A new polyazomethine-based pyrazole moiety and its reinforced nanocomposites @ ZnO for antimicrobial applications.

A new class of biologically active polyazomethine/pyrazole and their related nanocomposites, polyazomethine/pyrazole/zinc oxide nanoparticles, have been successfully synthesized through the polycondensation technique in the form of polyazomethine pyrazole (PAZm/Py4-6) and polyazomethine/pyrazole/zinc oxide nanoparticles (PAZm/Py/ZnOa-c). The polymeric nanocomposites were prepared with a 5% loading of zinc oxide nanofiller using the same preparation technique, in addition to the help of ultrasonic radiation. The characteristics of the new polymers, such as solubility, viscometry, and molecular weight, were examined. All the polymers were completely soluble in the following solvents: concentrated sulfuric acid, formic acid, dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran. Furthermore, the weight loss of the polyazomethine pyrazole (4, 5, and 6) at 800 °C was 67%, 95%, and 86%, respectively, which indicates the thermal stability of these polymers. At 800 °C, the polyazomethine/pyrazole/zinc oxide nanoparticles (a, b, and c) lost 74%, 68%, and 75% of their weight, respectively. This shows that adding zinc oxide nanoparticles made these compounds more stable at high temperatures. The X-Ray diffraction pattern of the polyazomethine pyrazole (PAZm/Py4-6) shows a number of sharp peaks with varying intensities. The polymers that were studied had straight crystal structures. Furthermore, the measurements of polyazomethine/pyrazole/zinc oxide nanoparticles (PAZm/Py/ZnOa-c) indicate a good merging of zinc oxide nanoparticles into the matrix of polymers. The antimicrobial activity of polymers and polymer nanocomposites was tested against some selected bacteria and fungi. The synthesized polymer (c) shows the highest activity against the two types of gram-negative bacteria selected. Most tested compounds were found to be effective against gram-positive bacteria except polyazomethine pyrazole (PAZm/Py5) and polyazomethine pyrazole (PAZm/Py6), which do not exhibit any activity. The synthesized polymers and their related nanocomposites were tested for their ability to kill the chosen fungi. All of them were effective against Aspergillus flavus, but only polyazomethine pyrazole (PAZm/Py4) and polyazomethine/pyrazole/zinc oxide (PAZm/Py/ZnOc) were effective against Candida albicans.

Discovery of novel benzimidazole derivatives as potent HDACs inhibitors against leukemia with (Thio)Hydantoin as zinc-binding moiety: Design, synthesis, enzyme inhibition, and cellular mechanistic study.

Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, a novel series of easy-to-synthesize benzimidazole-linked (thio)hydantoin derivatives was designed and synthesized as HDAC6 inhibitors. All target compounds potently inhibited HDAC6 at nanomolar levels with compounds 2c, 2d, 4b and 4c (IC50s = 51.84-74.36 nM) being more potent than SAHA reference drug (IC50 = 91.73 nM). Additionally, the most potent derivatives were further assessed for their in vitro cytotoxic activity against two human leukemia cells. Hydantoin derivative 4c was equipotent/superior to SAHA against MOLT-4/CCRF-CEM leukemia cells, respectively and demonstrated safety profile better than that of SAHA against non-cancerous human cells. 4c was also screened against different HDAC isoforms. 4c was superior to SAHA against HDAC1. Cell-based assessment of 4c revealed a significant cell cycle arrest and apoptosis induction. Moreover, western blotting analysis showed increased levels of acetylated histone H3, histone H4 and α-tubulin in CCRF-CEM cells. Furthermore, docking study exposed the ability of title compounds to chelate Zn2+ located within HDAC6 active site. As well, in-silico evaluation of physicochemical properties showed that target compounds are promising candidates in terms of pharmacokinetic aspects.

Recent Literature on the Synthesis of Thiazole Derivatives and their Biological Activities.

The thiazole ring is naturally occurring and is primarily found in marine and microbial sources. It has been identified in various compounds such as peptides, vitamins (thiamine), alkaloids, epothilone, and chlorophyll. Thiazole-containing compounds are widely recognized for their antibacterial, antifungal, anti-inflammatory, antimalarial, antitubercular, antidiabetic, antioxidant, anticonvulsant, anticancer, and cardiovascular activities. The objective of this review is to present recent advancements in the discovery of biologically active thiazole derivatives, including their synthetic methods and biological effects. This review comprehensively discusses the synthesis methods of thiazole and its corresponding biological activities within a specific timeframe, from 2017 until the conclusion of 2022.

Design and Synthesis of New bis-oxindole and Spiro(triazole-oxindole) as CDK4 Inhibitors with Potent Anti-breast Cancer Activity.

BACKGROUND: Since CDKs have been demonstrated to be overexpressed in a wide spectrum of human malignancies, their inhibition has been cited as an effective technique for anticancer drug development. METHODS: In this context, new bis-oxindole/spiro-triazole-oxindole anti-breast cancer drugs with potential CDK4 inhibitory effects were produced in this work. The novel series of bis-oxindole/spirotriazole- oxindole were synthesized from the reaction of bis-oxindole with the aniline derivatives then followed by 1,3-dipolar cycloaddition of hydrazonoyl chloride. RESULTS: The structure of these bis-oxindole/spiro-triazole-oxindole series was proven based on their spectral analyses. Most bis-oxindole and bis-spiro-triazole-oxindole compounds effectively inhibited the growth of MCF-7 (IC50 = 2.81-17.61 µM) and MDA-MB-231 (IC50 = 3.23-7.98 µM) breast cancer cell lines with low inhibitory activity against normal WI-38 cells. While the reference doxorubicin showed IC50 values of 7.43 µM against MCF-7 and 5.71 µM against the MDA-MB-231 cell line. Additionally, compounds 3b, 3c, 6b, and 6d revealed significant anti-CDK4 activity (IC50 = 0.157- 0.618 µM) compared to palbociclib (IC50 = 0.071 µM). Subsequent mechanistic investigations demonstrated that 3c was able to trigger tumor cell death through the induction of apoptosis. Moreover, it stimulated cancer cell cycle arrest in the G1 phase. Furthermore, western blotting disclosed that the 3c-induced cell cycle arrest may be mediated through p21 upregulation. CONCLUSION: According to all of the findings, bis-oxindole 3c shows promise as a cancer treatment targeting CDK4.

Synthesis and molecular docking simulation of new benzimidazole-thiazole hybrids as cholinesterase inhibitors.

Dementia is a cognitive disturbance that is generally correlated with central nervous system diseases, especially Alzheimer's disease. The limited number of medications available is insufficient to improve the lifestyle of the patients suffering from this disease. Thus, new benzimidazole-thiazole hybrids (3-10) were designed and synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory agents. The in vitro evaluation displayed that the derivatives 4b, 4d, 5b, 6a, 7a, and 8b demonstrated dual inhibitory efficiency against both AChE with IC50 ranging from 4.55 to 8.62 µM and BChE with IC50 ranging from 3.50 to 8.32 µM. By analyzing the Lineweaver-Burk plot, an uncompetitive form of inhibition was determined for the highly active compound 4d, revealing its inhibition type. The human telomerase reverse transcriptase-immortalized retinal pigment epithelial cell line was used to ensure the safety of the most potent cholinesterase inhibitors. Furthermore, compounds 4b, 4d, 5b, 6a, 7a, and 8b were evaluated for their neuroprotective and antioxidant properties, as well as their ability to suppress COX-2. The results demonstrated that compounds 4d, 5b, and 8b presented significant neuroprotection efficiency against H2 O2 -induced damage in SH-SY5Y cells with % cell viability of 67.42 ± 7.90%, 62.51 ± 6.71%, and 72.61 ± 8.10%, respectively, while the tested candidates did not reveal significant antioxidant activity. Otherwise, compounds 4b, 6a, 7a, and 8b displayed outstanding COX-2 inhibition effects with IC50 ranging from 0.050 to 0.080 µM relative to celecoxib (IC50 = 0.050 µM). In addition, molecular docking was carried out for the potent benzimidazole-thiazole hybrids with the active sites of both AChE (PDB ID: 4EY7) and BChE (PDB code: 1P0P). The tested candidates fit well in the active sites of both portions, with docking scores ranging from -8.65 to -6.64 kcal/mol (for AChE) and -8.71 to -7.73 kcal/mol (for BChE). In silico results show that the synthesized benzimidazole-thiazole hybrids have good physicochemical and pharmacokinetic properties with no Lipinski rule violations. The preceding results exhibited that compound 4d could be used as a new template for developing more significant cholinesterase inhibitors in the future.

A Literature Review Focusing on the Antiviral Activity of [1,2,4] and [1,2,3]-triazoles.

Out of a variety of heterocycles, triazole scaffolds have been shown to play a significant part in a wide array of biological functions. Many drug compounds containing a triazole moiety with important antimicrobial, anticancer and antidepressant properties have been commercialized. In addition, the triazole scaffold exhibits remarkable antiviral activity either incorporated into nucleoside analogs or non-nucleosides. Many synthetic techniques have been produced by scientists around the world as a result of their wide-ranging biological function. In this review, we have tried to summarize new synthetic methods produced by diverse research groups as well as provide a comprehensive description of the function of [1,2,4] and [1,2,3]-triazole derivatives as antiviral agents. Antiviral triazole compounds have been shown to target a wide variety of molecular proteins. In addition, several strains of viruses, including the human immunodeficiency virus, SARS virus, hepatitis B and C viruses, influenza virus, Hantavirus, and herpes virus, were discovered to be susceptible to triazole derivatives. This review article covered the reports for antiviral activity of both 1,2,3- and 1,2,4-triazole moieties up to 2022.

Recent Methods for the Synthesis of Quinoxaline Derivatives and their Biological Activities.

Quinoxaline derivatives have been incorporated into numerous marketed drugs used for the treatment of various diseases. Examples include glecaprevir (Mavyret), voxilaprevir (Vosevi), Balversa (L01EX16) (erdafitinib), carbadox, XK469R (NSC698215), and becampanel (AMP397). These quinoxaline derivatives exhibit a diverse range of pharmacological activities, including antibacterial, antitubercular, antiviral, anti-HIV, anti-inflammatory, antifungal, anticancer, antiproliferative, antitumor, kinase inhibition, antimicrobial, antioxidant, and analgesic effects. Recognizing the significance of these bioactive quinoxaline derivatives, researchers have dedicated their efforts to developing various synthetic methods for their production. This review aimed to compile the most recent findings on the synthesis and biological properties of quinoxaline derivatives from 2015 to 2023.

The most recent compilation of reactions of enaminone derivatives with various amine derivatives to generate biologically active compounds.

Heterocyclic derivatives serve as the fundamental components of both natural and synthetic drugs. Enaminones play a crucial role as foundational units in the synthesis of numerous bioactive heterocyclic compounds, including pyrazoles, pyridines, oxazoles, isoxazoles, as well as fused heterocyclic structures like indoles, carbazoles, quinolines, acridines, and phenanthridines. These diverse heterocyclic rings are well-known for their various therapeutic activities, encompassing anticancer, anti-inflammatory, antimicrobial, antidepressant, and antiviral properties. By reacting with nitrogen-based nucleophiles, enaminones can generate bioactive azoles, azines, and their fused systems. This comprehensive review article focuses on the recent advancements in enaminone reactions with (a) nitrogen-based nucleophiles, such as aliphatic amines, derivatives of aniline, heterocyclic amines, hydroxylamine, hydrazine derivatives, guanidine derivatives, urea, and thiourea derivatives, and (b) nitrogen-based electrophiles, such as diazonium salts. These reactions have led to the synthesis of a wide range of bioactive fused heterocyclic compounds from 2010 to the end of 2022.

Biologically Potent Benzimidazole-Based-Substituted Benzaldehyde Derivatives as Potent Inhibitors for Alzheimer's Disease along with Molecular Docking Study.

Twenty-one analogs were synthesized based on benzimidazole, incorporating a substituted benzaldehyde moiety (1-21). These were then screened for their acetylcholinesterase and butyrylcholinesterase inhibition profiles. All the derivatives except 13, 14, and 20 showed various inhibitory potentials, ranging from IC50 values of 0.050 ± 0.001 µM to 25.30 ± 0.40 µM against acetylcholinesterase, and 0.080 ± 0.001 µM to 25.80 ± 0.40 µM against butyrylcholinesterase, when compared with the standard drug donepezil (0.016 ± 0.12 µM and 0.30 ± 0.010 µM, against acetylcholinesterase and butyrylcholinesterase, respectively). Compound 3 in both cases was found to be the most potent compound due to the presence of chloro groups at the 3 and 4 positions of the phenyl ring. A structure-activity relationship study was performed for all the analogs except 13, 14, and 20, further, molecular dynamics simulations were performed for the top two compounds as well as the reference compound in a complex with acetylcholinesterase and butyrylcholinesterase. The molecular dynamics simulation analysis revealed that compound 3 formed the most stable complex with both acetylcholinesterase and butyrylcholinesterase, followed by compound 10. As compared to the standard inhibitor donepezil both compounds revealed greater stabilities and higher binding affinities for both acetylcholinesterase and butyrylcholinesterase.

Drug Repurposing Approach in Developing New Furosemide Analogs as Antimicrobial Candidates and Anti-PBP: Design, Synthesis, and Molecular Docking.

Multidrug-resistant microorganisms have become a global health problem, prompting research into new antimicrobials. Drug repurposing is a new technique in drug discovery used to improve drug development success. As a well-studied medication with a sulfonamide moiety, furosemide was chosen to study its antimicrobial effect on different microbial strains. In addition, a new family of furosemide analogs was investigated for their antimicrobial efficacy. According to the obtained results, the majority of the examined molecules exhibited potential antimicrobial activity. Compounds 3b and 4a had the best anti-MRSA results, with an MIC = 7.81 µg/mL. They also demonstrated potent anti-gram-negative activity against E. coli (MIC = 1.95 µg/mL and 3.91 µg/mL, respectively). A time-killing kinetics study against E. coli and MRSA showed bactericidal actions of 3b and 4a within 120-150 min. Moreover, an anti-PBP activity and an in vitro cytotoxicity evaluation were performed. Furosemide decreased the PBP2a levels in MRSA by 21.5% compared to the control. However, the furosemide analogs 3b and 4a demonstrated superior anti-PBP activity (55.9 and 57.1 % reduction in the expression of PBP2a, respectively). In addition, compound 4a was nearly nontoxic to normal WI-38 cells (IC50 = 248.60 µg /mL) indicating its high safety profile. Finally, the ability of furosemide and compounds 3b and 4a to bind to the target PBP2a enzyme has also been supported by molecular docking research.

Synthesis of tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives linked morpholine moiety as CDK2 inhibitors.

With the aim of developing cyclin-dependent kinase 2 (CDK2) inhibitors with strong antibreast cancer efficacy, new tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives were synthesized. The newly synthesized tri- and tetracyclic derivatives were achieved from the reaction of 4-(4-morpholin-4-yl-phenyl)-1,3,4,5,6,7-hexahydro-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-thione (5) with α-haloketone derivatives as hydrazonyl chlorides, phenacyl bromide derivatives, chloroacetone, and ethyl substituted acetate derivatives. The MCF-7 and MDA-MB-231 breast cancer cell lines were utilized to examine the anticancer properties. Compounds 5 and 8 were shown to be the most effective, with half-maximal inhibitory concentration (IC50 ) values between 5.73 and 9.11 µM, which are on the level with doxorubicin. Mechanistic studies showed that 5 and 8 caused tumor cell death by inducing apoptosis and they also produced cancer arrest in the S phase of the cell cycle. In addition, compounds 5 and 8 showed strong anti-CDK2 action (IC50 = 0.112 and 0.18 µM, respectively) comparable to roscovitine (IC50 = 0.127 µM). Moreover, the docking result demonstrated that derivatives 5 and 8 fit into the CDK2 active site in the proper orientation.

Indenyl-thiazole and indenyl-formazan derivatives: Synthesis, anticancer screening studies, molecular-docking, and pharmacokinetic/ molin-spiration properties.

Two new series of thiazole and formazan linked to 5-Bromo-indan were synthesized, and their structures were assured based on all possible analytical techniques. The size of the tested derivatives was calculated from the XRD technique and found five derivatives 3, 10a, 14a, 15, and 16 on the nanosized scale. The two series were tested for their efficacy and toxicity as anti-colon and stomach cancers. Derivative 10d showed activity more than the two reference drugs used in the case of SNU-16. Surpislly, in the case of COLO205, five derivatives 4, 6c, 6d, 6e, and 10a are better than the two benchmarks used, and two derivatives, 14a and 14b more potent than cisplatin. All potent derivatives showed a strong fit with the active site of the two tested proteins (gastric cancer (PDB = 2BID) and colon cancer (PDB = 2A4L)) in the molecular docking study. The Pharmacophore and ADME studies of the new derivatives showed that most derivatives revealed promising bioactivity, which indicates the drug-likeness properties against kinase inhibitors, protease, and enzyme inhibitors. In addition, the ProTox-II showed that the four compounds 10d, 16, 6d, and 10a are predicted to have oral LD50 values ranging from 335 to 3500 mg/kg in a rat model with (1 s,4 s)-Eucalyptol bearing the highest values and quercetin holding the lowest one.

Design, synthesis, antimicrobial screening and molecular modeling of novel 6,7 dimethylquinoxalin-2(1H)-one and thiazole derivatives targeting DNA gyrase enzyme.

New 6,7-dimethylquinoxalin-2(1H)-one and hydrazineylidene thiazol-4-one derivatives were synthesized, and evaluated for their in vitro antimicrobial activity. The obtained results revealed marked antimicrobial potential against four bacterial, and two fungal strains. Both 6,7-dimethyl-3-(2-(4-nitrophenyl)-2-oxoethyl)quinoxalin-2(1H)-one (4d), and 2-(2-(9H-fluoren-9-ylidene)hydrazineyl)-5-(2-(p-tolyl)hydrazineylidene)thiazol-4(5H)-one (11b) displayed significant antibacterial and antifungal activities having MIC ranges (1.98-15.6 mg/mL) and (1.98-3.9 mg/mL) compared to Tetracycline and Amphotericin B as standard drugs. In addition, they showed noticeable inhibitory activity against DNA gyrase enzyme. Interestingly the thiazole derivative (11b) showed marked inhibitory activity against DNA gyrase with IC50 = 7.82 ± 0.45 µM better than that of ciprofloxacin. The time-kill kinetics profile of the most active compounds against S. aureus and E. coli microorganisms displayed both concentration dependent and time dependent reduction in the number of viable cells. Furthermore, molecular docking study of both compounds in the DNA gyrase binding site was performed, showing agreement with the in vitro inhibitory activities.

Antiviral Activity of Pyrimidine Containing Compounds: Patent Review.

Viruses are still the most prevalent infectious pathogens on a worldwide scale, with many of them causing life-threatening illnesses in humans. Influenza viruses, because of their significant morbidity and mortality, continue to pose a major threat to human health. According to WHO statistics, seasonal influenza virus epidemics are predicted to cause over 2 million severe illness cases with high death rates yearly. The whole world has been suffering from the COVID-19 epidemic for two years and is still suffering so far, and the deaths from this virus have exceeded three million cases. Because the great majority of viral infections do not have a specific medication or vaccination, discovering novel medicines remains a vital task. This review covers reports in the patent literature from 1980 to the end of 2021 on the antiviral activities of pyrimidine moieties. The patent database, SciFinder, was used to locate patent applications. A large variety of pyrimidine molecules have been produced and tested for antiviral activity over the last decade. These molecules were reported to inhibit a wide range of viruses, including influenza virus, respiratory syncytial virus, rhinovirus, dengue virus, herpes virus, hepatitis B and C, and human immunodeficiency virus. The cytotoxicity of the developed pyrimidine derivatives was tested in almost all reported studies and the selectivity index was calculated to show the selectivity and safety of such molecules. From the remarkable activity of pyrimidine compounds as antivirals for several dangerous viruses, we expect that these derivatives will be used as potent drugs in the very near future.

An Exhaustive Compilation on the Synthesis of Heterocycles Pendant on the Fatty Acid Alkyl Chains.

Fatty acids derived from oils and fats of different plant and animal resources are considered one of the most valuable renewable precursors of the synthetic chemical and pharmaceutical industries. On the other hand, heterocyclic compounds are well known nowadays by their constitution of many commercialized drugs due to their unique biological activities. Combination between fatty acids and heterocyclic compounds has made important advances in the construction of valuable biologically relevant molecules in pharmaceutical industry. This review casts light on the synthetic pathways for construction of the fatty acid-heterocycle hybrid up to date in a simple classification and arranged manner.

The patent review of the biological activity of tropane containing compounds.

INTRODUCTION: Tropane-derived medications have historically played a substantial role in pharmacotherapy. Both natural and synthetic derivatives of tropane find application in addressing diverse medical conditions. Prominent examples of tropane-based drugs include hyoscine butylbromide, recognized for its antispasmodic properties, atropine, employed as a mydriatic, maraviroc, known for its antiviral effects. trospium chloride, utilized as a spasmolytic for overactive bladder, and ipratropium, a bronchodilator. AREAS COVERED: We compiled patents pertaining to the biological activity of substances containing tropane up to the year 2023 and categorized them according to the specific type of biological activity they exhibit. ScienceFinder, ScienceDirect, and Patent Guru were used to search for scientific articles and patent literature up to 2023. EXPERT OPINION: Pharmaceutical researchers in academic and industrial settings have shown considerable interest in tropane derivatives. Despite this, there remains a substantial amount of work to be undertaken. A focused approach is warranted for the exploration and advancement of both natural and synthetic bioactive molecules containing tropane, facilitated through collaborative efforts between academia and industry. Leveraging contemporary techniques and technologies in medicinal and synthetic chemistry, including high throughput screening, drug repurposing,and biotechnological engineering, holds the potential to unveil novel possibilities and accelerate the drug discovery process for innovative tropane-based pharmaceuticals.

Novel thiazole derivatives incorporating phenyl sulphonyl moiety as potent BRAFV600E kinase inhibitors targeting melanoma.

Novel thiazole derivatives possessing phenyl sulfonyl moiety were designed and synthesized as B-RAFV600E kinase inhibitors based on the clinically-approved anticancer drug, dabrafenib. All target compounds showed significant inhibition of B-RAFV600E kinase enzyme at nanomolar levels. Compounds 7b and 13a revealed excellent B-RAFV600E inhibitory activity, superior to that of dabrafenib with IC50 values of 36.3 ± 1.9, 23.1 ± 1.2, and 47.2 ± 2.5 nM, respectively. Moreover, the title compounds were much more selective toward B-RAFV600E kinase than B-RAF wild type. In addition, the most potent compounds were further evaluated for their anticancer activity against B-RAFV600E-mutated and wild type melanoma cells. A positive correlation between the cytotoxic activity and selectivity for B-RAF V600E over B-RAF wild type was clearly observed for compounds 7b, 11c, 13a, and 17. All the screened compounds potently inhibited the growth of WM266.4 melanoma cells with IC50 values in the range from 1.24 to 17.1 µM relative to dabrafenib (IC50 = 16.5 ± 0.91 µM). Compounds 7b, 11a and 11c, 13a, and 17 were much more potent than dabrafenib against B-RAFV600E-mutated WM266.4 melanoma cells. Furthermore, compound 7b suppressed the phosphorylation of downstream ERK1/2 from WM266.4 cells. Also, the docking study revealed the proper orientation and well-fitting of the title compounds into the ATP binding site of B-RAFV600E kinase.

Novel 6,7,8-trihydrobenzo[6',7']cyclohepta[2',1'-e]pyrazolo[2,3-a]pyrimidine derivatives as Topo IIα inhibitors with potential cytotoxic activity.

Novel tetracyclic pyrazolo[1,5-a]pyrimidine derivatives; namely benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2-amines 6a-e and benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2(6H)-ones 15a-d, were designed and synthesized as topoisomerase IIα inhibitors with potential anticancer activity. The structure and their mechanistic pathway were discussed and confirmed based on spectral data and DFT calculations. Compounds 6a, 6c, 15b, 15c and 15d exhibited potent Topo II inhibitory activity at one-digit IC50 values (2.35 - 7.18 µM). Among the tested compounds, aminopyrazolopyrimidine derivatives 6a (IC50 = 3.44 µM) and 6c (IC50 = 2.35 µM) were comparable/ equipotent to Doxorubicin (IC50 = 2.71 µM) against Topo II. The most active compounds in Topo II assay were further investigated in vitro for their cytotoxic potential. The oxo-pyrazolopyrimidine derivative 15c; was the most potent possessing one-digit IC50 values (HCT116 IC50 = 2.32 ± 0.13 µM, MCF7 IC50 = 1.137 ± 0.06 µM). Compound 15c was two times more potent than Doxorubicin against MCF7 breast cancer cells. 15c exhibited a safety profile much better than that of Doxorubicin against non-cancerous cells. Compound 15c was also found to be a good apoptotic inducer. Moreover, docking result revealed well-fitting and proper orientation of 15c into Topo II-DNA complex.

Design, synthesis, cytotoxicity, and molecular docking studies of novel thiazolyl-hydrazone derivatives as histone lysine acetyl-transferase inhibitors and apoptosis inducers.

Compounds containing both thiazole and arylsulfone moieties are recognized for their high biological activity and ability to fight a variety of ailments. Thus, in this context, new derivatives of (thiazol-2-yl)hydrazone with an arylsulfone moiety were synthesized as CPTH2 analogs with potent anti-histone lysine acetyl-transferase activity. Compounds 3, 4, 10b, and 11b showed an excellent inhibitory effect on P300 (E1A-associated protein p300), compared to CPTH2. Among all the tested derivatives, compound 10b revealed the highest activity against both P300 and pCAF. In addition, the new hits were tested for anticancer efficacy against two leukemia cell lines. Most of them showed a moderate to potent antitumor effect on the k562 and CCRF-CEM cell lines. Interestingly, the activity of compound 10b against the k562 cell line was found to be higher than that of CPTH2. Furthermore, it showed a good safety profile, better than CPTH2 on normal cells. Molecular docking analysis was carried out to reveal the crucial binding contacts in the inhibition of the P300 and pCAF enzymes.

Antiproliferative Activity of Some Newly Synthesized Substituted Nicotinamides Candidates Using Pyridine-2(1H) thione Derivatives as Synthon.

Some new pyridinethione and thienopyridine derivatives have been synthesized and evaluated for their antiproliferative activity using the MTT assay. Nicotinamide derivatives 3 have been synthesized and used for the preparation of new condensed thieno [2,3-b]pyridines by their reactions with active halo compounds. Finally the synthesized thienopyridine underwent ring closure whenever possible through boiling in a solution of sodium ethoxide. The antiproliferative evaluation against (HCT-116, HepG-2, and MCF-7) human cancer cells and one human healthy cell line (BJ-1) revealed that compounds 3b, 4c-5d, 7b-12a, 10d, and 13b have interesting antitumor activity specifically as antihepatocellular and anticolon cellular carcinoma agents. Besides, the docking results for most active derivatives were in agreement with the in vitro antitumor results.