Exploring of N-phthalimide-linked 1,2,3-triazole analogues with promising -anti-SARS-CoV-2 activity: synthesis, biological screening, and molecular modelling studies.

In this study, a library of phthalimide Schiff base linked to 1,4-disubstituted-1,2,3-triazoles was designed, synthesised, and characterised by different spectral analyses. All analogues have been introduced for in vitro assay of their antiviral activity against COVID-19 virus using Vero cell as incubator with different concentrations. The data revealed most of these derivatives showed potent cellular anti-COVID-19 activity and prevent viral growth by more than 90% at two different concentrations with no or weak cytotoxic effect on Vero cells. Furthermore, in vitro assay was done against this enzyme for all analogues and the results showed two of them have IC50 data by 90 µM inhibitory activity. An extensive molecular docking simulation was run to analyse their antiviral mechanism that found the proper non-covalent interaction within the Mpro protease enzyme. Finally, we profiled two reversible inhibitors, COOH and F substituted analogues that might be promising drug candidates for further development have been discovered.

N- and s-substituted Pyrazolopyrimidines: A promising new class of potent c-Src kinase inhibitors with prominent antitumor activity.

In this work, readily achievable synthetic pathways were utilized for construction of a library of N/S analogues based on the pyrazolopyrimidine scaffold with terminal alkyl or aryl fragments. Subsequently, we evaluated the anticancer effects of these novel analogs against the proliferation of various cancer cell lines, including breast, colon, and liver lines. The results were striking, most of the tested molecules exhibited strong and selective cytotoxic activity against the MDA-MB-231 cancer cell line; IC50 1.13 µM. Structure-activity relationship (SAR) analysis revealed that N-substituted derivatives generally enhanced the cytotoxic effect, particularly with aliphatic side chains that facilitated favorable target interactions. We also investigated apoptosis, DNA fragmentation, invasion assay, and anti-migration effects, and discussed their underlying molecular mechanisms for the most active compound 7c. We demonstrated that 7c N-propyl analogue could inhibit MDA-MB-231 TNBC cell proliferation by inducing apoptosis through the regulation of vital proteins, namely c-Src, p53, and Bax. In addition, our results also revealed the potential of these compounds against tumor metastasis by downregulating the invasion and migration modes. Moreover, the in vitro inhibitory effect of active analogs against c-Src kinase was studied and proved that might be the main cause of their antiproliferative effect. Overall, these compelling results point towards the therapeutic potential of these derivatives, particularly those with N-substitution as promising candidates for the treatment of TNBC type of breast cancer.

Development of Novel Class of Phenylpyrazolo[3,4-d]pyrimidine-Based Analogs with Potent Anticancer Activity and Multitarget Enzyme Inhibition Supported by Docking Studies.

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3-24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment.

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.

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.

The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro, and in silico mechanistic investigations.

Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival in breast cancer patients. Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR, 1H NMR, 13C NMR, 13C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC50 at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC50 values of 0.143 and 0.121 µM, respectively. Molecular docking experiments and molecular dynamics simulation were also conducted to further rationalize the in vitro obtained results.Communicated by Ramaswamy H. Sarma.

In vitro and computational investigations of novel synthetic carboxamide-linked pyridopyrrolopyrimidines with potent activity as SARS-CoV-2-MPro inhibitors.

An essential target for COVID-19 is the main protease of SARS-CoV-2 (Mpro). With the objective of targeting this receptor, a novel set of pyrido[1,2-a]pyrrolo[2,3-d]pyrimidines with terminal carboxamide fragments was designed, synthesized, and considered as an initial motif for the creation of effective pan-coronavirus inhibitors. Accordingly, nine derivatives (21-29) have been introduced for in vitro assay to evaluate their antiviral activity and cytotoxicity effect against COVID-19 virus using Vero cells. The obtained data revealed that the majority of these derivatives showed potent cellular anti-COVID-19 activity and prevent viral growth by more than 90% at two different concentrations with weak or even no detectable cytotoxic effect on Vero cells. Extensive molecular docking simulations highlighted proper non-covalent interaction of new compounds within the binding pocket of Mpro as a potential target for their antiviral activity. In vitro assay for all the synthesized derivatives against the viral Mpro target indicated that compounds 25 and 29 have promising inhibitory activity with IC50 values at low micromolar concentrations. The molecular dynamic simulation results predicted the stability of compound 29 in the binding cavity of SARS-CoV-2 Mpro and hence supported the high inhibitory activity shown by the In vitro assay. These results suggested that compounds 25 and 29 merit further investigations as promising drug candidates for the management of SARS-CoV-2.

Design and Synthesis of Benzene Homologues Tethered with 1,2,4-Triazole and 1,3,4-Thiadiazole Motifs Revealing Dual MCF-7/HepG2 Cytotoxic Activity with Prominent Selectivity via Histone Demethylase LSD1 Inhibitory Effect.

In this study, an efficient multistep synthesis of novel aromatic tricyclic hybrids incorporating different biological active moieties, such as 1,3,4-thiadiazole and 1,2,4-triazole, was reported. These target scaffolds are characterized by having terminal lipophilic or hydrophilic parts, and their structures are confirmed by different spectroscopic methods. Further, the cytotoxic activities of the newly synthesized compounds were evaluated using in vitro MTT cytotoxicity screening assay against three different cell lines, including HepG-2, MCF-7, and HCT-116, compared with the reference drug Taxol. The results showed variable performance against cancer cell lines, exhibiting MCF-7 and HepG-2 selectivities by active analogs. Among these derivatives, 1,2,4-triazoles 11 and 13 and 1,3,4-thiadiazole 18 were found to be the most potent compounds against MCF-7 and HepG-2 cancer cells. Moreover, structure-activity relationship (SAR) studies led to the identification of some potent LSD1 inhibitors. The tested compounds showed good LSD1 inhibitory activities, with an IC50 range of 0.04-1.5 µM. Compounds 27, 23, and 22 were found to be the most active analogs with IC50 values of 0.046, 0.065, and 0.074 µM, respectively. In addition, they exhibited prominent selectivity against a MAO target with apparent cancer cell apoptosis, resulting in DNA fragmentation. This research provides some new aromatic-centered 1,2,4-triazole-3-thione and 1,3,4-thiadiazole analogs as highly effective anticancer agents with good LSD1 target selectivity.

Pharmacological implications of ipriflavone against environmental metal-induced neurodegeneration and dementia in rats.

Long-term exposure to environmental neurotoxic metals is implicated in the induction of dementia and cognitive decline. The present study aims to illustrate the therapeutic role of ipriflavone as a synthetic isoflavone against environmental metal-induced cognitive impairment in rats. Dementia was induced by a mixture of aluminum, cadmium, and fluoride for 90 days followed by ipriflavone for a further 30 days.  Metal-treated animals exhibited abnormal behaviors in the Morris water maze task. Neuropathological biomarkers including oxidative stress (TBARS, NO, SOD, GPX, GST, and GSH), inflammation (TNF- α, IL-6, and IL-1ß), neurotransmission (AChE and MAO), and insulin resistance (insulin, insulin receptor, and insulin-degrading enzyme) were altered, which consequently elevated the level of amyloid-ß42 and tau protein in the hippocampus tissues inducing neuronal injury. Ipriflavone significantly (P < 0.05) ameliorated the neurobehavioral abnormalities and the cognitive dysfunction biomarkers via antioxidant/anti-inflammatory mechanism. Moreover, ipriflavone downregulated the mRNA expression level of amyloid precursor protein and tau protein, preventing amyloid plaques and neurofibrillary tangle aggregation at P < 0.05. A molecular docking study revealed that ipriflavone has a potent binding affinity towards AChE more than donepezil and acts as a strong AChE inhibitor. Our data concluded that the therapeutic potential of ipriflavone against dementia could provide a new strategy in AD treatment.

Design of molecular hybrids of phthalimide-triazole agents with potent selective MCF-7/HepG2 cytotoxicity: Synthesis, EGFR inhibitory effect, and metabolic stability.

This study reports an efficient and convenient click chemistry synthesis of a novel series of phthalimide scaffold linked to 1,2,3 triazole ring and terminal lipophilic fragments. Structures of newly synthesized compounds were well characterized by different spectroscopic tools. In vitro MTT cytotoxicity assay was performed comparing the cytotoxic effects of newly synthesized compounds to staurosporine using three different types: human liver cancer cell line (HepG2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). The initial screening showed excellent to moderate anticancer activity for these newly synthesized compounds with high degree of cell line selectivity with micromolar (µM) half maximal inhibitory concentration (IC50) values against tumor cells. The SAR analysis of these derivatives confirmed the role of molecular fragments including phthalimide, linker, triazole, and terminal tails in correlation to activity. In addition, enzymatic inhibitory assay against wild type EGFR was performed for the most active compounds to get more details about their mechanism of action. In order to further explore their binding affinities, molecular docking simulation was studied against EGFR site. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. One of the most prominent analogs is (6f) with terminal disubstituted ring and amide linker showed selective MCF-7 cytotoxicity profile with IC50 0.22 µM and 79 nM to EGFR target. Extensive structure activity relationship (SAR) analyses were also carried out. The pharmacokinetic profile of (6f) was studied showing good metabolic stability and long duration behavior. This design offered a potent selective anticancer phthalimide-triazole leads for further optimization in cancer drug discovery.

In vivo- and in silico-driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors.

The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.

Synthesis, antimicrobial evaluation, DNA gyrase inhibition, and in silico pharmacokinetic studies of novel quinoline derivatives.

Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram-positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66-5.29 µg/ml. Among them, compound 14 exhibited a particularly potent broad-spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66-3.98 µg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC50 value (3.39 µM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.

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.

Novel 1,2,4-triazole derivatives: Design, synthesis, anticancer evaluation, molecular docking, and pharmacokinetic profiling studies.

Three novel series of 1,2,4-triazole derivatives were designed and synthesized as potential adenosine A2B receptor antagonists. The design of the new compounds depended on a virtual screening of a previously constructed library of compounds targeting the human adenosine A2B protein. Spectroscopic techniques including 1 H nuclear magnetic resonance (NMR) and 13 C NMR, and infrared and mass spectroscopy were used to confirm the structures of the synthesized compounds. The in vitro cytotoxicity evaluation was carried out against a human breast adenocarcinoma cell line (MDA-MB-231) using the MTT assay, and the obtained results were compared with doxorubicin as a reference anticancer agent. In addition, in silico studies to propose how the two most active compounds interact with the adenosine A2B receptor as a potential target were performed. Furthermore, a structure-activity relationship analysis was performed, and the pharmacokinetic profile to predict the oral bioavailability and other pharmacokinetic properties was also explained. Four of our designed derivatives showed promising cytotoxic effects against the selected cancer cell line. Compound 15 showed the highest activity with an IC50 value of 3.48 µM. Also, compound 20 revealed an equipotent activity with the reference cytotoxic drug, with an IC50 value of 5.95 µM. The observed IC50 values were consistent with the obtained in silico docking scores. The newly designed compounds revealed promising pharmacokinetic profiles as compared with the reference marketed drug.

Novel scaffold hopping of potent benzothiazole and isatin analogues linked to 1,2,3-triazole fragment that mimic quinazoline epidermal growth factor receptor inhibitors: Synthesis, antitumor and mechanistic analyses.

A series of benzothiazole/isatin linked to 1,2,3-triazole moiety and terminal sulpha drugs 5a-e and 6a-e were synthesized and evaluated for cytotoxic activity against a panel of cancer cell lines. The novel compounds showed variable IC50 range of activity and some of them were potent compared to reference drug. The promising compounds were subjected as postulated the mimicry proposal for quinazoline-based EGFR inhibitors for their inhibitory profile against EGFR TK enzyme. That data obtained revealed that most of these compounds were potent EGFR TK inhibitors at nanomolar concentrations. Among these, compounds 5a and 5b showed more potent activity on EGFR compared to erlotinib (IC50 103 and 104 versus 67.6 nM). Based upon the results, molecular docking analysis was performed on EGFR receptor and proved the strong contribution of fragments; benzothiazole, isatin, and triazole to the binding ATP pocket. When these selected compounds 5a and 5b were tested in an HepG2 model, they could effectively inhibited tumor growth, strongly induced cancer cell apoptosis, and suppressed cell cycle progression leading to DNA fragmentation. Well-DMET profile of the most active derivatives was presented and compared to the reference drugs. Taken together, we introduced novel triazole-sulpha drug hybrid for the first time as EGFR inhibitors and the results of our studies indicate that the newly discovered inhibitors have significant potential for anticancer treatment.

Novel molecular discovery of promising amidine-based thiazole analogues as potent dual Matrix Metalloproteinase-2 and 9 inhibitors: Anticancer activity data with prominent cell cycle arrest and DNA fragmentation analysis effects.

Thiazole derivatives are known to possess various biological activities such as antiparasitic, antifungal, antimicrobial and antiproliferative activities. Matrix metalloproteinases (MMPs) are important protease target involved in tumor progression including angiogenesis, tissue invasion, and migration. Therefore, MMPs have also been reported as potential diagnostic and prognostic biomarkers in many types of cancer. Herein, new aryl thiazoles were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines including the invasive MDA-MB-231 line. Some of these compounds showed IC50 values in the submicromolar range in anti-proliferative assays. In order to examine the relationship between their anticancer activity and MMPs targets, the compounds were evaluated for their inhibitory effects on MMP-2 and 9. That data obtained revealed that most of these compounds were potent dual MMP-2/9 inhibitors at nanomolar concentrations. Among these, 2-(1-(2-(2-((E)-4-iodobenzylidene)hydrazineyl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (4a) was the most potent non-selective dual MMP-2/9 inhibitor with inhibitory concentrations of 56 and 38 nM respectively. When compound 4a was tested in an MDA-MB-231, HCT-116, MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibit cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Taken together, the results of our studies indicate that the newly discovered thiazole-based MMP-2/9 inhibitors have significant potential for anticancer treatment.

Introducing of potent cytotoxic novel 2-(aroylamino)cinnamamide derivatives against colon cancer mediated by dual apoptotic signal activation and oxidative stress.

Curcumin and trans-cinnamaldehyde are acrolein-based Michael acceptor compounds that are commonly found in domestic condiments, and known to cause cancer cell death via redox mechanisms. Based on the structural features of these compounds we designed and synthesized several 2-cinnamamido-N-substituted-cinnamamide (bis-cinnamamide) compounds. One of the derivatives, (Z)-2-[(E)-cinnamamido]-3-phenyl-N-propylacrylamide 8 showed a moderate antiproliferative potency (HCT-116 cell line inhibition of 32.0 µM), no inhibition of normal cell lines C-166, and proven cellular activities leading to apoptosis. SAR studies led to more than 10-fold increase in activity. Our most promising compound, [(Z)-3-(1H-indol-3-yl)-N-propyl-2-[(E)-3-(thien-2-yl)propenamido)propenamide] 45 killed colon cancer cells at IC50 = 0.89 µM (Caco-2), 2.85 µM (HCT-116) and 1.65 µM (HT-29), while exhibiting much weaker potency on C-166 and BHK normal cell lines (IC50 = 71 µM and 77.6 µM, respectively). Cellular studies towards identifying the compounds mechanism of cytotoxic activities revealed that apoptotic induction occurs in part as a result of oxidative stress. Importantly, the compounds showed inhibition of cancer stem cells that are critical for maintaining the potential for self-renewal and stemness. The results presented here show discovery of covalently acting Michael addition compounds that potently kill cancer cells by a defined mechanism, with prominent selectivity profile over non-cancerous cell lines.

Design, synthesis, molecular modelling and in vitro screening of monoamine oxidase inhibitory activities of novel quinazolyl hydrazine derivatives.

A new series of N'-substituted benzylidene-2-(4-oxo-2-phenyl-1,4-dihydroquinazolin-3(2H)-yl)acetohydrazide (5a-5h) has been synthesized, characterized by FT-IR, NMR spectroscopy and mass spectrometry and tested against human monoamine oxidase (MAO) A and B. Only (4-hydroxy-3-methoxybenzylidene) substituted compounds gave submicromolar inhibition of MAO-A and MAO-B. Changing the phenyl substituent to methyl on the unsaturated quinazoline ring (12a-12d) decreased inhibition, but a less flexible linker (14a-14d) resulted in selective micromolar inhibition of hMAO-B providing insight for ongoing design.

Novel triazolophthalazine-hydrazone hybrids as potential PCAF inhibitors: Design, synthesis, in vitro anticancer evaluation, apoptosis, and molecular docking studies.

Three novel series of triazolophthalazine derivatives bearing hydrazone moiety were designed, synthesized, and evaluated for their anticancer activity against four human cancer cell lines by MTT assay. Six derivatives demonstrated comparable activity with Doxorubicin reference drug against the selected cancer cells. Especially, compound 16 showed the most potent activity with IC50 values of 5.70, 8.04, 11.15, and 4.25, µM against HePG2, MCF-7, PC3, and HCT-116 respectively. Also, compound 26 exhibited comparable inhibitory effect with that of Doxorubicin against the selected cancer cell lines with IC50 values of 6.45, 8.63, 12.28, and 7.03 µM against HePG2, MCF-7, PC3, and HCT-116 respectively. Investigation of the apoptotic activity of the two most active compounds revealed that compounds 16 and 26 could induce both the early and the late apoptosis of HePG2. Further mechanistic study of the HePG2 cell cycle confirmed the spectacular cytotoxic and apoptotic effects of both compounds. Compounds 16 and 26 showed a pronounced increase in cells in G2/M and Pre G1 phases with a concomitant reduction of cells in G0-G1 and S phases. A follow up enzymatic assay indicated that these two compounds have comparable activities with that of bromosporine as PCAF inhibitors with IC50 values of 8.13 and 5.31 µM respectively. Moreover, molecular docking study for all the synthesized compounds was performed to predict their binding affinities toward the active site of histone acetyltransferase GCN5. Results of molecular docking were strongly correlated with that of the cytotoxicity study.

S-substituted 2-mercaptoquinazolin-4(3H)-one and 4-ethylbenzensulfonamides act as potent and selective human carbonic anhydrase IX and XII inhibitors.

We evaluated the hCA (CA, EC 4.2.1.1) inhibitory activity of novel 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides (compounds 2-20) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds 2 and 4 showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (KIs; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds 4 and 5 showed selective hCA IX inhibitory activity over hCA I (SI; 95 and 24), hCA IX/hCA II (SI; 23 and 5.8) and selective hCA XII inhibitory activity over hCA I (SI; 70 and 44), hCA XII/hCA II, (SI; 17 and 10) respectively compared to AAZ. Compounds 12-17, and 19-20 showed selective inhibitory activity towards hCA IX over hCA I and hCA II, with selectivity ranges of 27-195 and 3.2-19, respectively, while compounds 12, 14-17, and 19 exhibited selective inhibition towards hCA XII over hCA I and hCA II, with selectivity ratios of 48-158 and 5.4-31 respectively, compared to AAZ. Molecular docking analysis was carried out to investigate the selective interactions among the most active derivatives, 17 and 20 and hCAs isoenzymes. Compounds 17 and 20, which are highly selective CA IX and XII inhibitors, exhibited excellent interaction within the putative binding site of both enzymes, comparable to the co-crystallized inhibitors.HighlightsQuinazoline-linked ethylbenzenesulfonamides inhibiting CA were synthesised.The new molecules potently inhibited the hCA isoforms I, II, IV, and IX.Compounds 4 and 5 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds 4 and 5 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds 12-17, 19, and 20 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds 12, 14-17, 19 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds 4 and 5 are selective hCA IX and XII inhibitors over hCA I (selectivity ratios of 95, 23, and 24, 5.8, respectively) and hCA II (selectivity ratios of 70, 17, and 44, 10 respectively). Compounds 12-17, and 19-20 are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds 12, 14-17 and 19 are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31).