In this article, we continued our previous effort to develop new selective anticancer candidates based on the basic pharmacophoric requirements of both EGFR and VEGFR-2 inhibitors. Therefore, twenty-two novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives were designed and examined as dual EGFR/VEGFR-2 inhibitors. Besides, the previously reported antimicrobial activities of the aforementioned nuclei motivated us to screen their antibacterial and antifungal activities as well. First, the antitumor activities of the newly synthesized derivatives were evaluated against two cancer cell lines (HepG-2 and MCF-7). Notably, compounds 2a, 6a, 7a, 10b, 15a, and 18a exhibited superior anticancer activities against both HepG-2 and MCF-7 cancer cell lines. These candidates were selected to further evaluate their anti-EGFR and anti-VEGFR-2 potentialities which were found to be very promising compared to erlotinib and sorafenib, respectively. Both 10b and 2a derivatives achieved better dual EGFR/VEGFR-2 inhibition with IC₅₀ values of 0.161 and 0.141 μM and 0.209 and 0.195 μM, respectively. Moreover, the most active 10b was selected to evaluate the exact phase of cell cycle arrest and to investigate the exact mechanism of cancer cell death whether it be due to apoptosis or necrosis. On the other hand, all the synthesized compounds were tested against Gram-positive bacteria such as S. aureus and B. subtilis as well as Gram-negative bacteria such as E. coli and P. aeuroginosa. Also, the antifungal activity was investigated against C. albicans and A. flavus strains. The findings of the antimicrobial tests revealed that most of the investigated compounds exhibited strong to moderate antibacterial and antifungal effects. Furthermore, to understand the pattern by which the investigated compounds bound to the active site, all the newly synthesized candidates were subjected to two different docking processes into the EGFR and VEGFR-2 binding sites. Besides, we tried to correlate compound 10b and the reference drugs (erlotinib and sorafenib) through DFT calculations. Finally, following the biological data of the new pyrazole, pyridine, and pyrimidine derivatives as anticancer and antimicrobial candidates, we concluded a very interesting SAR for further optimization.

The exponential development of resistance to conventional chemical insecticides adds another important motive for the creation of novel insecticidal active agents. One of the keys to meeting this challenge is the exploration of novel classes of insecticidal molecules with different modes of action. Herein, a novel series of spiro pyrimidine derivatives was prepared using some green synthetic methodologies such as microwave irradiation, and sonication under ultrasound waves. Spiro pyrimidine aminonitrile 1 is a key starting material for the synthesis of targets 2–9 by reaction with different carbon electrophiles and nitrogen nucleophiles. The structures of all the newly synthesized compounds were approved using spectral data. The toxicological efficiency and biological impacts of the synthesized spiro pyrimidine derivatives were assessed against Culex pipiens L. larvae. The toxicity of synthesized compounds showed remarkable variations against the C. pipiens larvae. Where, 3, 4 and 2 were the most efficient compounds with LC₅₀ values of 12.43, 16.29 and 21.73 µg/mL, respectively. While 1 was the least potent compound with an LC₅₀ value of 95.18 µg/mL. As well, other compounds were arranged according to LC₅₀ values as follows 5 > 7 > 6 > 9 > 8. In addition, 3 and 4 exhibited significant prolongation of the developmental duration and greatly inhibited adult emergence. Moreover, many morphological deformities were observed in all developmental stages. Furthermore, cytotoxicity of the most effective compounds was assessed against the normal human cells (WI-38) as non-target organisms, where compounds 2, 4 and 3 showed weak to non-toxic effects. The study of binding affinity and correlation between chemical structure and reactivity was carried out using molecular docking study and DFT calculations to investigate their mode of action. This study shed light on promising compounds with larvicidal activity and biological impacts on the C. pipiens life cycle.

A new series of pyrazole–thiophene hybrid derivatives was rationally designed, synthesized, and biologically evaluated for anticancer potential. Cytotoxicity screening toward MCF-7 and HepG2 cell lines identified 2 as the most potent analogue (IC₅₀ = 6.57 μM, MCF-7; 8.86 μM, HepG2), with activity comparable to the reference drugs doxorubicin, erlotinib, and sorafenib. Selectivity toward MCF-7 was observed for 8 (IC₅₀ = 8.08 μM), while 14 displayed moderate dual activity (IC₅₀ = 12.94 μM, MCF-7; 19.59 μM, HepG2). Enzyme inhibition assays revealed that 2 effectively suppressed wild-type EGFR (IC₅₀ = 16.25 μg mL⁻¹) and the clinically relevant T790M mutant (17.8 μg mL⁻¹), whereas 14 showed balanced dual inhibition (16.33 and 16.6 μg mL⁻¹, respectively). Notably, 8 emerged as the most active VEGFR-2 inhibitor (35.85 μg mL⁻¹), significantly outperforming 14 (112.36 μg mL⁻¹) and 2 (242.94 μg mL⁻¹). Mechanistic studies demonstrated that 14 brought MCF-7 cells in the G0/G1 phase to cell-cycle arrest (74.16% vs. 55.31% in control), increased the apoptotic population to 26.32%, and caused minimal necrosis (4.2%). Molecular docking supported these findings, revealing strong binding affinities and favorable interactions of 2, 14, and 8 with EGFR (wild-type and T790M mutant) and VEGFR-2, respectively. Taken together, these results highlight 2, 8, and 14 as promising pyrazole–thiophene multitargeted anticancer leads, offering potential for further optimization to overcome kinase-driven resistance in cancer therapy.

Twelve spiro thiazolidinone compounds (A–L) were synthesized via either conventional thermal or ultrasonication techniques using Fe₂O₃ nanoparticles. The modification of the traditional procedure by using Fe₂O₃ nanoparticles led to enhancement of the yield of the desired candidates to 78–93% in approximately half reaction time compared with 58–79% without catalyst. The products were fully characterized using different analytical and spectroscopic techniques. The structure of the two derivatives 4-phenyl-1-thia-4-azaspirodecan-3-one (A) and 4-(p-tolyl)-1-thia-4-azaspirodecan-3-one (B) were also determined using single crystal X-ray diffraction and Hirshfeld surface analysis. The two compounds (A and B) were crystallized in the orthorhombic system with Pbca and P2₁2₁2₁ space groups, respectively. In addition, the crystal packing of compounds revealed the formation of supramolecular array with a net of intermolecular hydrogen bonding interactions. The energy optimized geometries of some selected derivatives were performed by density functional theory (DFT/B3LYP). The reactivity descriptors were also calculated and correlated with their biological properties. All the reported compounds were screened for antimicrobial inhibitions. The two derivatives, F and J, exhibited the highest levels of bacterial inhibition with an inhibition zone of 10–17 mm. Also, the two derivatives, F and J, displayed the most potent fungal inhibition with an inhibition zone of 15–23 mm. Molecular docking investigations of some selected derivatives were performed using a B-DNA (PDB: 1BNA) as a macromolecular target. Structure and activity relationship of the reported compounds were correlated with the data of antimicrobial activities and the computed reactivity parameters.

This research theoretically modeled the binding interaction of the Sars-Cov-2 (Spike protein) utilizing molecular docking with some potential repurposed antiviral medications and two botanical products (Curcumin and Quercetin). Molecular docking between the drugs and the Sars-Cov-2 proteins reflecting the pure electrostatic forces and H-bond formation is complemented with the DFT results that shed light on the electronic nature of the interactions. Moreover, DFT computations provide invaluable information about the drug reactivity indices calculated from the energies of the frontier orbitals. The DFT results indicate intermolecular electron donor-acceptor interaction besides the H-bond formation. Most of the considered medication molecules act as electron-sink candidates except EIDD-2801 (molnupiravir), the electron donor. The theoretical results show the high possibility of blocking the human cellular entry against Sare-Cov-2 via strong interaction of the drugs with its peptide sequence (β₆) measured by the high binding energy of docking or weakening its activity due to the electronic donor-acceptor interactions indicated by reactivity indices computed from the frontier molecular orbitals.