1. 7H-Pyrrolo[2,3-d]pyrimidine-4-amines as Potential Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinases
Tswene D Seanego, Hlamulo E Chavalala, Hendrik H Henning, Charles B de Koning, Heinrich C Hoppe, Kayode K Ojo, Amanda L Rousseau ChemMedChem. 2022 Nov 18;17(22):e202200421. doi: 10.1002/cmdc.202200421. Epub 2022 Sep 29.
A series of pyrrolo[2,3-d]pyrimidines were designed in silico as potential bumped kinase inhibitors targeting P. falciparum calcium dependent protein kinase 4 (PfCDPK4), with the potential to inhibit PfCDPK1 based on earlier studies of the two kinases. A small series of these compounds were prepared and assessed for inhibitory activity against PfCDPK4 and PfCDPK1 in vitro. Four of the compounds displayed promising inhibitory activity against either PfCDPK4 (IC50 =0.210-0.530 μM), or PfCDPK1 (IC50 =0.589 μM). These data will enable optimisation of the molecular model to better predict inhibitory activity against PfCDPK4.
2. Discovery of 7H-pyrrolo[2,3-d]pyrimidine derivatives as selective covalent irreversible inhibitors of interleukin-2-inducible T-cell kinase (Itk)
Guanghui Tang, Lihong Liu, Xueying Wang, Zhengying Pan Eur J Med Chem. 2019 Jul 1;173:167-183. doi: 10.1016/j.ejmech.2019.03.055. Epub 2019 Mar 26.
Interleukin-2-inducible T-cell kinase (Itk) plays an important role in multiple signal transduction pathways in T and mast cells, and is a potential drug target for treating inflammatory diseases, autoimmune diseases, and T cell leukemia/lymphoma. Herein, we describe the discovery of a series of covalent Itk inhibitors based on the 7H-pyrrolo[2,3-d]pyrimidine scaffold. Placing an appropriate substitution group at a hydration site of the ATP binding pocket of Itk and using a saturated heterocyclic ring as a linker to the reactive group were crucial for selectivity. The optimized compound 9 showed potent activity against Itk, excellent selectivity for Itk over Btk and other structurally related kinases, inhibition of phospholipase C-γ1 (PLC-γ1) phosphorylation in cells, and anti-proliferative effects against multiple T leukemia/lymphoma cell lines. Compound 9 can serve as a valuable compound for further determination of functions of Itk.
3. Synthesis and Antimicrobial, Anticancer and Anti-Oxidant Activities of Novel 2,3-Dihydropyrido[2,3-d]pyrimidine-4-one and Pyrrolo[2,1-b][1,3]benzothiazole Derivatives via Microwave-Assisted Synthesis
Aamal A Al-Mutairi, Hend N Hafez, Abdel-Rhaman B A El-Gazzar, Marwa Y A Mohamed Molecules. 2022 Feb 12;27(4):1246. doi: 10.3390/molecules27041246.
In our attempt towards the synthesis and development of effective antimicrobial, anticancer and antioxidant agents, a novel series of 2,3-dihydropyrido[2,3-d]pyrimidin-4-one 7a-e and pyrrolo[2,1-b][1,3]benzothiazoles 9a-e were synthesized. The synthesis of 2-(1,3-benzo thiazol-2-yl)-3-(aryl)prop-2-enenitrile (5a-e) as the key intermediate was accomplished by a microwave efficient method. Via a new variety oriented synthetic microwave pathway, these highly functionalized building blocks allowed access to numerous fused heteroaromatic such as 7-amino-6-(1,3-benzo thiazol-2-yl)-5-(aryl)-2-thioxo-2,3dihydropyrido [2,3-d]pyrimidin-4(1H)-one 7a-e and 1-amino-2-(aryl)pyrrolo[2,1-b][1,3]benzothiazole-3-carbonitrile derivatives 9a-e in order to study their antimicrobial and anticancer activity. The present investigation offers effective and rapid new procedures for the synthesis of the newly polycondensed heterocyclic ring systems. All the newly synthesized compounds were evaluated for antimicrobial, anticancer and antioxidant activity. Compounds 7a,d, and 9a,d showed higher antimicrobial activity than cefotaxime and fluconazole while the remaining compounds exhibited good to moderate activity against bacteria and fungi. An anticancer evaluation of the newly synthesized compounds against the three tumor cell lines (lung cell NCI-H460, liver cancer HepG2 and colon cancer HCT-116) exhibited that compounds 7a, d, and 9a,d have higher cytotoxicity against the three human cell lines compared to doxorubicin as a reference drug. These compounds also exhibited higher antioxidant activity and a great ability to protect DNA from damage induced by bleomycin.
