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One of the most effective approaches to discovering novel drugs for cancer treatment involves the exploration of new synthetic compounds. The pyrazinoic acid or pyrazine‐2‐carboxylic acid (PA)‐derivative compounds can be explored as a new anticancer agent due to their nitrogenous heteroaromatic ring. In this study, ten novels PA derivatives were synthesized by Ugi multicomponent reaction and characterized using IR, NMR, and mass spectroscopy. The cytotoxic activity was assayed in three different cancer cell lines, including colon (HT‐29), lung (A549), and breast (MCF‐7). The U10 was the most potent compound, exhibiting moderate cytotoxicity with IC50 of 8.26 μM, 8.23 μM, and 22.58 μM against HT‐29, A549, and MCF‐7 cell lines, respectively. In addition, the effect of U10 exposure in the MRC‐5 cell line as a non‐tumoral lung cell line showed a selectivity index of 3.76. The apoptotic activity and intracellular ROS level induction of U10 were assayed in MCF‐7 cells. The results demonstrated that apoptosis increases from 23.94 % at 10 μM to 36.8 % at 25 μM. Intracellular ROS level assay showed that U10 was able to significantly increase intracellular ROS by increasing the concentration. Molecular docking was utilized to predict the binding sites and interactions between the synthesized compound and DNA, as well as the Bcl‐2 apoptosis regulator. [ABSTRACT FROM AUTHOR]

Dichloroacetate (DCA) is considered as a highly bioavailable and small anticancer agent which reduces tumor growth through inhibition of pyruvate dehydrogenase kinases. Various DCA derivatives were designed, synthesized and eluated by FT‐IR, 1HNMR, 13CNMR and Mass spectrum. Biological evaluations of the synthesized compounds were evaluated against three human cancer cell lines, A549 (lung), MCF‐7 (breast), and MDA‐MB‐231 (breast), as well as a non‐tumorigenic breast cell line (MCF‐10A). Among synthesized compounds, N‐(2‐(tert‐butylamino)‐1‐(4‐nitrophenyl)‐2‐oxoethyl)‐2,2‐dichloro‐N‐(2‐fluorophenyl)acetamide (A5) had a promising cytotoxic effect with IC50 values of 11.94, 15.57, and 16.54 μM against MCF‐7, MDA‐MB‐231, and A549 cells, respectively. It can also induce apoptosis in MCF‐7 cell line. Molecular docking and molecular dynamic simulation studies were also carried out show binding sites and energies to the PDKs isoenzymes. All of the compounds demonstrated appropriate selectivity between cancerous and non‐cancerous cell lines. These results provide valuable insight for the additional development of novel dichloroacetate‐containing compounds. [ABSTRACT FROM AUTHOR]

Dichloroacetate (DCA) as a small and active anticancer agent through inhibition of pyruvate dehydrogenase kinases (PDKs), prevents proliferation of tumor growth. In this research, a series of novel piperidine and piperazine derivatives of DCA have been designed and subjected to molecular docking studies. Based on the docking results, nine compounds with the lowest binding energy and better interaction with PDKs isoenzymes have been selected and synthesized. The cytotoxic activities of the synthesized compounds have been evaluated against HT-29 and MCF7 human cancer cell lines. These compounds show moderate potencies with much higher anticancer activity than DCA. The most active of the series, f1, showed IC50 value of 7.79 µM against HT-29 cell line. [ABSTRACT FROM AUTHOR]

Dichloroacetate (DCA) as a mitochondria-targeting small molecule, through inhibition of pyruvate dehydrogenase kinases (PDK 1-4), promotes mitochondria-regulated apoptosis and hence, inhibits tumour growth and reduces its proliferation. In this study, a series of novel N-aryl-2,2-dichloroacetamide and aryl-2,2-dichloroacetate derivatives were designed and synthesized. Their cytotoxic activities against various human cancer cell lines including A549, HCA-7, MCF-7, MDA-MB-231, KB and SKOV3 were evaluated. These compounds showed satisfactory potencies with much higher anticancer activity than the parent compound DCA, against the studied cancer cell lines. Molecular docking studies were also done to find their binding site and types of their interactions with PDKs isoenzymes. Among the synthesized compounds, 2,2-dichloro-N-(9,10-dioxo-9,10-dihydroanthracen-1-yl)acetamide (f1) can also induce A549 cells apoptosis. Therefore, compound f1 might have a potential value for further study in drug development. QSAR studies of this class of compounds were also explored using a collection of chemometrics methods. A series of novel N-aryl-2,2-dichloroacetamide and aryl-2,2-dichloroacetate derivatives were designed and synthesized. Their cytotoxic activities against various human cancer cell lines including A549, HCA-7, MCF-7, MDA-MB-231, KB and SKOV3 were evaluated.Apoptosis, Molecular docking and QSAR studies of them were also explored. Image 1 • Design and synthesis of novel N-aryl-2,2-dichloroacetamide and aryl-2,2-dichloroacetate derivatives. • Compounds showed good cytotoxic activities against various human cancer cell lines. • Finding compound f1 for further study in drug development. • Well accommodation of the synthesized compounds in docking studies on pyruvate dehydrogenase kinases (PDKs) isoenzymes. • 2D-QSAR studies to make relations between structural characteristics and cytotoxic activities of the synthesized compounds. [ABSTRACT FROM AUTHOR]

• Synthesis of novel Phenylbutyrate (PB) derivatives using Passerini multicomponent reaction. • Biological evaluation of Phenylbutyrate (PB) derivatives. • Cytotoxicity and apoptosis of novel phenylbutyrate derivatives as potential anticancer agents. • Molecular docking studies on pyruvate dehydrogenase kinase 2 (PDK2) and histone deacetylase complex (HDAC). Phenylbutyrate (PB), a small aromatic fatty acid, has been known as an interesting compound with the ability of anti-proliferation and cell growth inhibition in cancer cells. In the present study, a series of PB derivatives were synthesized by Passerini multicomponent reaction and their cytotoxic activities against various human cancer cell lines including A549 (non-small cell lung cancer), MDA-MB-231 (breast cancer), and SW1116 (colon cancer) were evaluated. The results revealed that B9 , displayed significantly higher in vitro cytotoxicity with IC 50 of 6.65, 8.44 and 24.71 μM, against A549, MDA-MB-231 and, SW1116, respectively, in comparison to PB. The effects of these compounds on the proliferation of MCF-10A as non-tumoral breast cell line, showed good selectivity of the compounds between tumorigenic and non-tumorigenic cell lines. Moreover, B9 has indicated apoptosis-inducing activities to MDA-MB-231 cancer cell line in a dose-dependent manner. The molecular docking studies of the synthesized compounds on pyruvate dehydrogenase kinase 2 (PDK2; PDB ID: 2BU8) and histone deacetylase complex (HDAC; PDB ID: 1C3R), as the main targets of PB were applied to predict the binding sites and binding orientation of the compounds to these targets. [ABSTRACT FROM AUTHOR]