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Cancer is a leading cause of death globally and has been associated with Mycobacterium tuberculosis (Mtb). The angiogenesis-related VEGFR-2 is a common target between cancer and Mtb. Here, we aimed to synthesize and validate potent dual human VEGFR-2 inhibitors as anticancer and anti-mycobacterial agents. Two series of 1,2,4-triazole-based compounds (6a-l and 11a-e) were designed and synthesized through a molecular hybridization approach. Activities of all synthesized compounds were evaluated against human VEGFR-2 in addition to drug-sensitive, multidrug-resistant and extensive-drug resistant Mtb. Compounds 6a, 6c, 6e, 6f, 6h, 6l, 11a, 11d and 11e showed promising inhibitory effect on VEGFR-2 (IC 50  = 0.15 - 0.39 µM), anti-proliferative activities against cancerous cells and low cytotoxicity against normal cells. The most potent compounds (6e and 11a) increased apoptosis percentage. Additionally, compounds 6h, 6i, 6l and 11c showed the highest activities against all Mtb strains, and thus were evaluated against enoyl-acyl carrier protein reductase (InhA) which is essential for Mtb cell wall synthesis. Interestingly, the compounds showed excellent InhA inhibition activities with IC 50 range of 1.3 - 4.7 µM. Docking study revealed high binding affinities toward targeted enzymes; human VEGFR-2 and Mtb InhA. In conclusion, 1,2,4-triazole analogues are suggested as potent anticancer and antimycobacterial agents via inhibition of human VEGFR-2 and Mtb InhA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In this work, a novel promising hybrid mode of uracil/thiouracil based quinoline pharmacophore i.e. 5a-f was rationalized and synthesized based on rigidification and lipophilic principles, and following the reported pharmacophoric features of camptothecin & doxorubicin. Concurrently, a non-rigid mode pharmacophore i.e. 7a-f was also designed and synthesized. The anti-proliferative activity of the compounds was assessed against three different cancer cell lines, namely A549 lung cancer, MCF-7 breast adenocarcinoma, and HepG-2 hepatic carcinoma. Further, promising candidates were evaluated against A549, and MCF-7 and for their ability to inhibit topoisomerases I &II. Compound 5f was observed to be the most active congener, displaying the highest cell inhibition of 84.4% for topoisomerase I and 92%, for topoisomerase II at a concentration of 100 µM. When its cytotoxicity was evaluated against A549 cells, 5f arrested the cell cycle at the S phase and increased the apoptosis ratio by 46.31%. DFT calculation of 5f showed higher dipole moment and greater negative energy values (-247531.510 kcal/mol) with positive & negative poles, and better stability reflection. Furthermore, molecular docking of 5f to both enzymes showed good agreement with the biological assessment. This study has given insight for further consideration of the highly promising hybrid 5f., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A novel set of quinoline tailored with the sulfonamide as zinc-binding group (ZBG) has been rationalized and synthesized as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Such hybrids were decorated by a novel elongated imine linker with/without ethylene spacer with variable hydrophobic and lipophilic pockets. Therefore, a regioisomeric tactic has been established, most of which act as efficient inhibitors of the tumor-associated CA isoforms IX and XII. Interestingly, one hybrid 10b displayed an appreciable activity in MCF-7 cell line under normoxic condition (IC 50 of 8.42 µM) in comparison to the standard staurosporine (IC 50  = 5.34 µM) and excellent activity under hypoxic conditions (IC 50  = 1.56 µM) in comparison to staurosporine (IC 50  = 4.45 µM). Furthermore, hybrids 8a and 10b encouraged MCF-7 and MDA-MB-231 cell apoptosis alongside promising Bax/Bcl expression ratio change. Docking studies were also, performed and agreed with the biological results. Our SAR study suggested that our regiosiomerization tactic for the quinoline based-sulfonamide molecules led to effective inhibition of tumuor-relevant hCAs IX/XII., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)