TG-100115

Survivin is an important member of the antiapoptotic protein family and controls the cell’s life cycle. Overexpression of survivin in tumor cells leads to inhibition of apoptosis, thus contributing to cancer cell proliferation. The largest binding pocket in the survivin dimer was located in the BIR domain. The key to the efficacy of 3-cyanopyridines was their surface interaction with the survivin amino acid Ile74.

Through the optimization of the 3-cyanopyridine, 29 new compounds with a 3- Cyanopyridine structure were designed, synthesized, and characterized by NMR, IR, and mass spectrometry. The antitumor activity of the compounds in vitro was detected by the MTT method.

In vitro anti-tumor experiments showed that some compounds exhibited good anti-cancer effects. The IC50 values of the compound 2-amino-6-(2,4-difluorophenyl)-4-(4-hydroxyphenyl) nicotinonitrile (10n) against human liver cancer (Huh7), human glioma (U251), and human melanoma (A375) cells were 5.9, 6.0 and 7.2 μM, respectively. The IC50 values of the compound 6-(2,4-difluorophenyl)- 4-(4-hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (9o) against Huh7, U251 and A375 cells were 2.4, 17.5 and 7.2 μM, respectively, which were better than those of 10- hydroxycamptothecin and 5-fluorouracil. Analysis of the results of molecular dynamics simulation established that the BIR domain is the optimal binding site on the survivin protein, and the fingerprints of the eight most active compounds and the molecular docking to the survivin protein are analyzed.

3-Cyanopyridine is an excellent backbone for antitumor lead compounds, 10n and 9o, as derivatives of 3-Cyanopyridine are excellent survivin protein-targeting inhibitors worthy of further study. The key factor in inhibiting survivin protein through the action of amino acid Ile74.

Antimicrobial resistance (AMR) is one of the critical challenges that have been encountered over the past years. On the other hand, bacterial DNA gyrase is regarded as one of the most outstanding biological targets that quinolones can extensively inhibit, improving AMR. Hence, a novel series of 3-(7-nitro-3-oxo-3,4-dihydroquinoxalin-2-yl)propanehydrazide derivatives (3-6j) were designed and synthesized employing the quinoxaline-2-one scaffold and relying on the pharmacophoric features experienced by the quinolone antibiotic; ciprofloxacin. The antibacterial activity of the synthesized compounds was assessed via in-vitro approaches using eight different Gram-positive and Gram-negative bacterial species. Most of the synthesized compounds revealed eligible antibacterial activities. In particular, compounds 6d and 6e displayed promising antibacterial activity among the investigated compounds. For example, compounds 6d and 6e displayed MIC values of 9.40 and 9.00 µM, respectively, regarding S. aureus, and 4.70 and 4.50 µM, respectively, regarding S. pneumonia in comparison to ciprofloxacin (12.07 µM). The cytotoxicity of compounds 6d and 6e were performed on normal human WI-38 cell lines with IC50 values of 288.69 and 227.64 μM, respectively assuring their safety and selectivity. Besides, DNA gyrase inhibition assay of compounds 6d and 6e was carried out in comparison to ciprofloxacin, and interestingly, compounds 6d and 6e disclosed promising IC50 values of 0.242 and 0.177 μM, respectively, whereas ciprofloxacin displayed an IC50 value of 0.768 μM, assuring the proposed mechanism of action for the afforded compounds. Consequently, compounds 6d and 6e were further assessed via in-vivo approaches by evaluating blood counts, liver and kidney functions, and histopathological examination. Both compounds were found to be safer on the liver and kidney than the reference ciprofloxacin. Moreover, in-silico molecular docking studies were established and revealed reasonable binding affinities for all afforded compounds, particularly compound 6d which exhibited a binding score of -7.51 kcal/mol, surpassing the reference ciprofloxacin (-7.29 kcal/mol) with better anticipated stability at the DNA gyrase binding pocket. Moreover, ADME studies were conducted, disclosing an eligible bioavailability score of >0.55 for all afforded compounds, and reasonable GIT absorption without passing the blood brain barrier was attained for most investigated compounds, ensuring their efficacy and safety. Lastly, a structure activity relationship study for the synthesized compounds was established and unveiled that not only the main pharmacophores required for DNA gyrase inhibition are enough for exerting promising antimicrobial activities, but also derivatization with diverse aryl/hetero aryl aldehydes is essential for their enhanced antimicrobial potential.