Synthesis and cytotoxic evaluation of pyrido-dipyrimidine derivatives: Mechanism of action, DNA and HSA binding studies.

Novel antiviral compounds: Synthesis, biological studies on SARS-CoV-2, and structure-activity relationship analysis.

Imidazolones-based azo dye; design, synthesis, spectral characterization, biological evaluations, and combined in silico and in vitro analyses to assess the anticancer potential.

Lisboaeflavanonol A: a novel Amazonian molecule as a potent antiviral compound with activity against SARS-CoV-2.

Synthesis and antiprotozoal activity of β-carboline-(piperazinyl)-1,3,5-triazine hybrids.

Bridging In Silico design and experimental validation: Virtual screening and In Vitro assessment of biomimetic anticancer peptides inspired by horseshoe crab hemolymph proteins.

Lycorine from Lycoris radiata attenuates IBV-induced pathogenicity by boosting MDA5-dependent type I interferon response.

SARS-CoV-2 has precipitated a global health crisis. The Main Protease (Mpro) represents a validated pharmacological target. A series of benzothiazole-based derivatives was designed, synthesized, and evaluated as Mpro inhibitors. The synthesized 5-nitro benzothiazole intermediates (26-29) displayed moderate Mpro inhibition with low to moderate cytotoxicity (CC₅₀=16-83μM in HEK-293 cells). These compounds were subsequently optimized through SAR studies guided by binding site analyses. Lead optimization afforded highly potent derivatives, notably compound 35 (IC50=0.026μM), exhibiting superior potency compared to GC376 and an exceptionally high selectivity index (10,653.8), indicating a favorable potency and safety profile. Acute oral toxicity studies classified compound 35 (LD50=947.6mg/kg BW) and 48 (LD50=274.6mg/kg BW) as Category IV and III toxicants, indicating low acute oral toxicity. Histopathological analysis revealed that the intermediate compound 28 induced hepatic alterations, whereas the final SAR-optimized compound 35 exhibited preserved liver architecture with no apparent pathological changes. Molecular Docking analyses revealed that these benzothiazole derivatives effectively occupied the Mpro active site sub-pocket through stable H-bonding and hydrophobic interactions, thereby facilitating catalytic dyad engagement and pocket adaptability. Covalent docking of compound 35 indicated favorable binding and putative covalent interaction with Cys145. MD simulations confirmed that compound 35 stabilized the protein structure with enhanced compactness, stable interactions, and reduced conformational fluctuations compared to the apo protein. Collectively, these findings highlight benzothiazole-based scaffolds as promising SARS-CoV-2 Mpro inhibitors.

Aromatase inhibitory, anti-proliferative, and apoptosis-inducing effects of naphthoquinone-triazole derivatives for potential anti-breast cancer agents: In vitro and molecular docking studies.

Phytochemicals in ethanolic extract of Cinnamomum tamala induce cell cycle arrest, DNA damage and apoptosis in human breast cancer cell lines MDA-MB-231 and MCF-7.

Design and synthesis of novel 1,2,4-triazolobenzene sulfonamide derivatives as selective CDK1 inhibitors with potent in vivo anticancer efficacy.

A recombinant HiBiT-tagged porcine circovirus type 2 (PCV2) reporter system identifies potent antiviral activity of terameprocol.

Broad-spectrum antiviral activity of molnupiravir against fish rhabdoviruses through entry blockade and induced viral mutagenesis.

Discovery of triazole analogues as selective IDO1 inhibitors: Dual mechanistic effects on kynurenine pathway suppression and apoptosis in cancer cells.

Novel staurosporine-type indolocarbazole glycoalkaloids as potent and selective FLT3-ITD inhibitors for acute myeloid leukemia.

Exploration of 1,3-di substituted pyrazole conjugates as DNA gyrase inhibitors to combat Staphylococcus aureus and Mycobacterium tuberculosis.

Antiviral potential of galactose-binding lectin from Vatairea macrocarpa seeds against SARS-CoV-2.

A novel series of cyanoacrylamides based on thiazole was synthesized and characterized by different physicochemical and multispectral investigations. The new compounds have been assessed for their cytotoxic potential against several human cancer cell lines (HCT-116, MCF-7, HEp-2, and WI-38). Compound 5g,incorporating 4-(piperidin-1-yl)phenyl moiety,was selected as it emerged to achieve the potent cytotoxic effect against HCT-116 and MCF-7 cell lines, with IC50 values of 32 and 49 µM, respectively. In addition, the selectivity index was calculated to be > 3.1 against the HCT-116 cell line, where it exhibits a low cytotoxic effect against the WI-38 cell line. Compound 5g also has the capability to induce both early and late apoptosis of HCT-116 cells. Moreover, flow cytometric analysis ofHCT-116cells treated with compound 5g showed a pronounced increase in cells in the S and G2/M phases with a consequent reduction of cells in the G0/G1 phase, indicating that compound 5g induces cell cycle arrest and apoptosis. In addition, the results were confirmed by increased caspase-3 activity, downregulation of Bcl-2, CDK1, and CDK2 expression, and upregulation of Bax expression, as evidenced by qRT-PCR and ELISA analyses. Additionally, 5g exhibited a favorable DNA binding affinity as determined through UV-Vis measurements with a Kb value of 1.39 × 104 M-1. The drug-like features of 5g were evaluated, andits ADMET properties were predicted. Moreover, a molecular docking study of 5g was performed with different proteins, Bcl2, CDK1, and CDK2, which generates a docking score value range from -4.78 to -7.06 kcal mol-1.

Adopting both molecular hybridization and substituent variation strategies, a novel set of benzochromenoimidazopyrimidines with expected cyclin-dependent kinase 2 (CDK-2) inhibition potential was designed and synthesized. The NCI evaluated all novel hybrids in the 60 cell line panel, where five derivatives 6b, 6d, 6e, 6f, and 6g showed superior activity. The most active hybrids were assessed for the five-dose cytotoxicity toward the most sensitive NCI cancer cells EKVX, UACC-62, and HS 578T in addition to healthy cells (WI-38). Among the tested analogs, 6e, 6f, and 6g exerted promising cytotoxicity toward HS 578T cells where compound 6f exhibited significant antiproliferative activity with an IC50 of 3.06µM, exceeding that of Lapatinib by 7.6 fold. It also displayed a superior selectivity index (8.49) toward HS 578T cells that is greater than that of Lapatinib by 7.08 fold. Additional tests have been done on these hybrids to ascertain their precise mechanism of action. Hence, CDK-2 inhibition, apoptosis assay, and cell cycle analysis for the superior analogs were estimated. The findings illustrated that analog 6f exerted the most potent CDK-2 inhibition with an IC50 equal to 0.277µM, which is approximately threefold the activity of Roscovitine (0.833µM). As well, compound 6f arrested HS 578T cell cycle at both S and G2/M phases and stimulated apoptosis by increasing Bax and Caspase-3 expression with a concurrent decline in the expression of Bcl-2. Additionally, ADMET prediction and the binding interaction of the most active derivatives with CDK-2 have been studied in silico to evaluate their potential as important antitumor agents.

The drug resistance is one of the challenges in cancer chemotherapy, due to the development of different drug-efflux pumps that expels the drug out of the cells, thus, searching for new compounds with multiple targets in tumor cells, could be an affordable chemotherapy. Alternariol monomethyl ether (AME) was preliminary recognized as a cytotoxic compound, however, its availability and equivocal activity are the hurdles for further applications. Alternaria alternata EFBL-025, PV342518.1, endophyte of Catharanthus roseus, exhibited the highest AME productivity (550 μg/l). Chemically, the structure of putative compound of A. alternata was committed from the TLC, HPLC and LC-MS/MS, with molecular mass 274.2 m/z, and typical fragmentation pattern of authentic AME. The purified AME of A. alternata exhibited a substantial activity against the MCF-7 (IC50 2.5 μM), HepG-2 (IC50 3.5 μM), Caco2 (IC50 3.9 μM), compared to OEC (IC50 13.5 μM), i.e with selectivity indices 5.4, 3.9 and 3.5, respectively. The AME has a highest inhibitory activity of Topoisomerase II (IC50 10.2 nM), than Topoisomerase I (IC50 16.7 nM), with a noticeable ability to arrest the division of MCF-7 cells at the G2/M and S phases by 1.5 and 2 folds, respectively, compared to the control. The AME of A. alternata significantly induces the total apoptosis, early apoptosis and necrosis of MCF-7 by 20, 22 and 2.9 folds. The docking analysis showed that AME had a favorable binding affinity for topoisomerases I/II with binding scores -7.72 and -6.06 kcal/mol, normalized to camptothecin and etoposide that have binding scores -9.44 and -6.82 kcal/mol, respectively. The molecular dynamics simulations explored the reliable stability of protein-AME complexes.