Pom) also binds albeit weakly to p53-related protein kinase (PRPK, aka TP53RK), an understudied kinase reported to be associated with poor prognosis in MM patients. Here, we developed a series of IMiDs based on Pom and conducted a structure-activity relationship (SAR) study to identify a potent and selective PRPK binder. Structural analysis showed that IMiDs bind PRPK in a fundamentally different way from CRBN, and suggested specific derivatization to improve affinity. We employed a structure-guided strategy to develop compound TXM-02-118, which exhibited nanomolar affinityfor PRPK in binding assays, and showed high selectivity for PRPK over CRBN. Overall, the work represents an initial effort to develop tool compounds for studying PRPK. Moreover, it illustrates how a single class of molecules can use different recognition elements to bind diverse targets using fundamentally different binding poses. This has broad implications for chemical probe and lead compound selectivity profiling, and argues for more wide-spread use of global proteomics or similar methodologies.

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Synthesis, Antimalarial Evaluation and SAR Study of Some 1,3,5-Trisubstituted Pyrazoline Derivatives

Letters in Organic Chemistry ◽

10.2174/1570178616666190212145754 ◽

2019 ◽

Vol 16 (10) ◽

pp. 807-817 ◽

Cited By ~ 1

Author(s):

Shilpy Aggarwal ◽

Deepika Paliwal ◽

Dhirender Kaushik ◽

Girish Kumar Gupta ◽

Ajay Kumar

Keyword(s):

Antimalarial Activity ◽

Analysis Data ◽

Docking Study ◽

Maximum Activity ◽

Elemental Analysis Data ◽

Mass Spectral ◽

Structure Activity ◽

Pharmacokinetic Properties ◽

Sar Study

The synthesis of a novel series of 1,3,5-trisubstitiuted pyrazoline was achieved by refluxing chalcone derivative with different heteroaryl hydrazines. The newly synthesized compounds were characterized by 1H NMR, 13CNMR, mass spectral and elemental analysis data. The synthetic series of novel pyrazoline hybrids was screened for in vitro schizont maturation assay against chloroquine sensitive 3D7 strain of Plasmodium falciparum. Most of the compounds showed promising in vitro antimalarial activity against CQ sensitive strain. The preliminary structure-activity relationship study showed that quinoline substituted analog at position N-1 showed maximum activity followed by benzothiazole substitution, while phenyl substitution lowers the antimalarial activity. The observed activity was persistent by the docking study on P. falciparum cystein protease falcipain-2. The pharmacokinetic properties were also studied using ADME prediction.

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Novel Acetohydrazide Pyrazole Derivatives: Design, Synthesis, Characterization and Antimicrobial Activity

Asian Journal of Chemistry ◽

10.14233/ajchem.2019.22190 ◽

2019 ◽

Vol 31 (12) ◽

pp. 2740-2744

Author(s):

Anil Verma ◽

Vinod Kumar ◽

Ramesh Kataria ◽

Joginder Singh

Keyword(s):

Mass Spectrometry ◽

Antimicrobial Activity ◽

Antimicrobial Agents ◽

Antimicrobial Activities ◽

Pyrazole Derivatives ◽

Reaction Conditions ◽

Design Synthesis ◽

Structure Activity ◽

Electron Withdrawing Group ◽

Sar Study

Eleven acetohydrazide linked pyrazole derivatives were designed and synthesized via condensation of acetohyadrazide with different substituted formyl pyrazole derivatives under mild reaction conditions. Synthesized compounds were characterized on the basis of IR, NMR (1H & 13C) and mass spectrometry. The antimicrobial activities of all the compounds were screened against four bacterial and two fungal strains. Among the synthesized compounds, three compounds viz. 6b, 6c and 6d were found as efficient antimicrobial agents in reference to the standard drugs viz. ciprofloxacin and amphotericin-B. Further, structure-activity relationship (SAR) study revealed that electron-withdrawing group enhances the antimicrobial potential of synthesized derivatives as compared to other groups present in the ring. Hence, among compounds 6b-c, compound 6d could be explored further against other microbes to prove its vitality.

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Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2014.11.053 ◽

2015 ◽

Vol 97 ◽

pp. 419-443 ◽

Cited By ~ 165

Author(s):

Geeta Yadav ◽

Swastika Ganguly

Keyword(s):

Biological Activities ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Structure Activity ◽

Sar Study

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Asymmetric Synthesis and Cytotoxicity Evaluation of Right-Half Models of Antitumor Renieramycin Marine Natural Products

Marine Drugs ◽

10.3390/md17010003 ◽

2018 ◽

Vol 17 (1) ◽

pp. 3 ◽

Cited By ~ 3

Author(s):

Takehiro Matsubara ◽

Masashi Yokoya ◽

Natchanun Sirimangkalakitti ◽

Naoki Saito

Keyword(s):

Prostate Cancer ◽

Colorectal Cancer ◽

Natural Products ◽

Asymmetric Synthesis ◽

Active Compound ◽

Hct116 Cell ◽

Human Prostate Cancer ◽

Model Compounds ◽

Structure Activity ◽

Sar Study

A general protocol for the asymmetric synthesis of 3-N-arylmethylated right-half model compounds of renieramycins was developed, which enabled structure–activity relationship (SAR) study of several 3-N-arylmethyl derivatives. The most active compound (6a) showed significant cytotoxic activity against human prostate cancer DU145 and colorectal cancer HCT116 cell lines (IC50 = 11.9, and 12.5 nM, respectively).

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An Organocatalysis Based Carbocyclic Spiroindoline Synthesis Enables Facile Structure–Activity Relationship (SAR) Study at C2 Position

Organic Letters ◽

10.1021/acs.orglett.5b02031 ◽

2015 ◽

Vol 17 (17) ◽

pp. 4240-4243 ◽

Cited By ~ 10

Author(s):

Yongsheng Zheng ◽

Jacob Cleaveland ◽

David Richardson ◽

Yu Yuan

Keyword(s):

Structure Activity Relationship ◽

Activity Relationship ◽

Structure Activity ◽

Sar Study

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Identification and Evaluation of Potential SARS-CoV-2 Antiviral Agents Targeting mRNA Cap Guanine N7-Methyltransferase

10.26434/chemrxiv.14484933.v1 ◽

2021 ◽

Author(s):

Renata Kasprzyk ◽

Tomasz J. Spiewla ◽

miroslaw smietanski ◽

Sebastian Golojuch ◽

Laura Vangeel ◽

...

Keyword(s):

Antiviral Agents ◽

Therapeutic Interventions ◽

Binding Assays ◽

Inhibitory Effects ◽

Dot Blot ◽

Rp Hplc ◽

Structure Activity ◽

Mrna Capping ◽

New Ideas ◽

A Cell

SARS-CoV-2, the cause of the currently ongoing COVID-19 pandemic, encodes its own mRNA capping machinery. Insights into this capping system may provide new ideas for therapeutic interventions and drug discovery. In this work, we employ a previously developed Py-FLINT screening approach to study the inhibitory effects of compounds against the cap guanine N7-methyltransferase enzyme, which is involved in SARS-CoV-2 mRNA capping. We screened five commercially available libraries (7039 compounds in total) to identify 83 inhibitors with IC50 < 50 μM, which were further validated using RP HPLC and dot blot assays. Novel fluorescence anisotropy binding assays were developed to examine the targeted binding site. The inhibitor structures were analyzed for structure-activity relationships in order to define common structural patterns. Finally, the most potent inhibitors were tested for antiviral activity on SARS-CoV-2 in a cell based assay<br>

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Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

Biomolecules ◽

10.3390/biom9120870 ◽

2019 ◽

Vol 9 (12) ◽

pp. 870

Author(s):

Joanna Matysiak ◽

Alicja Skrzypek ◽

Monika Karpińska ◽

Kamila Czarnecka ◽

Paweł Szymański ◽

...

Keyword(s):

Molecular Docking ◽

High Selectivity ◽

Antioxidant Properties ◽

Binding Mode ◽

Biological Evaluation ◽

The Other ◽

Docking Simulations ◽

Sar Studies ◽

Structure Activity

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman’s spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC50 80–90 nM) AChE and moderate (IC50 5–0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure–activity relationships were discussed. The compounds inhibited also in vitro self-induced Aβ(1–42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine.

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The nucleolar-related protein Dyskerin pseudouridine synthase 1 (DKC1) predicts poor prognosis in breast cancer

British Journal of Cancer ◽

10.1038/s41416-020-01045-7 ◽

2020 ◽

Vol 123 (10) ◽

pp. 1543-1552

Author(s):

Khloud A. Elsharawy ◽

Omar J. Mohammed ◽

Mohammed A. Aleskandarany ◽

Ayman Hyder ◽

Hekmat L. El-Gammal ◽

...

Keyword(s):

Breast Cancer ◽

Poor Prognosis ◽

Related Protein ◽

Pseudouridine Synthase

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Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines

Molecules ◽

10.3390/molecules25173929 ◽

2020 ◽

Vol 25 (17) ◽

pp. 3929

Author(s):

Dyhia Amrane ◽

Armand Gellis ◽

Sébastien Hutter ◽

Marion Prieri ◽

Pierre Verhaeghe ◽

...

Keyword(s):

Cell Line ◽

Hepg2 Cell ◽

Alkoxy Group ◽

Hepg2 Cell Line ◽

Ccl3 Group ◽

Falciparum Strain ◽

Structure Activity ◽

Trichloromethyl Group ◽

Sar Study

From three previously identified antiplasmodial hit compounds (A–C) and inactive series (D), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 P. falciparum strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC50 K1 P. falciparum ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (2, 9, 16, and 24) and two among 4-alkoxy derivatives (41 and 44). Regarding the two most potent molecules (16 and 41), five derivatives without a 2-CCl3 group were prepared, evaluated, and appeared totally inactive (EC50 > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.

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