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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel series of ethylidenehydrazineylthiazol-4(5 H)-ones were generated using eco-friendly one-pot multicomponent synthetic techniques. • The anticancer potentials towards eleven cancer cell lines were evaluated. • The IC 50 values against MDA-MB-468 and FaDu cell lines were recorded. • 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M. • The cell cycle analysis, proapoptotic markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9), and the anti-apoptotic key marker (BCL-2) were measured for 4k. A novel series of ethylidenehydrazineylthiazol-4(5 H)-ones were synthesized using various eco-friendly one-pot multicomponent synthetic techniques. The anticancer activity of compounds (4a-m) was tested against 11 cancer cell lines. While the IC 50 of all compounds was evaluated against the most sensitive cell lines (MDA-MB-468 and FaDu). Our SAR study pinpointed that compound 4a , having a phenyl substituent, exhibited a significant growth inhibition % against all cancer cell lines. The frontier anticancer candidates against the MDA-MB-468 were also examined against the wild EGFR (EGFR-WT) and mutant EGFR (EGFR-T790M) receptors. Most of the synthesized compounds exhibited a higher inhibitory potential against EGFR-T790M than the wild type of EGFR. Remarkably, compound 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M with IC 50 values (0.051 and 0.021 µM), respectively. The pro-apoptotic protein markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9) and the anti-apoptotic key marker (BCL-2) were also measured to propose a mechanism of action for the compound 4k as an apoptotic inducer for MDA-MB-468. Investigation of the cell cycle arrest potential of compound 4k was also conducted on MDA-MB-468 cancer cells. We also evaluated the inhibitory activities of compounds (4a-m) against both EGFR-WT and EGFR-T790M using two different molecular docking processes. [ABSTRACT FROM AUTHOR]

Herein, a rapid and highly efficient method for the synthesis of a new series of pyrimidine derivatives was demonstrated. The strategy was emanated from the reaction of hydrazinyl pyrimidine derivative (1) with different electrophilic species such as ethyl acetoacetate, ethyl 4,4,4‐trifluoro acetoacetate, and phenyl isothiocyanate following cyclocondensation mechanism to afford the corresponding derivatives (2‐6). Furthermore, condensation of hydrazine derivative (1) with different carbonyl compounds via conventional heating and microwave irradiation conditions was employed as a source of Schiff base derivatives bearing pyrimidine moiety (7‐12). The structural features of all newly synthesized compounds were characterized by elemental and spectroscopic evidences. Some of the synthesized compounds were evaluated for in vitro cytotoxicity. The preliminary screening results showed that most of the tested compounds have moderate cytotoxic activity against HepG2 and HCT‐116 cell lines. Finally, a molecular docking study was conducted to reveal the probable interaction with the thymidylate synthase enzyme. [ABSTRACT FROM AUTHOR]

• Eighteen quinoxaline derivatives were designed and synthesized. • Cytotoxic activities were evaluated against HCT-116, HepG-2, MCF-7, and WI-38 cell lines. • In vitro Topo II inhibitory activities and DNA intercalating affinities were evaluated. • The effect on apoptosis, cell cycle, caspase-3 and caspase-9 was studied. • Molecular docking studies were carried out against DNA-Topo II complex. As an extension for our earlier effort in the field of discovery of anticancer agents acting on DNA and Topo II, eighteen quinoxaline derivatives were designed and synthesized. Such members were designed to possess the main essential pharmacophoric features of DNA intercalators. The cytotoxic potential of the synthesized compounds was assessed against a group of human cancer cell lines (HCT-116, HepG2, and MCF-7). Doxorubicin as potential intercalative Topo II inhibitor, was used as a positive reference. In general, compounds 12 , 15 , 19 , 21 , and 22 showed promising anti-proliferative activities against the three cell lines with IC 50 values ranging from 2.81 to 10.23 µM. The cytotoxicities of the most active compounds against normal human cells (WI-38) were evaluated, and the results revealed that these compounds have low toxicity. Further examination for the most active anti-proliferative members as Topo II inhibitors was also performed, showing a narrow range of the inhibitory activities (from 0.45 to 1.06 µM). In addition, DNA/methyl green assay was carried out to evaluate DNA-binding potential of such compounds. The results indicated that these compounds have strong to moderate DNA-binding affinities ranging from 33.48 to 51.23 µM. Further studies exhibited the capability of compound 22 to induce apoptosis in HepG2 cells and can arrest growth of such cells at G2/M phase. Also, compound 22 produced a significant increase in the level of caspase- 3 (10 folds) and caspase-9 (7 folds) compared to the control cells. Molecular docking studies were also conducted to investigate possible binding interactions between the target compounds and the DNA-Topo II complex. [ABSTRACT FROM AUTHOR]

A new series of 6-aryl-5-cyano thiouracil derivatives were synthesized. Cyanouracil1was condensed with monochloroacetic acid and different aldehydes to give thiazolopyrimidine2. On the other hand, treatment of cyanouracil1with 2-chloro-N-substituted-phenylac etamide afforded4. Hydrazinolysis of6afforded the hydrazino derivatives7which upon reaction with different electrophilic reagents such as acetic anhydride, benzoyl chloride, and carbon disulfide yielded pyrimidine derivatives8–15. Some of the new derivatives were explored for their antimicrobial activities. Compounds7and9have a promising activity, relatively equipotent to the reference drug. All of the new synthesized compounds were testedin vitrofor their antiproliferative activities against HePG-2 and MCF-7 cell lines. Compounds7,9, and2ddisplayed potent growth inhibitory effect toward the two cell lines more than the standard drug 5-FU. Furthermore, a docking study of the most active compounds was performed with thymidylate synthase enzyme. [ABSTRACT FROM AUTHOR]