A series of novel compounds carrying pyrazino[1,2-a]indol-1(2H)-one scaffold (5a-g) and their reaction
intermediates, indole-2-carboxamides, (3a-g) were synthesized and evaluated for their ability to
inhibit reactive oxygen species (ROS) generation, antioxidant activity and anticancer activity against a
panel of cancer cell lines using MTT assay. The results showed that these compounds can inhibit ROS
generation during the metabolic phase of phagocytosis in a dose-dependent manner where compounds
5d and 5e were the most potent samples with higher inhibitory activities (IC50 values 3.3 and
1.4 mM, respectively) than that of the reference acetylsalicylic acid (IC50 ¼ 9.7 mM). Results for the
determination of potential antioxidant properties of the synthesized compounds showed that compounds
5d and 5e containing pyrazino[1,2-a]indol-1-one backbone were the most acive and even
comparable to Trolox. Compounds 3d-f and 5d-f with the least IC50 values in MTT assay were tested
against three known anticancer targets EGFR, BRAF and Tubulin. Histopathological and immunohistochemical
study were performed to determine the consequence of exposure to chronic low dose of
chlorpyrifos on the testis of male mice and results revealed that these effects can be ameliorated by cotreatment
with the most active antioxidant compounds 5d and 5e. Finally, molecular docking studies
were performed to explore the binding mode of the most active compounds against EGFR and BRAF
kinases.

A series of novel compounds carrying 1,2,4-triazole scaffold was synthesized and evaluated for their anticancer
activity against a panel of cancer cell lines using MTT assay. Compounds 8a, 8b, 8c, 8d, 10b, 10e,
and 10 g showed remarkable antiproliferative activity against the tested cell lines. Compounds 8a, 8b, 8c,
8d, 10b, 10e, and 10 g with the least IC50 values in MTT assay were tested against three known anticancer
targets including EGFR, BRAF and Tubulin. The results revealed that compounds 8c and 8d showed almost
same BRAF inhibitory activity and were discovered to be potent inhibitors of cancer cell proliferation and
were also observed to be strong Tubulin inhibitors. Moreover, 8c also showed the best EGFR inhibition
with IC50 = 3.6 lM. Finally molecular modeling studies were performed to explore the binding mode
of the most active compounds to the target enzymes.

The ability of substituted acenaphthenequinone-thiosemicarbazones to do complexation with Pd(II) and Ag(I) salts was investigated. The obtained Pd(II) 5a-f and Ag(I) 7a-f complexes showed that ligation was occurred during the reaction of two equivalents of the ligands with one equivalent of the metal salts. In case of Pd complexes 5a-f, two moles of HCl were eliminated during complexation process. Whereas direct ligation was occurred during complexation of one mole of AgNO₃ and two moles of ligands to form the corresponding cationic-anionic salts 7a-f. IR, NMR, and UV–vis spectra were used to deduce the structure of the formed metal complexes. X-ray structure analysis proved the syn-form of bis(bidentate) structure of Pd complex 5e, as Pd showed a square planar coordination with two sulfur and two nitrogen atoms. The cationic-anionic nature of silver complexes was revealed by molar conductance. UV–visible spectra were also investigated by means of Time-Dependent Density-Functional Theory (TD-DFT) computations. The obtained metal complexes were also investigated asantibacterial and antifungal agents. Compounds 5f, 5e, 7d, and 7f were found to be the most active and effective against the four bacterial strains, with compound 7f having the most potent action. Compound 7f (R = 3-OMe-Ph) showed MIC values of 0.066, 0.018, 0.018, and 0.033 µg/mL against B. subtilis, S. aureus, E. coli, and K. pneumoniae, respectively. For compound 7d (R = Benzyl), the MIC values are found as 0.028, 0.057, 0.028, and 0.028 µg/mL against the same previous bacterial strains. Compounds 5d, 5e, 7c, and 7f demonstrated promising antifungal activity against C. albicans with MIC values of 0.029, 0.023, 0.018, and 0.027 µg/ml, respectively, when compared to the reference fluconazole, which had a MIC value of 0.020 µg/ml. Compound 7f revealed inhibitory activity of E. coli DNA gyrase (IC₅₀ = 210 ± 15 nM, respectively) being 1.2-folds less potent than the reference novobiocin (IC₅₀ = 170 ± 20 nM).

Introduction: Bacteria have acquired resistance to almost all antibiotics currently
in use due to their extensive, broad, and improper utilization over a prolonged
period. DNA gyrase and DHFR exhibit significant promise as targets for
antibacterial therapeutics.
Methods: We have developed a series of disalicylic acid methylene/Schiff bases
hybrids (6a-l) that function as antibacterial agents by targeting DNA gyrase
and DHFR.
Results and discussion: The findings showed that 6a-l have significant
antibacterial activity against both Gram-positive and Gram-negative bacteria, with inhibition zones (IZ) comparable to or even higher than the reference Ciprofloxacin. MIC testing revealed that 6h and 6l were 1.5 times as effective than ciprofloxacin against S. aureus. Compounds 6h and 6l had MBC values of 28 and 33 nM for S. aureus, compared to Ciprofloxacin’s 45 nM, indicating that they are more potent bactericidal agents. The MIC values for compounds 6c, 6e, 6h, 6j, and 6l against A. flavus were between 14.50 and 19.50 μM, while the MIC value for fluconazole was 11.50 μM. Also, the studied compounds had MIC values between 18.20 and 22.90 μM against C. albicans, while Fluconazole had a MIC value of 17.50 μM. Compound 6h showed a MIC value of 1.70 μM against the clinical strain S. aureus (ATCC 43300) (MRSA), making it an effective antibacterial agent. Compounds 6h, 6j, and 6l inhibited E. coli DNA gyrase with IC50 values of 79, 117, and 87 nM, respectively, compared to the reference novobiocin (IC50 = 170 nM). Additionally, compounds 6h and 6l, the most potent E. coli gyrase inhibitors, showed encouraging results on DHFR. Compounds 6h and 6l exhibit IC50 values of 3.80 μM and 4.25 μM, respectively. These values are significantly lower and hence more effective than Trimethoprim’s IC50 of 5.20 μM.

Dual targeting of EGFR and HER2 is a valid anti-cancer approach for treating solid tumors. We designed and synthesized a new series of EGFR/HER-2 dual-target inhibitors based on quinoline derivatives. The structure of the newly synthesized compounds was verified using 1 H NMR, 13C NMR, and elemental analysis. The targeted compounds were tested for antiproliferative efficacy against four cancer cell lines. All the compounds had GI50s ranging from 25 to 82 nM, with breast (MCF-7) and lung (A-549) cancer cell lines being the most sensitive. Compound 5a demonstrated the most significant antiproliferative action. With inhibitory (IC50) values of 71 and 31 nM, respectively, compound 5a proved to be the most effective dual-target inhibitor of EGFR and HER-2, outperforming the reference erlotinib (IC50 = 80 nM) as an EGFR inhibitor but falling short of the clinically used agent lapatinib (IC50 = 26 nM) as a HER2 inhibitor. The apoptotic potential activity of 5a was examined, and the findings demonstrated that 5a promotes apoptosis by activating caspase-3, 8, and Bax while simultaneously reducing the expression of the antiapoptotic protein Bcl-2. The docking studies provided valuable insights into the binding interactions of compounds 3e and 5a with EGFR, effectively rationalizing the observed SAR trends

Abstract: Background/Objectives: Supported by a comparative study between conventional, grinding,
and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition
of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good
yields was used. Methods: The newly synthesized compounds were analyzed with IR, 13C NMR,
1H NMR, mass, and elemental analysis methods. The products show interesting precursors for their
antiproliferative anti-breast cancer activity. Results: Pyrimidine-containing scaffold compounds 9
and 10 were the most active, achieving IC50 = 26.07 and 4.72 μM against the breast cancer MCF-7 cell
line, and 10.64 and 7.64 μM against breast cancer MDA-MB231-tested cell lines, respectively. Also,
compounds 9 and 10 showed a remarkable inhibitory activity against the Hsp90 protein with IC50
values of 2.44 and 7.30 μM, respectively, in comparison to the reference novobiocin (IC50 = 1.14 μM).
Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds
(supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions
of compound 9 were confirmed through molecular docking, and simulation studies displayed a
complete overlay into the Hsp90 protein pocket. Conclusions: Compounds 9 and 10 may have
apoptotic antiproliferative action as Hsp90 inhibitors.

The present study details the design, synthesis, and bio-evaluation of indoles
3–16 as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS)
with antiproliferative activity. The study evaluates the antiproliferative efficacy of
3–16 against various cancer cell lines, highlighting hybrids 12 and 16 for their
exceptional activity with GI50 values of 25 nM and 28 nM, respectively. The
inhibitory effects of the most active hybrids 5, 7, 12, and 16, on both aromatase
and iNOS were evaluated. Compounds 12 and 16 were investigated for their
apoptotic potential activity, and the results showed that the studied compounds
enhance apoptosis by activating caspase-3, 8, and Bax and down-regulating the
anti-apoptotic Bcl-2. Molecular docking studies are intricately discussed to
confirm most active hybrids’ 12- and 16-binding interactions with the
aromatase active site. Additionally, our novel study discussed the ADME
characteristics of derivatives 8–16, highlighting their potential as therapeutic
agents with reduced toxicity.

Since 2020, many compounds have been investigated for their potential use in the treatment of SARS-CoV-2
infection. Among these agents, a huge number of natural products and FDA-approved drugs have been evaluated as potential therapeutics for SARS-CoV-2 using virtual screening and docking studies. However, the identification of the molecular targets involved in viral replication led to the development of rationally designed anti-SARS-CoV-2 agents. Among these targets, the main protease (Mpro) is one of the key enzymes needed in the replication of the virus. The data gleaned from the crystal structures of SARS-CoV-2 Mpro complexes with small molecule covalent inhibitors has been used in the design and discovery of many highly potent and broadspectrum Mpro inhibitors. The current review focuses mainly on the covalent type of SARS-CoV-2 Mpro inhibitors. The design, chemistry, and classification of these inhibitors were also in focus. The biological activity of
these inhibitors, including their inhibitory activities against Mpro, their antiviral activities, and the SAR studies,
were discussed. The review also describes the potential mechanism of the interaction between these inhibitors
and the catalytic Cys145 residue in Mpro. Moreover, the binding modes and key binding interactions of these
covalent inhibitors were also illustrated. The covalent inhibitors discussed in this review were of diverse
chemical nature and origin. Their antiviral activity was mediated mainly by the inhibition of SARS-CoV-2 Mpro,
with IC50 values in the micromolar to the nanomolar range. Many of these inhibitors exhibited broad-spectrum
inhibitory activity against the Mpro enzymes of other coronaviruses (SARS-CoV-1 and MERS-CoV). The dual
inhibition of the Mpro and PLpro enzymes of SARS-CoV-2 could also provide higher therapeutic benefits than
Mpro inhibition. Despite the approval of nirmatrelvir by the FDA, many mutations in the Mpro enzyme of SARSCoV-
2 have been reported. Although some of these mutations did not affect the potency of nirmatrelvir, there is
an urgent need to develop a second generation of Mpro inhibitors. We hope that the data summarized in this
review could help researchers in the design of a new potent generation of SARS-CoV-2 Mpro inhibitors

A novel group of indolyl‐1,2,4‐triazole‐chalcone hybrids was designed, synthesized,
and assessed for their anticancer activity. The synthesized compounds exhibited
significant antiproliferative activity. Compounds 9a and 9e exhibited significant
cancer inhibition with GI50 ranging from 3.69 to 20.40 μM and from 0.29 to
>100 μM, respectively. Both compounds displayed a broad spectrum of anticancer
activity with selectivity ratios ranging between 0.50–2.78 and 0.25–2.81 at the
GI50 level, respectively. The synthesized compounds were also screened for their
cytotoxicity by 3‐(4,5‐dimethylthiazole‐2‐yl)‐2,5‐diphenyltetrazol (MTT) assay and
for inhibition of epidermal growth factor receptor (EGFR) and c‐MET (mesenchymalepithelial
transition factor). Some of the tested compounds exhibited significant
inhibition against EGFR and/or c‐MET. Compound 9b showed the highest c‐MET
inhibition (IC50 = 4.70 nM) compared to foretinib (IC50 = 2.5 nM). Compound 9d
showed equipotent activity compared with erlotinib against EGFR (IC50 = 0.052 μM)
and displayed significant c‐MET inhibition with an IC50 value of 4.90 nM.

The current study focuses on developing a single molecule that acts as an antiproliferative agent with dual
or multi-targeted action, reducing drug resistance and adverse effects. A new series of
4-pyrazolylquinolin-2-ones (5a–j) with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors
were designed and synthesized. Compounds 5a–j were investigated for their cell viability effect against a
normal cell line (MCF-10A). Results showed that none of the compounds were cytotoxic, and all 5a–j
demonstrated more than 90% cell viability at 50 μM concentration. Using erlotinib as a reference, the MTT
assay investigated the antiproliferative impact of targets 5a–j against four human cancer cell lines.
Compounds 5e, 5f, 5h, 5i, and 5j were the most potent antiproliferative agents with GI50 values of 42, 26,
29, 34, and 37 nM, making compounds 5f and 5h more potent than erlotinib (GI50 = 33 nM). Moreover,
compounds 5e, 5f, 5h, 5i, and 5j were further investigated as dual EGFR/BRAFV600E inhibitors, and results
revealed that compounds 5f, 5h, and 5i are potent antiproliferative agents that act as dual EGFR/BRAFV600E
inhibitors. Cell cycle analysis and apoptosis detection revealed that compound 5h displaying cell cycle
arrest at the G1 transition could induce apoptosis with a high necrosis percentage. Docking studies revealed that compound 5f exhibited a strong affinity for EGFR and BRAFV600E, with high docking scores of −8.55 kcal mol−1 and −8.22 kcal mol−1, respectively. Furthermore, the ADME analysis of compounds 5a–j highlighted the diversity in their pharmacokinetic properties, emphasizing the importance of experimental validation.