Designing Potent Anti-Cancer Agents: Synthesis and Molecular Docking Studies of Thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine Derivatives.

A new series of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was designed and synthesized using readily available starting materials, specifically, ß-enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC50 = 19.4 ± 0.22 and 14.5 ± 0.30 µM, respectively) compared with doxorubicin (IC50 = 40.0 ± 3.9 µM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research.

Nanoparticles of a Pyrazolo-Pyridazine Derivative as Potential EGFR and CDK-2 Inhibitors: Design, Structure Determination, Anticancer Evaluation and In Silico Studies.

The strategic planning of this study is based upon using the nanoformulation method to prepare nanoparticles 4-SLNs and 4-LPHNPs of the previously prepared 4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-amine (4) after confirming its structure with single crystal X-ray analysis. These nanoparticles exhibited promising cytotoxic activity against HepG-2, HCT-116 and MCF-7 cancer cell lines in comparison with the reference doxorubicin and the original derivative 4. Moreover, their inhibitory assessment against EGFR and CDK-2/cyclin A2 displayed improved and more favorable impact than the parent 4 and the references. Detection of their influence upon cancer biomarkers revealed upregulation of Bax, p53 and caspase-3 levels and downregulation of Bcl-2 levels. The docking simulation demonstrated that the presence of the pyrazolo[3,4-c]pyridazin-3-amine scaffold is amenable to enclosure and binding well within EGFR and CDK-2 receptors through different hydrophilic interactions. The pharmacokinetic and physicochemical properties of target 4 were also assessed with ADME investigation, and the outcome indicated good drug-like characteristics.

New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies.

The antibiotic resistance problems constitute a considerable threat to human health worldwide; thus, the discovery of new antimicrobial candidates to conquer this issue is an imperative requirement. From this view, new thiophenyl-pyrazolyl-thiazole hybrids 3-10 were synthesized and screened for their antibacterial efficiency versus Gram - and Gram + bacterial strains compared to the reference drug amoxicillin. It was noticed that the new hybrids displayed significant antibacterial efficacy versus Gram - bacteria, especially against Pseudomonas aeruginosa. Also, all the screened candidates demonstrated a noticeable antifungal effect against Candida albicans (MICs = 3.9-125 µg/mL) relative to fluconazole (MIC = 250 µg/mL). Moreover, the new hybrids were investigated for their antituberculosis potency against Mycobacterium tuberculosis (RCMB 010126). Derivatives 4c, 6b, 8b, 9b, and 10b demonstrated prominent antituberculosis efficiency (MICs = 0.12-1.95 µg/mL) compared with the reference drug isoniazid (MIC = 0.12 µg/mL). The latter derivatives were further assessed for their inhibitory potency versus M. tuberculosis DHFR enzyme. The compounds 4c, 6b and 10b presented a remarkable suppression effect with IC50 values of 4.21, 5.70, and 10.59 µM, respectively, compared to that of trimethoprim (IC50 = 6.23 µM). Furthermore, biodistribution profile using radiolabeling way revealed a perceived uptake of 131I-compound 6b into infection induced models. The docking study for the new hybrids 4c, 6b, 8b, 9b and 10b was performed to illustrate the various binding modes with Mtb DHFR enzyme. In silico ADMET studies for the most potent inhibitors 4c, 6b and 10b were also accomplished to predict their pharmacokinetic and physicochemical features.

New pyrazolopyridine and pyrazolothiazole-based compounds as anti-proliferative agents targeting c-Met kinase inhibition: design, synthesis, biological evaluation, and computational studies.

c-Met tyrosine kinase plays a key role in the oncogenic process. Inhibition of the c-Met has emerged as an attractive target for human cancer treatment. This work deals with the design and synthesis of a new set of derivatives bearing pyrazolo[3,4-b]pyridine, pyrazolo[3,4-b]thieno[3,2-e]pyridine, and pyrazolo[3,4-d]thiazole-5-thione scaffolds, 5a,b, 8a-f, and 10a,b, respectively, utilizing 3-methyl-1-tosyl-1H-pyrazol-5(4H)-one (1) as a key starting material. All the new compounds were evaluated as antiproliferative agents against HepG-2, MCF-7, and HCT-116 human cancer cell lines utilizing 5-fluorouracil and erlotinib as two standard drugs. Compounds 5a,b and 10a,b represented the most promising cytotoxic activity of IC50 values ranging from 3.42 ± 1.31 to 17.16 ± 0.37 µM. Both 5a and 5b showed the most cytotoxicity and selectivity toward HepG-2, with IC50 values of 3.42 ± 1.31 µM and 3.56 ± 1.5 µM, respectively. The enzyme assay demonstrated that 5a and 5b had inhibition potency on c-Met with IC50 values in nanomolar range of 4.27 ± 0.31 and 7.95 ± 0.17 nM, respectively in comparison with the reference drug cabozantinib (IC50; 5.38 ± 0.35 nM). The impact of 5a on the cell cycle and apoptosis induction potential in HepG-2 and on the apoptotic parameters; Bax, Bcl-2, p53, and caspase-3 was also investigated. Finally, the molecular docking simulation of the most promising derivatives 5a and 5b was screened against c-Met to investigate the binding patterns of both compounds in the active site of the c-Met enzyme. In silico ADME studies were also performed for 5a and 5b to predict their physicochemical and pharmacokinetic characteristics.

Design, Synthesis, Anticancer Activity and Molecular Docking of New 1,2,3-Triazole-Based Glycosides Bearing 1,3,4-Thiadiazolyl, Indolyl and Arylacetamide Scaffolds.

New 1,3,4-thiadiazole thioglycosides linked to a substituted arylidine system were synthesized via heterocyclization via click 1,3-dipolar cycloaddition. The click strategy was used for the synthesis of new 1,3,4-thiadiazole and 1,2,3-triazole hybrid glycoside-based indolyl systems as novel hybrid molecules by reacting azide derivatives with the corresponding acetylated glycosyl terminal acetylenes. The cytotoxic activities of the compounds were studied against HCT-116 (human colorectal carcinoma) and MCF-7 (human breast adenocarcinoma) cell lines using the MTT assay. The results showed that the key thiadiazolethione compounds, the triazole glycosides linked to p-methoxyarylidine derivatives and the free hydroxyl glycoside had potent activity comparable to the reference drug, doxorubicin, against MCF-7 human cancer cells. Docking simulation studies were performed to check the binding patterns of the synthesized compounds. Enzyme inhibition assay studies were also conducted for the epidermal growth factor receptor (EGFR), and the results explained the activity of a number of derivatives.

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation.

Toxicity and resistance to newly synthesized anticancer drugs represent a challenging phenomenon of intensified concern arising from variation in drug targets and consequently the prevalence of the latter concern requires further research. The current research reports the design, synthesis, and anticancer activity of new 1,2,3-triazole-coumarin-glycosyl hybrids and their 1,2,4-triazole thioglycosides as well as acyclic analogs. The cytotoxic activity of the synthesized products was studied against a panel of human cancer cell lines. Compounds 8, 10, 16 and 21 resulted in higher activities against different human cancer cells. The impact of the hybrid derivative 10 upon different apoptotic protein markers, including cytochrome c, Bcl-2, Bax, and caspase-7 along with its effect on the cell cycle was investigated. It revealed a mitochondria-apoptotic effect on MCF-7 cells and had the ability to upregulate pro-apoptotic Bax protein and downregulate anti-apoptotic Bcl-2 protein and thus implies the apoptotic fate of the cells. Furthermore, the inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases for 8, 10 and 21 were studied to detect the mechanism of their high potency. The coumarin-triazole-glycosyl hybrids 8 and 10 illustrated excellent broad inhibitory activity (IC50= 0.22 ± 0.01, 0.93 ± 0.42 and 0.24 ± 0.20 µM, respectively, for compound 8), (IC50 = 0.12 ± 0.50, 0.79 ± 0.14 and 0.15± 0. 60 µM, respectively, for compound 10), in comparison with the reference drugs, erlotinib, sorafenib and roscovitine (IC50 = 0.18 ± 0.05, 1.58 ± 0.11 and 0.46 ± 0.30 µM, respectively). In addition, the docking study was simulated to afford better rationalization and put insight into the binding affinity between the promising derivatives and their targeted enzymes and that might be used as an optimum lead for further modification in the anticancer field.

Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers.

A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 µM. The highest active derivatives (8a, 8 b, 8d, 9a, and 12b) were selected for IC50 screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFRWT and mutant EGFRT790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFRWT and EGFRT790M with IC50 values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFRWT and EGFRT790M.

New thiophene, thienopyridine and thiazoline-based derivatives: Design, synthesis and biological evaluation as antiproliferative agents and multitargeting kinase inhibitors.

Multitargeting kinase inhibitors recently proved to be a profitable approach for conquering cancer proliferation. The current study represents the design and synthesis of new thiophene, thienopyridine, and thiazoline-based derivatives 4-14a,b. All the target compounds were examined in vitro against three cancer cell lines; the liver (HepG-2), breast (MCF-7), and colon (HCT-116) where the thiophene-based compounds 5a-c, demonstrated the most potent activity. Furthermore, the latter derivatives revealed a safety profile against WI-38 normal cell line of selectivity indices ranging from 4.43 to 17.44. In vitro enzyme assay of 5a-c revealed that the carbohydrazide analog 5c has the most promising multitargeting inhibiting activity against Pim-1, VEGFR-2, and EGFRWT enzymes of IC50 values; 0.037 ± 0.02, 0.95 ± 0.24, and 0.16 ± 0.05 µM, respectively. As it was the most potent analog, 5c was further subjected to cell cycle and apoptosis analysis. The results indicated that it induced preG1 arrest and an apoptotic effect in the early and late stages. Moreover, further apoptosis studies were carried out for 5c to evaluate its proapoptotic potential. Interestingly, 5c enhanced the levels of Bax/Bcl-2 ratio, p53, and active caspase 3 by 18, 6.4, and 24 folds, respectively compared to the untreated cells. The antimicrobial evaluation showed that only compounds 3 and 5a produced broad-spectrum potency, while 5b and 5c exhibited outstanding antifungal effects. Finally, a molecular docking study was carried out to discover the probable interactions of compound 5c with the active sites of Pim-1, VEGFR-2, and EGFRWT kinases.

Design, synthesis, anti-inflammatory evaluation and molecular docking of novel thiophen-2-ylmethylene-based derivatives as potential TNF-α production inhibitors.

Inflammation is considered to be an alarming signal for the progress of varied biological complications. Based on the previous reports in the literature that proved the noticeable efficacy of thiophene scaffold as well as nitrogen heterocyclic based compounds against acute and chronic inflammatory disease, a new set of thiophen-2-ylmethylene-based derivatives incorporated with various nitrogenous heterocyclic rings was synthesized and evaluated for their in vivo anti-inflammatory efficiency via applying formalin-induced paw edema bioassay using celecoxib as a standard drug. Compounds 6 and 11a displayed fast onset as well as long duration of anti-inflammatory potency better than that of celecoxib. However, compounds 4a, 7a, 7b and 9b exhibited moderate anti-inflammatory efficiency compared with celecoxib. Ulcerogenic activity and histopathology studies were also carried out. Moreover, the analgesic evaluation of some bioactive candidates revealed that compound 6 showed a promising and long acting analgesic effect exceeding that of the reference drug. While, compounds 4a and 7a displayed mild analgesic activity. Furthermore, the inhibitory effects of some potent anti-inflammatory derivatives on the production of tumor necrosis factor-alpha (TNF-α) were tested. The obtained results revealed that compounds 6 and 11a displayed a remarkable inhibitory effect on the production of TNF-α greater than that of celecoxib. Otherwise, compounds 4a and 7a showed nearly the same inhibitory effect as celecoxib. Finally, the molecular docking study was performed for the tested derivatives 4a, 4b, 6, 7a, 9a and 11a to understand the binding interactions with the active site of TNF-α.

Novel 1,2,3-Triazole-Coumarin Hybrid Glycosides and Their Tetrazolyl Analogues: Design, Anticancer Evaluation and Molecular Docking Targeting EGFR, VEGFR-2 and CDK-2.

This study represents the design and synthesis of a new set of triazole-coumarin-glycosyl hybrids and their tetrazole hybrid analogues possessing various sugar moieties and modified analogues. All the newly synthesized derivatives were screened for their cytotoxic activities against a panel of human cancer cell lines. The coumarin derivatives 10, 13 and 15 derivatives revealed potent cytotoxic activities against Paca-2, Mel-501, PC-3 and A-375 cancer cell lines. These promising analogues were further examined for their inhibitory assessment against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases. The coumarin-tetrazole 10 displayed broad superior inhibitory activity against all screened enzymes compared with the reference drugs, erlotinib, sorafenib and roscovitine, respectively. The impact of coumarin-tetrazole 10 upon cell cycle and apoptosis induction was determined to detect its mechanism of action. Additionally, it upregulated the levels of casp-3, casp-7 and cytochrome-c proteins and downregulated the PD-1 level. Finally, molecular docking study was simulated to afford better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes, which could be used as an optimum lead for further modification in the anticancer field.

New Benzimidazole-, 1,2,4-Triazole-, and 1,3,5-Triazine-Based Derivatives as Potential EGFRWT and EGFRT790M Inhibitors: Microwave-Assisted Synthesis, Anticancer Evaluation, and Molecular Docking Study.

A new series of benzimidazole, 1,2,4-triazole, and 1,3,5-triazine derivatives were designed and synthesized using a microwave irradiation synthetic approach utilizing 2-phenylacetyl isothiocyanate (1) as a key starting material. All the new analogues were evaluated as anticancer agents against a panel of cancer cell lines utilizing doxorubicin as a standard drug. Most of the tested derivatives exhibited selective cytotoxic activity against MCF-7 and A-549 cancer cell lines. Furthermore, the new target compounds 5, 6, and 7 as the most potent antiproliferative agents have been assessed as in vitro EGFRWT and EGFRT790M inhibitors compared to the reference drugs erlotinib and AZD9291. They represented more potent suppression activity against the mutated EGFRT790M than the wild-type EGFRWT. Moreover, the compounds 5, 6, and 7 down-regulated the oncogenic parameter p53 ubiquitination. A docking simulation of compound 6b was carried out to correlate its molecular structure with its significant EGFR inhibition potency and its possible binding interactions within the active site of EGFRWT and the mutant EGFRT790M.

Synthesis, Antibacterial Evaluation, and Computational Studies of a Diverse Set of Linezolid Conjugates.

The development of new antibiotics to treat multidrug-resistant (MDR) bacteria or possess broad-spectrum activity is one of the challenging tasks. Unfortunately, there are not many new antibiotics in clinical trials. So, the molecular hybridization approach could be an effective strategy to develop potential drug candidates using the known scaffolds. We synthesized a total of 31 diverse linezolid conjugates 3, 5, 7, 9, 11, 13, and 15 using our established benzotriazole chemistry with good yield and purity. Some of the synthesized conjugates exhibited promising antibacterial properties against different strains of bacteria. Among all the synthesized compounds, 5d is the most promising antibacterial agent with MIC 4.5 µM against S. aureus and 2.25 µM against B. subtilis. Using our experimental data pool, we developed a robust QSAR (R2 = 0.926, 0.935; R2cvOO = 0.898, 0.915; R2cvMO = 0.903, 0.916 for the S. aureus and B. subtilis models, respectively) and 3D-pharmacophore models. We have also determined the drug-like properties of the synthesized conjugates using computational tools. Our findings provide valuable insight into the possible linezolid-based antibiotic drug candidates.

Antibacterial and anticancer profiling of new benzocaine derivatives: Design, synthesis, and molecular mechanism of action.

The need for new chemotherapeutics to overcome development of resistance merits research to discover new agents. Benzocaine derivatives are essential compounds in medicinal chemistry due to their various biological activities including antibacterial and anticancer activities. Therefore, this study focuses on the synthesis of new benzocaine derivatives 3a-e, 6, 7a and 7b, 8, 10-14, and 16a-d and their in vitro evaluation as antibacterial agents against gram +ve and -ve strains and as anticancer agents against HepG-2, HCT-116, and MCF-7 human cancer cell lines. The obtained results demonstrated that thiazolidines 6 and 7b showed higher antibacterial and anticancer activity in comparison with the reference drugs. In addition, 6 and 7b showed high potency as inhibitors toward their biological targets, that is DNA gyrase and human topoisomerase IIα, as compared to the reference standard drugs novobiocin and etoposide, respectively. Molecular docking demonstrated that both compounds could identify the active site of their target enzymes and develop effective binding interactions. Absorption, distribution, metabolism and elimination (ADME) and drug-likeness predictions of both compounds showed that they both have good ADME profiles and no structural alerts that might cause toxicity. Based on this, 6 and 7b could serve as lead compounds for the design of more potent antibacterial and anticancer agents.

Identification of Antibacterial Metabolites from Endophytic Fungus Aspergillus fumigatus, Isolated from Albizia lucidior Leaves (Fabaceae), Utilizing Metabolomic and Molecular Docking Techniques.

The rapid spread of bacterial infection caused by Staphylococcus aureus has become a problem to public health despite the presence of past trials devoted to controlling the infection. Thus, the current study aimed to explore the chemical composition of the extract of endophytic fungus Aspergillus fumigatus, isolated from Albizia lucidior leaves, and investigate the antimicrobial activity of isolated metabolites and their probable mode of actions. The chemical investigation of the fungal extract via UPLC/MS/MS led to the identification of at least forty-two metabolites, as well as the isolation and complete characterization of eight reported metabolites. The antibacterial activities of isolated metabolites were assessed against S. aureus using agar disc diffusion and microplate dilution methods. Compounds ergosterol, helvolic acid and monomethyl sulochrin-4-sulphate showed minimal inhibitory concentration (MIC) values of 15.63, 1.95 and 3.90 µg/mL, respectively, compared to ciprofloxacin. We also report the inhibitory activity of the fungal extract on DNA gyrase and topoisomerase IV, which led us to perform molecular docking using the three most active compounds isolated from the extract against both enzymes. These active compounds had the required structural features for S. aureus DNA gyrase and topoisomerase IV inhibition, evidenced via molecular docking.

Synthesis, anticancer evaluation and molecular docking of new benzothiazole scaffolds targeting FGFR-1.

This work deals with the design and synthesis of a series of new substituted 2-arylbenzothiazole compounds attached to 4-oxothiazolidin-2-ylidene ring 2-12 and chain elongation with different amino acids and their corresponding ester derivatives 13-18. All prepared derivatives were screened for their in vitro cytotoxicity activities against two cancer cell lines (HepG-2 and MCF-7) in comparison with doxorubicin; in addition to their safety towards thenormal cell line. Furthermore, all compounds 2-18 were evaluated as FGFR-1 inhibitors using AZD4547 as a reference. The 4-oxothiazolidin-2-ylidene derivatives 3 and 8 exhibited the highest cytotoxic activity (IC50 HepG-2 = 2.06, 2.21 µM and IC50 MCF-7 = 0.73, 0.77 µM, respectively) through their promising FGFR-1 suppression effects (IC50 = 16.31 and 18.08 nM, respectively) in comparison to AZD4547 (IC50 = 21.45 nM). Cell cycle and apoptosis analysis indicated that compounds 3 and 8 induce pronounced increase in the cell percentages at pre-G1 and G2/M phase compared to the untreated MCF-7 cancer cells, in addition to their up regulation of caspase-3/7/9. The molecular docking simulation was created to elucidate the binding modes of benzothiazole derivatives 1-18 bearing various scaffolds within the ATP-binding pocket of FGFR-1 enzyme compared with AZD4547.

Synthesis, anticancer activity and molecular docking of new triazolo[4,5-d]pyrimidines based thienopyrimidine system and their derived N-glycosides and thioglycosides.

A series of new substituted triazolo[4,5-d]pyrimidine derivatives linked to thienopyrimidine ring system were prepared as a hybrid heterocyclic systems, as possible nucleobases analogs, starting from the key carboxamide derivative 2 and its azide precursor via heterocyclization reactions and their structures were characterized. Glycosylation of the prepared triazolopyrimidine derivatives was performed and afforded, regioselctively, the corresponding thienopyrimidine-triazolopyrimidine hybrid N1-glycosides and their thioglycoside analogues in good yields. The synthesized glycosyl heterocycles were studied for their cytotoxic activity against HepG-2 and MCF-7 human cancer cells and significant results were obtained. Compounds 7a, 8 b, 9 b, 9a and 7 b demonstrated promising activities comparable to the activity of the doxorubicin for (HepG-2) cell line. Furthermore, a number of the afforded triazolopyrimidine glycosides were found potent against cancer cells (MCF-7). Furthermore, docking simulation the promising thienopyrimidine analogues 7-13 was done against EGFR kinase to provide a binding model that could serve in discovery of further anticancer agents.

Synthesis, Characterization, In Vitro Anticancer Potentiality, and Antimicrobial Activities of Novel Peptide-Glycyrrhetinic-Acid-Based Derivatives.

Glycyrrhetinic acid (GA) is one of many interesting pentacyclic triterpenoids showing significant anticancer activity by triggering apoptosis in tumor cell lines. This study deals with the design and synthesis of new glycyrrhetinic acid (GA)-amino acid peptides and peptide ester derivatives. The structures of the new derivatives were established through various spectral and microanalytical data. The novel compounds were screened for their in vitro cytotoxic activity. The evaluation results showed that the new peptides produced promising cytotoxic activity against the human breast MCF-7 cancer cell line while comparing to doxorubicin. On the other hand, only compounds 3, 5, and 7 produced potent activity against human colon HCT-116 cancer cell line. The human liver cancer (HepG-2) cell line represented a higher sensitivity to peptide 7 (IC50; 3.30 µg/mL), while it appeared insensitive to the rest of the tested peptides. Furthermore, compounds 1, 3, and 5 exhibited a promising safety profile against human normal skin fibroblasts cell line BJ-1. In order to investigate the mode of action, compound 5 was selected as a representative example to study its in vitro effect against the apoptotic parameters and Bax/BCL-2/p53/caspase-7/caspase-3/tubulin, and DNA fragmentation to investigate beta (TUBb). Additionally, all the new analogues were subjected to antimicrobial assay against a panel of Gram-positive and Gram-negative bacteria and the yeast candida Albicans. All the tested GA analogues 1-8 exhibited more antibacterial effect against Micrococcus Luteus than gentamicin, but they exhibited moderate antimicrobial activity against the tested bacterial and yeast strains. Molecular docking studies were also simulated for compound 5 to give better rationalization and put insight to the features of its structure.

New quinoline-triazole conjugates: Synthesis, and antiviral properties against SARS-CoV-2.

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)-1H-1,2,3-triazol-4-yl)methoxy)-6-fluoro-2-(trifluoromethyl)quinoline (10g) and 6-fluoro-4-(2-(1-(4-methoxyphenyl)-1H-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.

New pyrimidine and pyrazole-based compounds as potential EGFR inhibitors: Synthesis, anticancer, antimicrobial evaluation and computational studies.

This study was focused on the synthesis of new pyrimidines 4a,b, 5a,b and pyrazoles 6a, b as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). The new compounds were assessed as cytotoxic candidates against human breast cancer cells (MCF-7) and hepatocellular carcinoma cells (HepG-2). All the new compounds appeared as more potent cytotoxic agents than erlotinib, while only compound 4a exhibited more potency than 5-flourouracil and 4b analogue was equipotent to it. Accordingly, the kinase suppression effect of 4a and 4b was further evaluated against EGFRWT, EGFRL858R and EGFRT790M. Both pyrimidine analogues 4a and 4b displayed outstanding inhibitory activity against EGFRWT and its two mutated isoforms EGFRL858R and EGFRT790M in comparing to erlotinib and osimertinib as reference drugs. Additionally, all the new analogues were subjected to antimicrobial assay. Interestingly, both 4a and 4b represented the most promising activity of wide spectrum antimicrobial effect against the examined microbes in comparison to gentamycin and ketoconazole as standard drugs. Moreover, docking results proved the good binding interactions of the compounds 4a and 4b with EGFRWT and EGFRT790M which were in accordance with the results of the in vitro enzyme assay. Additional in silico ADMET studies were performed for the new derivatives which represented their good oral absorption, good drug-likeness properties and low toxicity risks in human.

Design, Synthesis, Anticancer Evaluation, Enzymatic Assays, and a Molecular Modeling Study of Novel Pyrazole-Indole Hybrids.

The molecular hybridization concept has recently emerged as a powerful approach in drug discovery. A series of novel indole derivatives linked to the pyrazole moiety were designed and developed via a molecular hybridization protocol as antitumor agents. The target compounds (5a-j and 7a-e) were prepared by the reaction of 5-aminopyrazoles (1a-e) with N-substituted isatin (4a,b) and 1H-indole-3-carbaldehyde (6), respectively. All products were characterized via several analytical and spectroscopic techniques. Compounds (5a-j and 7a-e) were screened for their cytotoxicity activities in vitro against four human cancer types [human colorectal carcinoma (HCT-116), human breast adenocarcinoma (MCF-7), human liver carcinoma (HepG2), and human lung carcinoma (A549)] using the MTT assay. The obtained results showed that the newly synthesized compounds displayed good-to-excellent antitumor activity. For example, 5-((1H-indol-3-yl)methyleneamino)-N-phenyl-3-(phenylamino)-1H-pyrazole-4-carboxamide (7a) and 5-((1H-indol-3-yl)methyleneamino)-3-(phenylamino)-N-(4-methylphenyl)-1H-pyrazole-4-carboxamide (7b) provided excellent anticancer inhibition performance against the HepG2 cancer cell line with IC50 values of 6.1 ± 1.9 and 7.9 ± 1.9 µM, respectively, compared to the standard reference drug, doxorubicin (IC50 = 24.7 ± 3.2 µM). The two powerful anticancer compounds (7a and 7b) were further subjected to cell cycle analysis and apoptosis investigation in HepG2 using flow cytometry. We have also studied the enzymatic assay of these two compounds against some enzymes, namely, caspase-3, Bcl-2, Bax, and CDK-2. Interestingly, the molecular docking study revealed that compounds 7a and 7b could well embed in the active pocket of the CDK-2 enzyme via different interactions. Overall, the prepared pyrazole-indole hybrids (7a and 7b) can be proposed as strong anticancer candidate drugs against various cancer cell lines.