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.
 

A new series of 1,3,4-thiadiazin-3-ium bromide derivatives 9a–g were prepared as a six-member ring by
interactions between 4-substituted thiosemicarbazides 8a–e and a-halo ketones 2a,b. The reaction was
conducted using hydrazine-NH2 and yielded a hexagonal shape. The structures of all obtained
compounds have been verified using IR, NMR spectra, mass spectrometry, elemental analysis, and X-ray
crystallography. The X-ray crystallographic analysis of compounds 9a and 9b has revealed that the salt is
formed with the nitrogen atom N3 when the aromatic substituents 9a and 9d are present, but in the
case of compounds 9b, 9c, 9e, 9f, and 9g with the aliphatic substituent, the salt is formed outside the
ring. Compounds 9a–g were evaluated for antiproliferative activity as multitargeted inhibitors. Results
revealed that targets 9a–g displayed good antiproliferative activity, with GI50 ranging from 38 nM to
66 nM against a panel of four cancer cell lines compared to the reference Erlotinib (GI50 = 33 nM).
Compounds 9a, 9c, and 9d were the most potent antiproliferative derivatives, with GI50 values of 43, 38,
and 47 nM, respectively. Compounds 9a, 9c, and 9d were evaluated for their inhibitory activity against
EGFR, BRAFV600E, and VEGFR-2. The in vitro experiments demonstrated that the compounds being
examined exhibit potent antiproliferative properties and have the potential to function as multitargeted
inhibitors. In addition, the western blotting investigation demonstrated the inhibitory effects of 9c on
EGFR, BRAFV600E, and VEGFR-2.

We developed and synthesized tetrahydropyrimidine derivatives as possible cytotoxic agents to inhibit EGFR and
VEGFR-2 in the present study. Our study completely assesses the cytotoxic efficiency of pyrimidine-based derivatives 4−15 against various cancer cell lines, revealing derivatives 12 and 15 for their remarkable activity with GI50 values of 37 and 35 nM, respectively, when compared to the reference erlotinib (33 nM). In vitro
enzyme assays showed that target compounds, particularly 12, 14, and 15, effectively inhibited EGFR and VEGFR-2. In vitro enzyme testing revealed that compound 15 was the most promising, with IC50 values of 84 and 3.50 nM for EGFR and VEGFR-2, respectively. Additionally, an in vitro assessment of the novel targets’ apoptotic potential revealed that both pro-apoptotic and antiapoptotic behaviors were promising, indicating that the apoptotic induction pathway is a strongly proposed action method for the newly developed targets. Finally, molecular docking experiments are elaborately discussed to corroborate the exact binding interactions of the most active hybrids 12 and 15 with the EGFR and VEGFR-2 active sites 

A series of 1,2,4-triazolo[1,5-a]pyrimidine-based derivatives were developed and prepared by reacting chalcones 8a−p with 3-phenyl-1,2,4-triazole-5-amine (5). The novel compounds were analyzed using several spectroscopic techniques, and their antimicrobial efficacies against six pathogens (Gram-negative,
Gram-positive, and fungi) were tested. Most of the tested compounds exhibited significant antimicrobial activity compared to ciprofloxacin and fluconazole. Four compounds (9d, 9n, 9o, and 9p) showed promising results. Their minimal inhibitory concentration (MIC) values were between 16 and 102 μM, similar to ciprofloxacin’s 10−90 μM values. MIC values against the tested fungal species were between 15.50 and 26.30 μM, higher than
fluconazole’s 11.50−17.50 μM values. Compounds 9n and 9o, in particular, showed excellent bactericidal activity. Compounds 9n and 9o, the most effective antibacterial agents, were further evaluated for their inhibitory effects on bacterial DNA gyrase and DHFR enzymes as possible molecular targets. The results indicated that 9n and 9o demonstrated a similar level of activity against DNA gyrase and DHFR when compared to the reference
drugs ciprofloxacin and trimethoprim. We conducted molecular docking to investigate the binding mechanism and evaluate the reactivity of the intriguing compounds. Compounds 9n and 9o demonstrated favorable binding interactions with the essential amino acids necessary for the inhibition of E. coli DNA gyrase and DHFR enzymes.