Compounds 4n Research Articles

Novel quinazoline sulfonamide-based scaffolds modulate methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in immunodeficient irradiated model: Regulatory role of TGF-β

A library of new quinazoline pharmacophores bearing benzenesulfonamide moiety was designed and synthesized. Compounds 3a–n were screened for their in vitro antimicrobial activity against eight multidrug-resistant clinical isolates. Compounds 3d and 3n exhibited prominent antibacterial activity, specifically against MRSA. After exhibiting relative in vitro and in vivo safety, compound 3n was selected to assess its anti-inflammatory activity displaying promising COX-2 inhibitory activity compared to Ibuprofen. In vivo experimental MRSA pneumonia model was conducted on immunodeficient (irradiated) mice to reveal the antimicrobial and anti-inflammatory responses of compound 3n compared to azithromycin (AZ). Treatment with compound 3n (10 and 20 mg/kg) as well as AZ resulted in a significant decrease in bacterial counts in lung tissues, suppression of serum C-reactive protein (CRP), lung interleukin-6 (IL-6), myeloperoxidase activity (MPO) and transforming growth factor-β (TGF-β). Compound 3n showed a non-significant deviation of lung TGF-β1 from normal values which in turn controlled the lung inflammatory status and impacted the histopathological results. Molecular docking of 3n showed promising interactions inside the active sites of TGF-β and COX-2. Our findings present a new dual-target quinazoline benzenesulfonamide derivative 3n, which possesses significant potential for treating MRSA-induced pneumonia in an immunocompromised state.

Structure-Based Drug Design of ADRA2A Antagonists Derived from Yohimbine.

Yohimbine, a natural indole alkaloid and a nonselective adrenoceptor antagonist, possesses potential benefits in treating inflammatory disorders and sepsis. Nevertheless, its broader clinical use faces challenges due to its low receptor selectivity. A structure-activity relationship study of novel yohimbine analogues identified amino esters of yohimbic acid as potent and selective ADRA2A antagonists. Specifically, amino ester 4n, in comparison to yohimbine, showed a 6-fold higher ADRA1A/ADRA2A selectivity index (SI > 556 for 4n) and a 25-fold higher ADRA2B/ADRA2A selectivity index. Compound 4n also demonstrated high plasma and microsomal stability, moderate-to-low membrane permeability determining its limited ability to cross the blood-brain barrier, and negligible toxicity on nontumor normal human dermal fibroblasts. Compound 4n represents an important complementary pharmacological tool to study the involvement of adrenoceptor subtypes in pathophysiologic conditions such as inflammation and sepsis and a novel candidate for further preclinical development to treat ADRA2A-mediated pathologies.

Enzymatic synthesis of pyridine heterocyclic compounds and their thermal stability

An efficient method was discovered for catalyzing the esterification under air using Novozym 435 to obtain pyridine esters. The following conditions were found to be optimal: 60 mg of Novozyme 435, 5.0 mL of n-hexane, a molar ratio of 2:1 for nicotinic acids (0.4 mmol) to alcohols (0.2 mmol), 0.25 g of molecular sieve 3A, a revolution speed of 150 rpm, a reaction temperature of 50 °C, and reaction time of 48 h. Under nine cycles of Novozym 435, the 80 % yield was consistently obtained. Optimum conditions were used to synthesize 23 pyridine esters, including five novel compounds. Among them, gas chromatography-mass spectrometry-olfactometry (GC-MS-O) showed phenethyl nicotinate (3g), (E)-hex-4-en-1-yl nicotinate (3m), and octyl nicotinate (3n) possessed strong aromas. Thermogravimetric analysis (TG) revealed that the compounds 3g, 3m and 3n exhibited stability at the specified temperature. This finding provides theoretical support for adding pyridine esters fragrance to high-temperature processed food.

Synthesis, antifungal evaluation, two-dimensional quantitative structure-activity relationship and molecular docking studies of isoxazole derivatives as potential fungicides.

Sheath blight and bakanae disease, prominent among emerging rice ailments, exert a profound impact on rice productivity, causing severe impediments to crop yield. Excessive use of older fungicides may lead to the development of resistance in the pathogen. Indeed, a pressing and immediate need exists for novel, low-toxicity and highly selective fungicides that can effectively combat resistant fungal strains. A series of 20 isoxazole derivatives were synthesized using alkoxy/halo acetophenones and N,N-dimethylformamidedimethylacetal. These compounds were characterized by various spectroscopic techniques, namely 1H nuclear magnetic resonance (NMR), 13C NMR and liquid chromatography-high-resolution mass spectrometry, and were evaluated for their fungicidal activity against Rhizoctonia solani and Fusarium fujikuroi. Compound 5n (5-(2-chlorophenyl) isoxazole) exhibited highest activity (effective dose for 50% inhibition [ED50] = 4.43 μg mL-1) against R. solani, while 5p (5-(2,4-dichloro-2-hydroxylphenyl) isoxazole) exhibited highest activity (ED50 = 6.7 μg mL-1) against F. fujikuroi. Two-dimensional quantitative structural-activity relationship (QSAR) analysis, particularly multiple linear regression (MLR) (Model 1), highlighted chi6chain and DistTopo as the key descriptors influencing fungicidal activity. Molecular docking studies revealed the potential of these isoxazole derivatives as novel fungicides targeting sterol 14α-demethylase enzyme, suggesting their importance as crucial intermediates for the development of novel and effective fungicides. All test compounds were effective in inhibiting both fungi, according to the QSAR model, with various descriptors, such as structural, molecular shape analysis, electronic and thermodynamic, playing an important role. Molecular docking studies confirmed that these compounds can potentially replace commercially available fungicides and help control fungal pathogens in rice crops effectively. © 2024 Society of Chemical Industry.

N,N-Diarylsulfonamide Reduces Proinflammatory Cytokine Interleukin-6 Levels in Cells through Nuclear Factor-κB Regulation.

The arylsulfonamides were synthesized from aryl sulfonyl chloride and aromatic amines in dichloromethane in the presence of pyridine. The aryne chemistry was used to prepare diarylsulfonamide from arylsulfonamides and O-silylaryl triflate with CsF in acetonitrile at room temperature for 30 min. The synthesized compounds were evaluated for cytotoxicity followed by the cytokine/inflammatory marker's inhibition capability and its mechanism of action in RAW-264.7 cells. Elevated interleukin-6 (IL-6) levels have been reported in inflammatory conditions and inflammation-associated disorders. Hence, reducing the IL-6 levels in inflammatory conditions can serve as an attractive therapeutic target in dealing the inflammation. Among 42 compounds, seven compounds showed significant inhibition of IL-6 levels in lipopolysaccharide (LPS) challenged RAW-264.7 cells at 12.5 μM concentration. Further, investigation revealed that the IC50 value of these compounds for reducing IL-6 levels was found to be in the range of 2.6 to 9.7 μM. The promising compounds 5y (IC50 of 2.6 μM) and 5n (IC50 of 4.1 μM) along with other derivatives fulfil drug-likeness parameters laid down by Lipinski's rule of five. Further, RT-qPCR and Western-blot analysis revealed that treatment with 5n significantly reduced the expression of pro-inflammatory, inflammatory and macrophage marker's expression (IL-1β, CCL2, COX2 and CD68) compared to LPS control. The mechanistic evaluation showed that 5n exhibited anti-inflammatory properties by modulating the nuclear factor-κB (NF-κB) activation. The identified compound can be a promising candidate for further discovery efforts to generate a preclinical candidate effective in inflammation.

In silico and in vitro study of pyrimidones synthesized with ethylenediamine- modified β-cyclodextrin: potential against ESBL E. coli

Modern organic synthesis is primarily focused on developing environmentally benign synthetic protocols by employing green chemistry principles. Accordingly, in our recent research work, we herein report the use of modified supramolecular host cyclodextrin as an effective solid based green catalyst for accessing structurally diverse and medicinally relevant pyrimidone architectures. The catalyst and the synthesized compounds 4 (a-r) were characterized using FT-IR, NMR and GC-mass spectroscopy. Major highlights of the reported work include the economical atom process, remarkably gentler reaction conditions, ease of operation, high isolated yields, and excellent catalyst turnover numbers. The molecular docking studies suggest that the compound 4n has hydrogen bonding, hydrophobic and π-pair interactions with the active site of the CXT M 15 receptor. Further, the in-vitro antibacterial study as well as the screening of anti-biofilm activity resulted in a BIC value of 76.79 ± 0.785% at a concentration of 10 µg/mL and morphological alterations induced by DHPMs against the ESBL E. coli strain aggregated with a good result. KEY WORDS: Ethylenediamine modified β-CD, Multicomponent reaction, 3,4-dihydropyrimidin-2(1H)-ones DHPM derivatives, Solvent-free conditions, Reusability, Antibactercidal Bull. Chem. Soc. Ethiop. 2024, 38(4), 1103-1118. DOI: https://dx.doi.org/10.4314/bcse.v38i4.23

Synthesis of the chromone-thiosemicarbazone scaffold as promising α-glucosidase inhibitors: An in vitro and in silico approach towardantidiabetic drug design.

Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 μM, ~2183-fold higher than acarbose having an IC50 of 873.34 ± 1.67 μM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase.

Design, synthesis and structure-activity relationship of 1,8-naphthalimide derivatives as highly potent hCYP1B1 inhibitors

Human cytochrome P450 1B1 enzyme (hCYP1B1), a member of hCYP1 subfamily, plays a crucial role in multiple diseases by participating in many metabolic pathways. Although a suite of potent hCYP1B1 inhibitors have been previously reported, most of them also act as aryl hydrocarbon receptor (AhR) agonists that can up-regulate the expression of hCYP1B1 and then counteract their inhibitory potential in living systems. This study aimed to develop novel efficacious hCYP1B1 inhibitors that worked well in living cells but without AhR agonist effects. For these purposes, a series of 1,8-naphthalimide derivatives were designed and synthesized, and their structure-activity relationships (SAR) as hCYP1B1 inhibitors were analyzed. Following three rounds SAR studies, several potent hCYP1B1 inhibitors were discovered, among which compound 3n was selected for further investigations owing to its extremely potent anti-hCYP1B1 activity (IC50 = 0.040 nM) and its blocking AhR transcription activity in living cells. Inhibition kinetic analyses showed that 3n potently inhibited hCYP1B1 via a mix inhibition manner, showing a Ki value of 21.71 pM. Docking simulations suggested that introducing a pyrimidine moiety to the hit compound (1d) facilitated 3n to form two strong interactions with hCYP1B1/heme, viz., the C-Br⋯π halogen bond and the N-Fe coordination bond. Further investigations demonstrated that 3n (5 μM) could significantly reverse the paclitaxel (PTX) resistance in H460/PTX cells, evidenced by the dramatically reduced IC50 values, from 632.6 nM (PTX alone) to 100.8 nM (PTX plus 3n). Collectively, this study devised a highly potent hCYP1B1 inhibitor (3n) without AhR agonist effect, which offered a promising drug candidate for overcoming hCYP1B1-associated drug resistance.

Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV-1 NNRTIs.

NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC50 = 0.009-17.7 μM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile (T1/2 = 5.09 h, F = 108.96%) compared that of DOR (T1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy.

Discovery and synthesis of novel benzoylhydrazone neuraminidase inhibitors

Neuraminidase (NA) serves as a promising target for the exploration and development of anti-influenza drugs. In this work, lead compound 5 was discovered through pharmacophore-based virtual screening and molecular dynamics simulation, and 14 new compounds were obtained by modifying the lead compound 5 based on pharmacophore features. The biological activity test shows that 5n (IC50 = 0.13 μM) has a better inhibitory effect on wild-type NA (H5N1), while 5i (IC50 = 0.44 μM) has a prominent inhibitory effect on mutant NA (H5N1-H274Y), both of them are better than the positive control oseltamivir carboxylate (OSC). The analysis of docking results indicate that the good activities of compounds 5n and 5i may be attributed to the thiophene ring in 5n can stretch into the 150-cavity of NA, whereas the thiophene moiety in 5i can extend to the 430-cavity of NA. The findings of this study may be helpful for the discovery of new NA inhibitors.

Microwave Assisted Groebke-Blackburn-Bienayme Multicomponent Reaction to Synthesis of Imidazo[1,2-a]pyridine-furan Hybrids as Possible Therapeutic Option for Leukemia, Colon Cancer and Prostate Cancer

Aims: Microwave assisted ecofriendly catalytic protocol for the Groebke-Blackburn-Bienayme multicomponent reaction to synthesis imidazo[1,2-a]pyridine-furan hybrids as possible therapeutic option for leukemia, colon cancer and prostate cancer Background: Microwave synthesis has emerged as a potent tool for the more economical and environmental friendly synthesis of organic compounds, such as derivatives of imidazo[1,2-a]pyridine. Compared to traditional synthesis, microwave radiation causes molecules to be ex-cited and distributes thermal energy evenly in a shorter amount of time. Objective: The primary objective of the work presented in this article was to prepare imidazo[1,2-a]pyridine-furan hybrids via Groebke-Blackburn-Bienayme multicomponent reaction using PEG 400 in microwave irradiation as green approach. Characterized it and evaluated their anticancer activities. Methods: In a sealed microwave glass vial, 5-methylfuran-2-carbaldehyde 1, 2-aminoazines 2a-g, isocyanides 3a-c in presence of 20mol% acetic acid were dissolved in PEG 400 (polyethylene glycol 400) reaction solvent. The glass vial was sealed and irradiate in microwave with stirring at temperature of 75°C for 10 min. This method is an efficient alternative approach to synthesizing imidazo[1,2-a]pyridine-furan hybrids via Groebke-Blackburn-Bienayme multicomponent reac-tion. Results: We have successfully synthesised the imidazo[1,2-a]pyridine-furan hybrids via Groebke-Blackburn-Bienayme multicomponent reaction using PEG 400 in microwave irradiation as green approach. The structures of the compounds were confirmed through various spectro-scopic techniques and evaluated their anticancer activities. Conclusion: The reported protocol is advantageous over conventional methods of imidazo[1,2-a]pyridine derivatives. The time required for the reaction is much less as compared to the usual requirements of reflux. Compound 4e, 4f, 4n and 4o shows the most increased activity against cell line RPMI-8226, HCT-116 and PC-3 of Leukemia, Colon cancer and Prostate cancer respectively. By using the potential of imidazo[1,2-a]pyridine-furan based compounds via sustainable green approach, more effective and accurate cancer treatments can be designed in future.

Molecular Docking, Toxicity Study and Antimicrobial Assessment of Novel Synthesized 1,3-(Disubstituted)-thiazol-2-amines

In current study, a novel analogous of substituted-2-aminothiazoles (3a-o) were synthesized through a multi-step synthetic process. Structural elucidation of these newly synthesized substituted-2-aminothiazoles were achieved using combination of analytical techniques, comprising proton nuclear magnetic resonance (PNMR), mass spectrometry and FTIR. An in vitro investigation was performed to measure the efficacy of antibacterial and antimycotic characteristics of these novel compounds (3a-o). Specifically, the growth-inhibiting action against the test fungal strains, including A. niger, M. purpureos and A. flavus was examined. Additionally, their inhibitory antibacterial activity against key bacterial strains, including P. aeruginosa, S. aureus and E. coli was ascertained employing the agar diffusion technique. The results of antibacterial screening disclosed that maximum number of the thiazole derivatives viz. 3a, 3d, 3e, 3i, 3k, 3l and 3n displayed minimum inhibitory concentration of 12.5 µg/mL for E. coli. While compounds 3k and 3n displayed minimum inhibitory concentration of 12.5 µg/mL for S. aureus. A minimum inhibitory concentration of 25 µg/mL was exhibited by compounds 3i, 3l and 3n against P. aeruginosa. None of the 2-aminothiazole derivative disclosed promising action against the fungal strains. Screening for in silico ADME and toxicity studies revealed that compounds are fairly compatible and were devoid of potential toxicity except compounds 3j and 3m. The docking studies on DNA gyrase (PDB ID; 1KZN) shows favourable binding interaction comparable to the pre-occupied ligand clorobiocin.

Exploring pyrrolidinyl-spirooxindole natural products as promising platforms for the synthesis of novel spirooxindoles as EGFR/CDK2 inhibitors for halting breast cancer cells.

Cancer represents a global challenge, and the pursuit of developing new cancer treatments that are potent, safe, less prone to drug resistance, and associated with fewer side effects poses a significant challenge in cancer research and drug discovery. Drawing inspiration from pyrrolidinyl-spirooxindole natural products, a novel series of spirooxindoles has been synthesized through a one-pot three-component reaction, involving a [3 + 2] cycloaddition reaction. The cytotoxicity against breast cancer cells (MCF-7 and MDA-MB-231) and safety profile against WISH cells of the newly developed library were assessed using the MTT assay. Compounds 5l and 5o exhibited notable cytotoxicity against MCF-7 cells (IC50 = 3.4 and 4.12μM, respectively) and MDA-MB-231 cells (IC50 = 8.45 and 4.32μM, respectively) compared to Erlotinib. Conversely, compounds 5a-f displayed promising cytotoxicity against MCF-7 cells with IC50 values range (IC50 = 5.87-18.5μM) with selective activity against MDA-MB-231 cancer cells. Compound 5g demonstrated the highest cytotoxicity (IC50 = 2.8μM) among the tested compounds. Additionally, compounds 5g, 5l, and 5n were found to be safe (non-cytotoxic) against WISH cells with higher IC50 values ranging from 39.33 to 47.2μM. Compounds 5g, 5l, and 5n underwent testing for their inhibitory effects against EGFR and CDK-2. Remarkably, they demonstrated potent EGFR inhibition, with IC50 values of 0.026, 0.067, and 0.04μM and inhibition percentages of 92.6%, 89.8%, and 91.2%, respectively, when compared to Erlotinib (IC50 = 0.03 μM, 95.4%). Furthermore, these compounds exhibited potent CDK-2 inhibition, with IC50 values of 0.301, 0.345, and 0.557μM and inhibition percentages of 91.9%, 89.4%, and 88.7%, respectively, in contrast to Roscovitine (IC50 = 0.556 μM, 92.1%). RT-PCR analysis was performed on both untreated and 5g-treated MCF-7 cells to confirm apoptotic cell death. Treatment with 5g increased the gene expression of pro-apoptotic genes P53, Bax, caspases 3, 8, and 9 with notable fold changes while decreasing the expression of the anti-apoptotic gene Bcl-2. Molecular docking and dynamic simulations (100 ns simulation using AMBER22) were conducted to investigate the binding mode of the most potent candidates, namely, 5g, 5l, and 5n, within the active sites of EGFR and CDK-2.

Scaffold hopping for designing of potent and selective CYP1B1 inhibitors to overcome docetaxel resistance: synthesis and evaluation

Cytochrome P450 1B1, a tumor-specific overexpressed enzyme, significantly impairs the pharmacokinetics of several commonly used anticancer drugs including docetaxel, paclitaxel and cisplatin, leading to the problem of resistance to these drugs. Currently, there is no CYP1B1 inhibition-based adjuvant therapy available to treat this resistance problem. Hence, in the current study, exhaustive in-silico studies including scaffold hopping followed by molecular docking, three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular dynamics and free energy perturbation studies were carried out to identify potent and selective CYP1B1 inhibitors. Initially, scaffold hopping analysis was performed against a well-reported potent and selective CYP1B1 inhibitor (i.e. compound 3n). A total of 200 scaffolds were identified along with their shape and field similarity scores. The top three scaffolds were further selected on the basis of these scores and their synthesis feasibility to design some potent and selective CYP1B1 inhibitors using the aforementioned in-silico techniques. Designed molecules were further synthesized to evaluate their CYP1B1 inhibitory activity and docetaxel resistance reversal potential against CYP1B1 overexpressed drug resistance MCF-7 cell line. In-vitro results indicated that compounds 2a, 2c and 2d manifested IC50 values for CYP1B1 ranging from 0.075, 0.092 to 0.088 μM with at least 10-fold selectivity. At low micromolar concentrations, compounds 1e, 1f, 2a and 2d exhibited promising cytotoxic effects in the docetaxel-resistant CYP1B1 overexpressed MCF-7 cell line. In particular, compound 2a is most effective in reversing the resistance with IC50 of 29.0 ± 3.6 μM. All of these discoveries could pave the way for the development of adjuvant therapy capable of overcoming CYP1B1-mediated resistance. Communicated by Ramaswamy H. Sarma

Discovery of Novel Cinnamic Acid Derivatives as Fungicide Candidates.

Structural diversity derivatization from natural products is an important and effective method of discovering novel green pesticides. Cinnamic acids are abundant in plants, and their unparalleled structures endow them with various excellent biological activities. A series of novel cinnamic oxime esters were designed and synthesized to develop high antifungal agrochemicals. The antifungal activity, structure-activity relationship, and action mechanism were systematically studied. Compounds 7i, 7u, 7v, and 7x exhibited satisfactory activity against Gaeumannomyces graminis var. tritici, with inhibition rates of ≥90% at 50 μg/mL. Compounds 7z and 7n demonstrated excellent activities against Valsa mali and Botrytis cinerea, with median effective concentration (EC50) values of 0.71 and 1.41 μg/mL, respectively. Compound 7z exhibited 100% protective and curative activities against apple Valsa canker at 200 μg/mL. The control effects of 7n against gray mold on tomato fruits and leaves were all >96%, exhibiting superior or similar effects to those of the commercial fungicide boscalid. Furthermore, the quantitative structure-activity relationship was established to guide the further design of higher-activity compounds. The preliminary results on the action mechanism revealed that 7n treatment could disrupt the function of the nucleus and mitochondria, leading to reactive oxygen species accumulation and cell membrane damage. Its primary biochemical mechanism may be inhibiting fungal ergosterol biosynthesis. The novel structure, simple synthesis, and excellent activity of cinnamic oxime esters render them promising potential fungicides.

Identification of thienopyrimidine derivatives tethered with sulfonamide and other moieties as carbonic anhydrase inhibitors: Design, synthesis and anti-proliferative activity

Eighteen novel compounds harboring the privileged thienopyrimidine scaffold (5a-q, and 6a),were designed based on molecular hybridization strategy. These compounds were synthesized and tested for their inhibitory activity against four different carbonic anhydrase isoforms: CA I, II, IX, and XII. Microwave and conventional techniques were applied for their synthesis. Compounds 5b, 5g, 5l, and 5p showed the highest inhibition activity against the four CA isoforms. Compound 5p exhibited promising inhibitory activity against CA II, CA IX and CA XII with KI values of8.6, 13.8, and 19 nM, respectively, relative to AAZ, where KIs = 12, 25, and 5.7 nM, respectively. Also, compound 5 l showed significant activity against the tumor-associated isoform CA IX with KI = 16.1 nM. All the newly synthesized compounds were also screened for their anticancer activity against NCI 60 cancer cell lines at a 10 µM concentration. Compound 5n showed 80.38, 83.95, and 87.39 % growth inhibition against the leukemic cell lines CCRF-CEM, HL-60 (TB), and RPMI-8226, respectively. Also, 5 h showed 87.57 % growth inhibition against breast cancer cell line MDA-MB-468; and 66.58 and 60.95 % inhibitionagainst renal cancer cell lines UO-31, and ACHN, respectively. A molecular docking studywas carried out to predict binding modes of our synthesized compounds in the binding pockets of the four carbonic anhydrase isoforms, and results revealed that compounds 5b, 5g, 5l, and 5p succeeded in mimicking the binding mode of AAZ through metal coordination with Zn+2 ion and binding to the amino acids Thr199, His94, and His96 that are critical for activity.

Organo NHC catalyzed aqueous synthesis of 4β-isoxazole-podophyllotoxins: in vitro anticancer, caspase activation, tubulin polymerization inhibition and molecular docking studies.

We present, for the first time, the organo-N-heterocyclic carbene (NHC) catalyzed 1,3-dipolar cycloaddition of 4β-O-propargyl podophyllotoxin (1) with in situ aromatic nitrile oxides to afford regioselective 4β-isoxazolepodophyllotoxin hybrids (6a-n) in benign aqueous-organic media. Preliminary anticancer activity results showed that compound 6e displayed superior activity against MCF-7, HeLa and MIA PaCa2 human cell lines compared with podophyllotoxin. Compounds 6j and 6n showed greater activity against the MCF-7 cell line than the positive control. Caspase activation studies revealed that compound 6e at 20 μg ml-1 concentration had greater caspase 3/7 activation in MCF-7 and MIAPaCa2 cells than podophyllotoxin. Furthermore, in vitro tubulin polymerization inhibition studies revealed that compound 6e showed comparable activity with podophyllotoxin. Finally, in silico molecular docking studies of compounds 6e, 6j, 6n and podophyllotoxin on α,β-tubulin (pdb id 1SA0) revealed that compound 6n showed excellent binding energies and inhibition constants compared with podophyllotoxin.

Synthesis and characterization of 4(3-(4-Fluorophenyl)2-methyl-1-(4-(sulfonamidesubtituted)phenyl)-4-oxoazitidin-2-yl)-3-methyl-1-(p-tolyl)-1H-pyrazol-5(4H)One as Antibacterial, and Antioxidant Candidates

A series of all novels 4(3-(4-Fluorophenyl)2-methyl-1-(4-(sulfonamidesubtituted)phenyl)-4-oxoazitidin-2-yl)-3-methyl-1-(p-tolyl)-1H-pyrazol-5(4H) One 5a-5r poly functionalized derivatives were containing sulfonamide functionality united with 2-Azitidinone (Azitidin-2-one or β-lactam) group which designed and synthesized with moderate to good yield. The starting with 4-acyl-2-pyrazolin-5-one (APYZ) 1 which condensed with different sulfonamides 2 produced intermediate Schiff bases 4-(arylideneamino)-N-(thiazol-2-yl)benzensulfonamide 3a-r were cyclization with 2-(4-flourophenyl)chloroacetylchloride (F-CAC) 4 which produced targeted compounds 5a-5r of 2-Azitidinone versatile group in good yield. The isolated compounds were recognized by spectral and elemental investigation. The compounds 5f, 5l, 5n, and 5r showed excellent increased antibacterial activity compared to streptomycin standard drug and 5c, 5f, 5l, 5o, and 5r showed moderate to good antioxidant properties with used DPPH radical scavenging assay.

Design and synthesis of Meldrum's acid based 7-azaindole anchored 1,2,3-triazole hybrids as anticancer agents.

A series of Meldrum's acid, 7-azaindole and 1,2,3-triazole hybrids were synthesized and evaluated for their in vitro anticancer activity against five different cancer cell lines viz. MCF-7 (breast cancer), HeLa (cervical cancer), DU-145 (prostate cancer), HepG2 (liver cancer) and K562 (myelogenous leukemia cell). Among the series, compound 6b containing a 4-methyl substitution showed potent activity against HeLa cell line. Cell cycle analysis revealed that compound 6b induced cell cycle arrest at the G2/M phase and induced apoptosis. Apoptotic activity was further confirmed by Hoechst staining and Annexin V-FITC assay. Compound 6b has been found to exhibit higher activity in all four cell lines, with IC50 values of 6.67 ± 0.39 μM, 4.44 ± 0.32 μM, 12.38 ± 0.51 μM and 9.97 ± 0.25 μM against MCF-7, HeLa, DU-145 and HepG2 cell lines respectively. Compounds 6m (9.68 ± 0.10 μM) and 6n (9.52 ± 0.38 μM), which have dimethoxy and trimethoxy substitutions, respectively, have demonstrated significant anticancer activity against HeLa cells compared to the other cells. The molecular docking study of ligand 6b against the crystal structure of EGFR and Mcl-1 scored notable binding energy values and displayed important interactions like H-bond, π-cation and other hydrophobic interactions.

New pyrrolidine-carboxamide derivatives as dual antiproliferative EGFR/CDK2 inhibitors.

Cancer is one of the leading causes of mortality worldwide, making it a public health concern. A novel series of pyrrolidine-carboxamide derivatives 7a-q were developed and examined in a cell viability assay utilizing a human mammary gland epithelial cell line (MCF-10A), where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 μM. Antiproliferative activity was evaluated invitro against four panels of cancer cell lines A-549, MCF-7, Panc-1, and HT-29. Compounds 7e, 7g, 7k, 7n, and 7o were the most active as antiproliferative agents capable of triggering apoptosis. Compound 7g was the most potent of all the derivatives, with a mean IC50 of0.90 μM compared to IC50 of 1.10 μM for doxorubicin. Compound 7g inhibited A-549 (epithelial cancer cell line), MCF-7 (breast cancer cell line), and HT-29 (colon cancer cell line) more efficiently than doxorubicin. EGFR inhibitory assay results of 7e, 7g, 7k, 7n, and 7o demonstrated that the tested compounds inhibited EGFR with IC50 values ranging from 87 to 107 nM in comparison with the reference drug erlotinib (IC50 = 80 nM). 7e, 7g, 7k, 7n, and 7o inhibited CDK2 efficiently in comparison to the reference dinaciclib (IC50 = 20 nM), with IC50 values ranging from 15 to 31 nM. The results of inhibitory activity assay against different CDK isoforms revealed that the tested compounds had preferential inhibitory activity against the CDK2 isoform.