Design, synthesis, and anticancer evaluation of N-sulfonylpiperidines as potential VEGFR-2 inhibitors, apoptotic inducers.

A new panel of N-sulfonylpiperidine derivatives has been designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Anti-proliferative activities of the synthesized members were tested against colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), and breast cancer (MCF-7) cell lines. Compounds 3a, 4, 8, and 9 showed the highest activities against the tested cell lines. In particular, compound 8 showed excellent activities against HCT-116, HepG-2, and MCF-7 with IC50 values of 3.94, 3.76, and 4.43 µM, respectively. Such IC50 values are comparable to vinblastine (IC50 = 3.21, 7.35, 5.83 µM, respectively) and doxorubicin (IC50 = 6.74, 7.52, 8.19 µM, respectively). In vitro VEGFR-2 inhibitory activity of the most promising molecules (3a, 4, 8, and 9) indicated that compound 8 is the highest VEGFR-2 inhibitor with an IC50 of 0.0554 µM, compared to sorafenib (IC50 = 0.0416 µM). The most promising candidates (3a, 4, 8, and 9) were subjected to flow cytometry analyses to assess their effects on the cell cycle behavior and the apoptotic power against the three tested cell lines (HCT-116, HepG-2, and MCF-7). The tested compound arrested the tumor cells at both the G2/M and Pre-G1 phases. In addition, compound 9 was proved as the most effective apoptotic inducer among the tested compounds against the tested cells. Molecular docking studies against VEGFR-2 (PDB ID: 2OH4) revealed good binding modes of the synthesized compound similar to that of sorafenib. Computational investigation of ADMET parameters revealed the drug-likeness of the synthesized compounds.

Exploring the dual effect of novel 1,4-diarylpyranopyrazoles as antiviral and anti-inflammatory for the management of SARS-CoV-2 and associated inflammatory symptoms.

COVID-19 and associated substantial inflammations continue to threaten humankind triggering death worldwide. So, the development of new effective antiviral and anti-inflammatory medications is a major scientific goal. Pyranopyrazoles have occupied a crucial position in medicinal chemistry because of their biological importance. Here, we report the design and synthesis of a series of sixteen pyranopyrazole derivatives substituted with two aryl groups at N-1 and C-4. The designed compounds are suggested to show dual activity to combat the emerging Coronaviruses and associated substantial inflammations. All compounds were evaluated for their in vitro antiviral activity and cytotoxicity against SARS-CoV infected Vero cells. As well, the in vitro assay of all derivatives against the SARS-CoV Mpro target was performed. Results revealed the potential of three pyranopyrazoles (22, 27, and 31) to potently inhibit the viral main protease with IC50 values of 2.01, 1.83, and 4.60 µM respectively compared with 12.85 and 82.17 µM for GC-376 and lopinavir. Additionally, in vivo anti-inflammatory testing for the most active compound 27 proved its ability to reduce levels of two cytokines (TNF-α and IL-6). Molecular docking and dynamics simulation revealed consistent results with the in vitro enzymatic assay and indicated the stability of the putative complex of 27 with SARS-CoV-2 Mpro. The assessment of metabolic stability and physicochemical properties of 27 have also been conducted. This investigation identified a set of metabolically stable pyranopyrazoles as effective anti-SARS-CoV-2 Mpro and suppressors of host cell cytokine release. We believe that the new compounds deserve further chemical optimization and evaluation for COVID-19 treatment.

Synthesis, anticancer evaluation and molecular docking studies of new heterocycles linked to sulfonamide moiety as novel human topoisomerase types I and II poisons.

A series of heterocyclic compounds with a sulfonamide moiety were synthesized from reaction of enaminone 4 with active methylene compounds, glycine derivatives, 1,4-benzoquinone, hydroxylamine hydrochloride, hydrazonyl halides and dimethylacetylenedicarboxylate. The newly synthesized sulfonamide derivatives were characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy, elemental analysis and alternative synthetic routes. The reactions products were evaluated for their antiproliferative activity against a panel of three different human cancerous cell lines, MCF-7 (breast), HepG-2 (liver) and HCT-116 (colon) and the results were deployed to derive the structure-activity relationships (SAR). Various test compounds were potent antiproliferative to cancerous cells; reaching very low micromolar levels, as in case of 21 which showed IC50 value of 6.2 µM against HepG-2 cell. In addition, treatment of cancerous cells with the synthesized compounds induced cell apoptosis and G2/M phase arrest evidenced by flow cytometric analysis. Furthermore, the activity of the synthesized compounds against TOP I and II were documented by DNA relaxation assays. Data revealed that compound 24 significantly interfered with TOP I- and II-mediated DNA relaxation, nicking and decatenation, with IC50 values 27.8 and 33.6 µM, respectively. Moreover, the molecular docking studies supported the results from enzymatic assays, where compound 24 was intercalated between nucleotides flanking the DNA cleavage site via pi-pi stacking and hydrophobic interactions. In conclusion, aromatic heterocycles linked to sulfonamides are excellent molecular frameworks amenable for optimization as dual TOP I and II poisons to control various human malignancies.

Targeted potent antimicrobial benzochromene-based analogues: Synthesis, computational studies, and inhibitory effect against 14α-Demethylase and DNA Gyrase.

7H-Benzo[7,8]chromeno[2,3-d]pyrimidin-9(8H)-amine (6a,b) have been synthesized via hydrazinolysis of the imidates (5a,b). Polysubstituted chromenotriazolopyrimidine (7a-j), (12a,b) and Schiff base (8a,b) derivatives have also been prepared. The new heterocyclic derivatives were affirmed by spectral data. The target compounds have been screened for antibacterial and antifungal activity. Compounds 6a,b and 7a-c, g,h displayed the most favorable antimicrobial activities in resemblance to the reference antimicrobial agents by IZ range over 24 mm. In addition, MIC, MBC and MFC were also tested and screen for most active compound 6a by 6.25 µg/mL showing bactericidal effect. SAR study revealed that the antimicrobial vitality of the target compounds was safely influenced by the lipophilicity substituents and the calculated log P value. The potent compounds were subjected into in vitro enzyme screening (14α-Demethylase and DNA Gyrase) against both interesting targets and showed good inhibitory profile. Molecular modeling analyses were introduced and discussed focusing on the docking of active compounds into two essential targets, and their ADMET properties were studied.

Antiproliferative effect, cell cycle arrest and apoptosis generation of novel synthesized anticancer heterocyclic derivatives based 4H-benzo[h]chromene.

Novel ß-enaminonitrile/ester compounds (4, 6) and an imidate of 4 (9) were utilized as key scaffolds for the synthesis of newly 2-substituted 4H-benzo[h]chromene (7, 8, 10, 11, 13, 14) and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives (15-19). The spectral data confirmed the successful isolation of the desired compounds. The targeted compounds were assessed for their in vitro anticancer activity against mammary gland breast cancer cell line (MCF-7), human colon cancer (HCT-116), and liver cancer (HepG-2), while doxorubicin, vinblastine, and colchicine were utilized as standard references drugs. Some of the examined compounds displayed high growth inhibitory activity against the three different cell lines. For example, the aminoimino derivative (18) exhibited excellent antitumor activity versus all cancer cell lines with IC50 values = 0.45 µg/mL, 0.7 µg/mL, and 1.7 µg/mL. Among the tested molecules, compounds 9, 15, and 18 were selected for further study regarding their effects on cell cycle analysis, apoptosis assay, caspase 3/7 activity, and DNA fragmentation. We found that these three potent cytotoxic compounds induce cell cycle arrest at the S and G2/M phases, which causes apoptosis. Furthermore, these compounds significantly inhibit the invasion and migration of the different tested cancer cells. Finally, the SAR survey highlighted the antitumor activity of the new molecules that was remarkably influenced by the hydrophilicity of substituent as well the fused rings at certain positions.

Rational Design and Synthesis of Diverse Pyrimidine Molecules Bearing Sulfonamide Moiety as Novel ERK Inhibitors.

Protein kinases orchestrate diverse cellular functions; however, their dysregulation is linked to metabolic dysfunctions, associated with many diseases, including cancer. Mitogen-Activated Protein (MAP) kinase is a notoriously oncogenic signaling pathway in human malignancies, where the extracellular signal-regulated kinases (ERK1/2) are focal serine/threonine kinases in the MAP kinase module with numerous cytosolic and nuclear mitogenic effector proteins. Subsequently, hampering the ERK kinase activity by small molecule inhibitors is a robust strategy to control the malignancies with aberrant MAP kinase signaling cascades. Consequently, new heterocyclic compounds, containing a sulfonamide moiety, were rationally designed, aided by the molecular docking of the starting reactant 1-(4-((4-methylpiperidin-1-yl)sulfonyl)phenyl)ethan-1-one (3) at the ATP binding pocket of the ERK kinase domain, which was relying on the molecular extension tactic. The identities of the synthesized compounds (4-33) were proven by their spectral data and elemental analysis. The target compounds exhibited pronounced anti-proliferative activities against the MCF-7, HepG-2, and HCT-116 cancerous cell lines with potencies reaching a 2.96 µM for the most active compound (22). Moreover, compounds 5, 9, 10b, 22, and 28 displayed a significant G2/M phase arrest and induction of the apoptosis, which was confirmed by the cell cycle analysis and the flow cytometry. Thus, the molecular extension of a small fragment bounded at the ERK kinase domain is a valid tactic for the rational synthesis of the ERK inhibitors to control various human malignancies.

Design and Synthesis of Novel Heterocyclic-Based 4H-benzo[h]chromene Moieties: Targeting Antitumor Caspase 3/7 Activities and Cell Cycle Analysis.

Novel fused chromenes (4,7⁻11) and pyrimidines (12⁻16) were designed, synthesized, and evaluated for their mammary gland breast cancer (MCF-7), human colon cancer (HCT-116), and liver cancer (HepG-2) activities. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR, and mass spectroscopy. The preliminary results of the bioassay disclosed that some of the target compounds were proven to have a significant antiproliferative effect against the three cell lines, as compared to Doxorubicin, Vinblastine, and Colchicine, used as reference drugs. Particularly, compounds 7 and 14 exerted promising anticancer activity towards all cell lines and were chosen for further studies, such as cell cycle analysis, cell apoptosis, caspase 3/7 activity, DNA fragmentation, cell invasion, and migration. We found that these potent cytotoxic compounds induced cell cycle arrest at the S and G2/M phases, prompting apoptosis. Furthermore, these compounds significantly inhibit the invasion and migration of the different tested cancer cells. The structure-activity relationship (SAR) survey highlights that the antitumor activity of the desired compounds was affected by the hydrophobic or hydrophilic nature of the substituent at different positions.

Synthesis, biological activity and molecular modeling study of new Schiff bases incorporated with indole moiety.

A new series of heterocyclic Schiff bases 2-9 containing indole moiety were synthesized by facile and efficient condensation of indole-3/2/5-carboxaldehyde (1a/1b/1c) with different aromatic and heterocyclic primary amines using conventional and/or microwave irradiation methods. The structures of the obtained compounds were assigned by sophisticated spectroscopic and spectrometric techniques (1D-NMR, 2D-NMR and MS). The synthesized compounds were screened for their cytotoxicity and antibacterial activities. In vitro cytotoxicity screening revealed that compound 5 exhibited moderate activity against KB-3-1 cell line (IC50=57.7 µM) while 5-indolylimino derivative 7 indicated close to the activity (IC50=19.6 µM) in comparison with the positive control (+)-Griseofulvin (IC50=19.2 µM), while the tested compounds 5, 6b, 7 and 9 revealed good or moderate antibacterial activity. In addition, molecular docking study of Schiff bases 2-9 was performed by Molecular Operating Environment (MOE 2014.09) program on the matrix metalloproteinase-8 (MMP-8) (Protein Data Bank (PDB) ID: 1MNC) in an attempt to explore their mode of action as anticancer drugs.

A novel class of phenylpyrazolone-sulphonamides rigid synthetic anticancer molecules selectively inhibit the isoform IX of carbonic anhydrases guided by molecular docking and orbital analyses.

All the previously reported phenylpyrazoles as carbonic anhydrase inhibitors (CAIs) were found to have small sizes and high levels of flexibility, and hence showed low selectivity profiles toward a particular isoform of CA. Herein, we report the development of a more rigid ring system bearing a sulfonamide hydrophilic head and a lipophilic tail to develop novel molecules that are suggested to have a better selectivity toward a special CA isoform. Accordingly, three novel sets of pyrano[2,3-c]pyrazoles attached with sulfonamide head and aryl hydrophobic tail were synthesized to enhance the selectivity toward a specific isoform of human carbonic anhydrases (hCAs). The impact of both attachments on the potency and selectivity has been extensively discussed in terms of in vitro cytotoxicity evaluation under hypoxic conditions, structure-activity relationship and carbonic anhydrase enzyme assay. All of the new candidates displayed good cytotoxic activities against breast and colorectal carcinomas. Results of the carbonic anhydrase enzyme assay demonstrated the preferential of compounds 22, 24 and 27 to inhibit the isoform IX of hCAs selectively. Wound-healing assay has also been performed and revealed the potential of 27 to decrease the wound closure percentage in MCF-7 cells. Molecular docking and molecular orbital analysis have finally been conducted. Results indicate the potential binding interactions of 24 and 27 with several crucial amino acids of the hCA IX.Communicated by Ramaswamy H. Sarma.

Introducing of novel class of pyrano[2,3-c]pyrazole-5-carbonitrile analogs with potent antimicrobial activity, DNA gyrase inhibition, and prominent pharmacokinetic and CNS toxicity profiles supported by molecular dynamic simulation.

Microbiological DNA gyrase is recognized as an exceptional microbial target for the innovative development of low-resistant and more effective antimicrobial drugs. Hence, we introduced a one-pot facile synthesis of a novel pyranopyrazole scaffold bearing different functionalities; substituted aryl ring, nitrile, and hydroxyl groups. All new analogs were characterized with full spectroscopic data. The antimicrobial screening for all analogs was assessed against standard strains of Gm + ve and Gm-ve through in vitro considers. The screened compounds displayed very promising MIC/MBC values against some of the bacterial strains with broad or selective antibacterial effects. Of these, 4j biphenyl analog showed 0.5-2/2-8 µg/mL MIC/MBC for suppression and killing of Gm + ve and Gm-ve strains. Moreover, the antimicrobial screening was assessed for the most potent analogs against certain highly resistant microbial strains. Consequently, DNA gyrase supercoiling assay was done for all analogs using ciprofloxacin as reference positive control. Obviously, the results showed a different activity profile with potent analog 4j with IC50 value 6.29 µg/mL better than reference drug 10.2 µg/mL. Additionally, CNS toxicity testing was done using the HiB5 cell line for attenuation of GABA/NMDA expression to both 4j and ciprofloxacin compounds that revealed better neurotransmitter modulation by novel scaffold. Importantly, docking and dynamic simulations were performed for the most active 4j analog to investigate its interaction with DNA binding sites, which supported the in vitro observations and compound stability with binding pocket. Finally, a novel scaffold pyranopyrazole was introduced as a DNA gyrase inhibitor with prominent antibacterial efficacy and low CNS side effect toxicity better than quinolones.Communicated by Ramaswamy H. Sarma.

Synthesis, reactions and biological evaluation of some new naphtho[2,1-b]furan derivatives bearing a pyrazole nucleus.

Vilsmeier formylation of 2-(1-phenylhydrazonoethyl)naphtho[2,1-b]furan (2) gave 3-naphtho[2,1-b]furan-2-yl-1-phenyl-1H-pyrazole-4-carbaldehyde (3), which was reacted with C- and N-nucleophiles to afford naphthofuranpyrazol derivatives 4-8. Treatment of 2-[(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene]-malononitrile (4a) with reactants having active hydrogen and Et3N gave the corresponding pyrazoline, pyran and chromene addition product derivatives 10, 12 and 13, consisting of three different connected heterocyclic moieties. Reaction of 1-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl) methylene)-2-phenylhydrazone (6b) with AcONa and ethyl bromoacetate or chloroacetone afforded the thiazolidinone and methylthiazole derivatives 14 and 15, respectively. In addition, intramolecular cyclization of 6d with Ac2O afford the corresponding 1,3,4-thiadiazol-2-yl acetamide derivative 16. The structures of the synthesized compounds were confirmed by IR, ¹H-NMR/¹³C-NMR and mass spectral studies. Compound 14 showed promising effects against the tested Gram positive and negative bacteria and fungi.

Metal-free domino amination-Knoevenagel condensation approach to access new coumarins as potent nanomolar inhibitors of VEGFR-2 and EGFR.

A metal-free, atom-economy and simple work-up domino amination-Knoevenagel condensation approach to construct new coumarin analogous (4a-f and 8a-e) was described. Further, new formyl (5a,d-f) and nitro (9a,d-f) coumarin derivatives were synthesized via C-N coupling reaction of various cyclic secondary amines and 4-chloro-3-(formyl-/nitro)coumarins (1a,c), respectively. The confirmed compounds were screened for their in vitro anti-proliferative activity against KB-3-1, A549 and PC3 human cancer cell lines using resazurin cellular-based assay. Among them, coumarin derivatives 4e and 8e displayed the best anti-cervical cancer potency (KB-3-1) with IC50 values of 15.5 ± 3.54 and 21 ± 4.24 µM, respectively. Also, 4e showed the most promising cytotoxicity toward A549 with IC50 value of 12.94 ± 1.51 µM. As well, 9d presented a more significant impact of potency against PC3 with IC50 7.31 ± 0.48 µM. Moreover, 8d manifested selectivity against PC3 (IC50 = 20.16 ± 0.07 µM), while 8e was selective toward KB-3-1 cell line (IC50 = 21 ± 4.24 µM). Matching with docking profile, the enzymatic assay divulged that 8e is a dual potent single-digit nanomolar inhibitor of VEGFR-2 and EGFR with IC50 values of 24.67 nM and 31.6 nM that were almost equipotent to sorafenib (31.08 nM) and erlotinib (26.79 nM), respectively.