Isatin (1H-indole-2,3-dione) is a privileged nitrogen-containing heterocyclic framework that has received considerable attention in anticancer drug discovery owing to its diverse biological behavior and structural modifications.

Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC₅₀ values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (2) at 40 µM. Of the synthesized compounds, 2-(1H-pyrazolo[3,4-b]pyridin-3-ylamino)-N-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (21a) achieved the highest in vitro cytotoxic activity against H1299, with an IC₅₀ value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC₅₀ of the approved drug imatinib (1). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic interactions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (21a) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), which caused novel corona virus disease-2019 (COVID-19) pandemic, necessitated a global demand for studies related to genes and enzymes of SARS-CoV2. SARS-CoV2 infection depends on the host cell Angiotensin-Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease-2 (TMPRSS2), where the virus uses ACE2 for entry and TMPRSS2 for S protein priming. The TMPRSS2 gene encodes a Transmembrane Protease Serine-2 protein (TMPS2) that belongs to the serine protease family. There is no crystal structure available for TMPS2, therefore, a homology model was required to establish a putative 3D structure for the enzyme. A homology model was constructed using SWISS-MODEL and evaluations were performed through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). Molecular dynamics simulations were employed to investigate the stability of the constructed model. Docking of TMPS2 inhibitors, camostat, nafamostat, gabexate, and sivelestat, using Molecular Operating Environment (MOE) software, into the constructed model was performed and the protein-ligand complexes were subjected to MD simulations and computational binding affinity calculations. These in silico studies determined the tertiary structure of TMPS2 amino acid sequence and predicted how ligands bind to the model, which is important for drug development for the prevention and treatment of COVID-19.

Many cancers have displayed resistance to chemotherapeutic drugs over the past few decades. EGFR has emerged as a leading target for cancer therapy via inhibiting tumor angiogenesis. Besides, studies strongly suggest that blocking telomerase activity could be an effective way to control the growth of certain cancer cells. Based on the fact that multi-target design rationale can afford candidates with greater treatment effectiveness. Besides, it was evidenced that inhibition of human telomerase enhances the effect of some tyrosine kinase inhibitors. So, in the current work, we aimed to design and synthesize novel 1,2,3-triazole-tethered Schiff bases (5a–l) to act as dual EGFR and telomerase inhibitors. Growth inhibition (GI)% was conducted for the synthesized compounds using a panel of eleven cancer cell lines as well as two normal cell lines. Interestingly, compound 5e displayed the highest mean GI% (76.78%) among the investigated compounds surpassing the mean GI% of the reference drug doxorubicin (65.79%). In addition, compound 5g displayed notably the lowest IC₅₀ values (13.31, 13.31, 12.62, and 31.19 μM) for the four utilized cancer cell lines HNO97, HCT116, A375, and HEPG2, respectively. Interestingly, the investigated compounds exhibited significant inhibitory potential to EGFR and telomerase protein expression; in particular, compound 5g recorded inhibitory potentials of 3.45 and 1.31 ng mL⁻¹, respectively. Hence, protein expression of the apoptosis-related proteins was carried out for compound 5g. Pro-apoptotic proteins (caspases 3, 8, and 9) were upregulated by 1.35, 1.55, and 1.51-fold change, respectively. Meanwhile, the anti-apoptotic proteins (CDK-2, CDK-4, and CDK-6) were downregulated by 2.91, 2.01, and 9.15-fold change, respectively, ensuring the apoptotic potential of compound 5g. Accordingly, compound 5g was selected for further investigation of its effects on cell cycle progression in A375 cancer cells. Obviously, compound 5g prompted cell cycle arrest at the G0–G1 phase. Additionally, the investigated compounds showed eligible pharmacokinetic profiles with feasible oral bioavailability. Consequently, the synthesized compounds can be treated as lead multi-target anticancer ligands for future optimization.

The global impact of emerging and re-emerging viral agents during epidemics and pandemics leads to serious health and economic burdens. Among the major emerging or re-emerging viruses include SARS-CoV-2, Ebola virus (EBOV), Monkeypox virus (Mpox), Hepatitis viruses, Zika virus, Avian flu, Influenza virus, Chikungunya virus (CHIKV), Dengue fever virus (DENV), West Nile virus, Rhabdovirus, Sandfly fever virus, Crimean-Congo hemorrhagic fever (CCHF) virus, and Rift Valley fever virus (RVFV). A comprehensive literature search was performed to identify existing studies, clinical trials, and reviews that discuss drug repositioning strategies for the treatment of emerging and re-emerging viral infections using databases, such as PubMed, Scholar Google, Scopus, and Web of Science. By utilizing drug repositioning, pharmaceutical companies can take advantage of a cost-effective, accelerated, and effective strategy, which in turn leads to the discovery of innovative treatment options for patients. In light of antiviral drug resistance and the high costs of developing novel antivirals, drug repositioning holds great promise for more rapid substitution of approved drugs. Main repositioned drugs have included chloroquine, ivermectin, dexamethasone, Baricitinib, tocilizumab, Mab114 (Ebanga™), ZMapp (pharming), Artesunate, imiquimod, saquinavir, capmatinib, naldemedine, Trametinib, statins, celecoxib, naproxen, metformin, ruxolitinib, nitazoxanide, gemcitabine, Dorzolamide, Midodrine, Diltiazem, zinc acetate, suramin, 5-fluorouracil, quinine, minocycline, trifluoperazine, paracetamol, berbamine, Nifedipine, and chlorpromazine. This succinct review will delve into the topic of repositioned drugs that have been utilized to combat emerging and re-emerging viral pathogens.