Search

• A new series of dispiro-oxindoles have been designed as anti-breast cancer agents with dual VEGFR-2 and cholinesterase inhibition activities. • Derivative 12 was the most potent on MCF-7 cells superior to tamoxifen and has a prominent effect on the suppression of VEGFR-2 kinase expression. • Analogs 18 and 21 exhibited dual VEGFR-2 and cholinesterase inhibitory properties. • The possible applicability of the mutual most potent candidates is supported by the promising safety profiles on normal VERO cells. • Molecular docking study was introduced to highlight the interactions of the promising candidates with the amino acids of VEGFR2, AChE and BChE. Oxindole-based compounds are deemed to be an interesting scaffold with significant VEGFR-2 and cholinesterase inhibitory properties. Regarding the studies that displayed the adverse effect of cancer chemotherapy on cognitive function which can be long-lasting and negatively affect the quality of life, a series of dispiropyrrolodinyl-oxindoles 4‒27 have been designed and synthesized through a classical 1,3-dipolar cycloaddition reaction. Derivatives 9‒12, 18 and 21 were the best among the tested series that disclosed auspicious mutual inhibitory properties against breast cancer and VEGFR-2 kinase. Whereas compound 12 displayed superior activity than that of the reference drug, tamoxifen. PI-flow cytometry of compound 12 supported the cessation of the cell cycle at the G1/S phase and can be considered as an apoptotic inducer via activation of caspase-3. Moreover, the new chemical entities 17, 18, 21 and 22 exhibited dual-targeted cholinesterase inhibitory properties against AChE and BChE. comparable with donepezil. The possible applicability of the mutual most potent candidates 9‒13, 17, 18, 21 and 22 were supported by the promising safety profiles on normal (non-cancer, VERO) cells. Analogs 18 and 21 exhibited dual VEGFR-2 and cholinesterase inhibitory properties, which can be used as lead compounds for the discovery of prominent dual anti-breast cancer agents and cholinesterase inhibitors. Molecular docking studies of the most promising derivatives within the active sites of VEGFR-2, AChE and BChE enzymes were carried out to confirm the improvement of the binding features through the substituent variation at p-3 and p-4′ of dispiropyrrolodinyl-oxindole as well as the chain length of an alkyl group at indolyl N -1. [Display omitted] [ABSTRACT FROM AUTHOR]

• A variety of tri-substituted pyrazole derivatives 3 - 15 were synthesized and evaluated for their anti-inflammatory, analgesic, antipyretic and ulcerogenic properties. • Some of the tested conjugates showed promising biological observations comparable to standard reference celecoxib, in addition, to their safety margin for gastric mucosa when evaluated for their ulcer-producing activity. • The most potent derivatives 3a, 3b, 6, 8 and 11 were assayed for their COX-2, TNF-α, PGE2 and IL1β levels in rat paws using the carrageenan inflammation model with the ELISA kit. • Compound 8 possesses the best promising anti-inflammatory observations, antipyretic effect and long-lasting analgesic activity without ulcerogenic potential in addition to showing mutual inhibitory effects on all tested enzymes. • A molecular docking study was introduced to recognize the binding interactions of the most potent candidates into active sites of COX-2 and TNF-α. • Compound 8 has the best binding interaction scores with both targeted enzymes that supported its obtained bio-observations and proves that it has the potential to be developed into an anti-inflammatory drug. Starting from the precursors 3-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (1) and 3-(4-bromophenyl)-1-ethyl-1 H -pyrazole-4-carbaldehyde (2), a variety of trisubstituted pyrazole derivatives 3 - 15 were synthesized and evaluated for their anti-inflammatory, analgesic, antipyretic and ulcerogenic properties. Derivatives 3a, 3b, 6, 8 and 11 showed promising anti-inflammatory observations with potencies of 99.5, 100.3, 92.4, 77.1 and 103.1, respectively, compared with celecoxib the used standard reference, they also exhibited a promising onset action of analgesic with efficiency superior to the used reference drug, in addition to their antipyretic effect and safety margin for gastric mucosa compared with the reference drugs. Based on the obtained observations, derivatives 3a, 3b, 6, 8 and 11 were assayed for their COX-2, TNF- α , PGE2 and IL1 β levels in rat paws using the carrageenan inflammation model with the ELISA kit. Compound 8 has the best promising anti-inflammatory observations, antipyretic effect and long-lasting analgesic activity without ulcerogenic potential in addition to showing mutual inhibitory effects on all tested enzymes. Furthermore, a molecular docking study was introduced to recognize the binding interactions of the most potent candidates 3a, 3b, 6, 8 and 11 into the active sites of COX-2 and TNF- α. Compound 8 has the best binding interaction scores with both targeted enzymes that supported its obtained bio-observations and prove that it has the potential to be developed into an anti-inflammatory drug. [Display omitted] [ABSTRACT FROM AUTHOR]

Series of salicylate-curcumin mimics were synthesized of potential antiproliferative (against A431 and HCT116 cell lines) and anti-SARS-CoV-2 properties. [Display omitted] • Salicylate-curcumin mimics were prepared in a facile pathway. • They reveal promising properties against A431 and HCT116 cell lines. • They are multi-targeted inhibitors against VEGFR-2 and EGFR. • Docking studies support the EGFR inhibitory properties. • Some of them are anti-SARS-CoV-2 with high SI. Series of piperidone-salicylate conjugates were synthesized through the reaction of 3 E ,5 E -bis(arylidene)-4-piperidones with the appropriate acid chloride of acetylsalicylate in the presence of triethylamine. All the synthesized conjugates reveal antiproliferative properties against A431 (squamous skin) cancer cell line with potency higher than that of 5-fluorouracil. Many of the synthesized agents also exhibit promising antiproliferative properties against HCT116 (colon) cancer cell line, of which 5o and 5c are the most effective with 12.9, 9.8 folds potency compared with Sunitinib. Promising activity is also shown against MCF7 (breast) cancer cell line with 1.19, 1.12 folds relative to 5-fluorouracil. PI-flow cytometry of compound 5c supports the arrest of cell cycle at G1-phase. However, compound 5o and Sunitinib arrest the cell cycle at S-phase. The synthesized conjugates can be considered as multi-targeted tyrosine kinase inhibitors due to the promising properties against VEGFR-2 and EGFR in MCF7 and HCT116. CDOCKER studies support the EGFR inhibitory properties. Compounds 5p and 5i possessing thienylidene heterocycle are anti-SARS-CoV-2 with high therapeutic indices. Many of the synthesized agents show enhanced COX-1/2 properties than aspirin with better selectivity index towards COX-2 relative to COX-1. The possible applicability of the potent candidates discovered as antitumor and anti-SARS-CoV-2 is supported by the safe profile against normal (non-cancer, RPE1 and VERO-E6) cells. [ABSTRACT FROM AUTHOR]

New functionalized thiazol-benzimidazole derivatives were designed, synthesized and evaluated for their in vitro EGFR inhibiting activities. In vitro anti-breast cancer activity of the promising derivatives was also evaluated. The pro-apoptotic activity of the analogue 4a was evaluated against caspase-3, p53, Bax/Bcl-2 expression levels, cell cycle analysis as well as PARP-1 inhibition. QSAR analysis and molecular modelling studies were carried out representing the binding modes of the promising compounds in the active pocket of EGFR. • New thiazol-benzimidazole derivatives 4a-q have been synthesized. • Utilizing EGFR as a putative target, the new compounds 4a-q were evaluated in vitro as EGFR inhibitors. • The promising compounds (4a, 4b, 4d, 4f, 4h, 4i, 4j, 4m, 4n) were examined as anticancer agents against MCF-7 cancer cells. • Compound 4a was selected to study its effect on cell cycle and apoptosis induction as well as its pro-apoptotic activity against caspase-3, p53, Bax/Bcl-2 and PARP-1 expression levels. • QSAR and molecular modelling of 4a , 4d , 4h , 4i and 4n were also performed to elucidate their binding modes with amino acid residues of EGFR. Heterocyclic rings such as thiazole and benzimidazole are considered as privileged structures, since they constitute several FDA-approved drugs for cancer treatment. In this work, a new set of 2-(2-(substituted) hydrazinyl)-4-(1-methyl-1 H -benzo d imidazol-2-yl) thiazoles 4a-q were designed as epidermal growth factor receptor (EGFR) inhibitors and synthesized using concise synthetic methods. The new target compounds have been evaluated in vitro for their suppression activity against EGFR TK. Compounds 4n , 4h , 4i, 4a and 4d exhibited significant potency in comparison with erlotinib which served as a reference drug (IC50, 71.67–152.59 nM; IC50 erlotinib, 152.59 nM). Furthermore, MTT assay revealed that compounds 4j , 4a, 4f, 4h, 4n produced the most promising cytotoxic potency against the human breast cancer cell line (MCF-7) (IC50; 5.96–11.91 µM; IC50 erlotinib; 4.15 µM). Compound 4a showed promising activity as EGFR TK inhibitor as well as anti-breast cancer agent. In addition, 4a induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Moreover, 4a upregulated the oncogenic parameters; caspase-3, p53, Bax/Bcl-2 as well as it inhibited the level of PARP-1 enzyme. QSAR study was carried out for the new derivatives and it revealed the goodness of the models. Furthermore, molecular docking studies represented the binding modes of the promising compounds in the active pocket of EGFR. [ABSTRACT FROM AUTHOR]

A series of quinolone-triazole conjugates synthesized as potential antiviral agents for SARS-CoV2. Some of the conjugates are more potent than the standards. [Display omitted] • A set of quinolone-triazole conjugates was designed and synthesized. • Some conjugates show promising antiviral properties against SARS-CoV2. • The selectivity index (SI) of the synthesized potent conjugates better than the reference drugs. • Potential conjugates could be further explored for the development of potential antiviral drug candidates. At present therapeutic options for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are very limited. We designed and synthesized three sets of small molecules using quinoline scaffolds. A series of quinoline conjugates (10a-l, 11a-c, and 12a-e) by incorporating 1,2,3-triazole were synthesized via a modified microwave-assisted click chemistry technique. Among the synthesized conjugates, 4-((1-(2-chlorophenyl)-1 H -1,2,3-triazol-4-yl)methoxy)-6-fluoro-2-(trifluoromethyl)quinoline (10g) and 6-fluoro-4-(2-(1-(4-methoxyphenyl)-1 H -1,2,3-triazol-4-yl)ethoxy)-2-(trifluoromethyl)quinoline (12c) show high potency against SARS-CoV-2. The selectivity index (SI) of compounds 10g and 12c also indicates the significant efficacy compared to the reference drugs. [ABSTRACT FROM AUTHOR]