Synthesis, Characterization, and Computational Insights of Flavone Derivatives as Promising Antimicrobial Agents.

Design, synthesis, in-silico and biological evaluation of novel chalcone-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer's disease

A potent moiety of (E)-5-(4-(5-chlorothiophene-2-carbonyl) piperazin-1-yl)-N'-(substituted methylene) benzofuran-2-carbohydrazide: Molecular docking, synthesis and antimicrobial evaluation

The current study aimed to synthesize novel pyrazolo[1,5-a]pyrimidines based on 5- aminopyrazoles 3, evaluate their antimicrobial activity, and study the minimum inhibitory concentration (MIC) for the most active compounds. In addition, molecular docking studies and RNA polymerase inhibitory activity were determined. Starting with our previously reported 5-aminopyrazoles 3, a number of novel pyrazolo[1,5- a]pyrimidines were synthesized. Due to the similarity of pyrazolopyrimidine derivatives with the purine systems, pyrazolopyrimidines are important in many different biological applications, most notably as anti-tumor, antibacterial, and hepatitis C virus inhibitors. The pharmaceutical applications of the pyrazolopyrimidine derivatives were explained in several approved drugs like Indiplon, Zaloplan, and Ocinaplon. To prepare a novel antimicrobial agent, namely pyrazolo[1,5-a]pyrimidine, reveal their structures using different spectral data, the minimum inhibitory concentration (MIC) for the most active compounds was evaluated, and both the molecular docking and the RNA polymerase inhibitory activity were determined. A number of different pyrazolopyrimidines namely 2-(phenylamino)-6,11-dihydrobenzo[g]pyrazolo [1,5-a]quinazoline-3-carboxamides (5a-c), (E)-5,7-dimethyl-2-(phenylamino)-6-(phenyldiazenyl)pyrazolo-[1,5- a]pyrimidine-3-carboxamides (7a-c), 7-amino-2-(phenylamino) pyrazolo[1,5-a]pyrimidine-3-carboxamides (11af), 7-amino-2-(phenylamino)-5-(2-thienyl)pyrazolo[1,5-a]pyrimidine-3-carboxamides (14-f) and ethyl 7-amino-3- carbamoyl-2-(phenylamino)-5-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate derivatives (14g-i) were synthesized through the reaction of 5-aminopyrazoles 3 with a variety of chemical reagents. On the other hand, the evaluation of the antimicrobial activity for all the prepared compounds was screened through different strains as Gram-positive bacteria, such as staphylococcus aureus and Streptococcus mutans, and Gram-negative bacteria, such as Escherichia coli, Pseudomonas aeruginosa, and klebsiella. The antifungal activity was determined by Candids Albicans fungal strain, and the MIC of the most active compounds was measured. The molecular docking was recorded, and the RNA polymerase inhibitory activity was estimated for the high docking score compounds. Compounds 5a, 5b, 5c, 7a, 7b, 7c, 11d, 14b, and 14h were the most active compounds against some of the bacterial and fungal tested strains. MIC was determined for the most active tested compounds. As an antimicrobial agent, compound 7b was the most potent, with a high docking score and RNA polymerase inhibitory activity (IC50= 0.213 μg/ml) compared to Rifampicin (IC50= 0.244 μg/ml). The reactivity of the latter compound was attributed to the presence of 4-Br-C6H4 moiety. The results demonstrated that docking studies on the most active compounds in the RNA polymerase active site were consistent with in vitro assays. The resultant novel bioactive pyrazolo[1,5-a]pyrimidine derivatives were synthesized based on 5- aminopyrazole derivatives 3. The current study evaluated the antimicrobial activity for all the prepared compounds, followed by the determination of the MIC for the most potent active compounds. The molecular docking study was performed, and it was appropriate with the in vitro activity. The RNA polymerase inhibitory activity was assessed for the most active antimicrobial compounds with a high docking score (7b, 7c, 14a, 14b, 14e, 14i). Compound 7b was the most potent compound inhibiting RNA polymerase enzyme compared to the reference drug Rifampicin. Other: The novel prepared heterocyclic systems are extremely important in a variety of domains, especially biological and pharmacological ones.

3-Imino derivative-sulfahydantoins: Synthesis, in vitro antibacterial and cytotoxic activities and their DNA interactions

A series of 12 S-substituted tetrahydrobenzothienopyrimidines were designed and synthesized based on the donepezil scaffold. All the newly synthesized compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and the most active compounds were tested for their butyrylcholinesterase (BuChE) inhibitory activity. Moreover, all the synthesized compounds were evaluated for their inhibitory effects against Aβ aggregation and antioxidant activity using the oxygen radical absorbance capacity method. Compounds 4b, 6b, and 8b displayed the most prominent AChE inhibitory action comparable to donepezil. Compound 6b showed the greatest AChE inhibitory action (IC50 = 0.07 ± 0.003 µM) and the most potent BuChE inhibitory action (IC50 = 0.059 ± 0.004 µM). Furthermore, the three compounds exhibited significant antioxidant activity. Compounds 6b and 8b exerted more inhibitory action on Aβ aggregation than donepezil. The cytotoxic activity of compounds 4b, 6b, and 8b against the WI-38 cell line in comparison with donepezil was examined using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay. The results revealed that compounds 6b and 8b were less cytotixic than donepezil, while compound 4b showed nonsignificant cytotoxicity compared to donepezil. For more insights about the binding patterns of the most promising compounds (4b, 6b, and 8b) with the AChE at molecular levels; molecular docking and molecular dynamics simulations were performed. The densityfunctional theory calculations and absorption, distribution, metabolism, excretion and toxicity properties were described as well. The results highlighted compound 6b, which incorporates a phenylpiperazine moiety coupled to a thienopyrimidone scaffold via two-atom spacer, to be a promising multifunctional therapeutic agent for the treatment of Alzheimer's disease. It is a potent dual AChE and BuChE inhibitor. Furthermore, it had stronger Aβ aggregation inhibitory action than donepezil. Additionally, compound 6b exerted significant antioxidant activity.

The aim of the present study was to evaluate pharmacological and toxicological properties of (Z)-2-(methylthio)-1-(butyltelluro)-1-phenylethene 1a, (Z)-1-(4-methylphenylsulfonyl)-2-(phenyltelluro)-2-phenylethene 1b, (Z)-2-(butyltelluro)-1-(benzylthio)-1-heptene 1c and (Z)-2-(phenylthio)-1-(butyltelluro)-1-phenylethene 1d. In vitro, vinylic telluride derivatives 1a, 1d and 1c were more effective in reducing lipid peroxidation than compound 1b. The maximal inhibitory effect of vinylic telluride derivatives on lipid peroxidation was in the following order: 1a = 1d > 1c > 1b. Compound 1b was more potent in inhibiting delta-ALA-D activity (delta-aminolevulinate dehydratase) than compounds 1c and 1d. Based on the in vitro properties presented by compounds 1a (an antioxidant) and 1b (a pro-oxidant), toxicological parameters were assessed in vivo and ex vivo in rats. Calculated LD50 of compounds 1a and 1b, administered by oral route, were 20.5 and 1.44 micromol kg(-1), respectively. Compound 1b induced behavioral alterations in the open field test. Renal and spleenic delta-ALA-D activities were inhibited in rats treated orally with compound 1a. Compound 1b stimulated delta-ALA-D activity in liver and spleen of rats. Rats treated with compound 1b had increased hepatic, renal and spleenic lipid peroxidation. Renal and hepatic markers were not altered when compounds 1a and 1b were administered to rats at doses of around LD50, while compound 1a at high doses changed aspartate aminotransferase activity and urea levels. Based on in vitro results, this study demonstrated that compounds 1a and 1d are promising antioxidant compounds. Ex vivo data reinforce compound 1a as a promising drug for more detailed pharmacological studies.

Background: The isatin molecule is present in many natural substances, including plants and animals, and is used to prepare compounds with various biological activities. Objectives: To synthesize a new series of isatin derivatives with the expectation that they will have antimicrobial activity. Methods: Thiazole Schiff bases were synthesized from various Mannich bases of isatin to evaluate their antimicrobial properties. Initially, Mannich bases (2a–e) were synthesized by reacting isatin with formaldehyde and different secondary amines. Subsequently, they were treated with 2-aminothiazole to yield the final compounds (3a–e). Spectroscopic characterization was done via FT-IR and 1H-NMR. The antimicrobial screening was conducted on all derivatives. Molecular docking and ADMET analysis were performed on the final compounds, comparing them with standard drugs (ciprofloxacin and fluconazole). Results: The antimicrobial activity was assessed on two Gram-positive bacteria, Staphylococcus aureus and Bacillus licheniformis; two Gram-negative bacteria, Escherichia coli and Acinetobacter baumannii; and one fungus species, Candida albicans. Molecular docking has recorded higher docking scores for 3d and 3e compared to ciprofloxacin and fluconazole. The virtually active molecules showed an adequate drug-like profile and desired pharmacokinetic properties in the ADMET analysis. Conclusions: Most derivatives displayed significant antimicrobial activity, with compound 3e being the most active, followed by compound 3b. Molecular docking revealed higher scores for compound 3e compared to fluconazole and for compounds 3d and 3e compared to ciprofloxacin. ADMET analysis of compound 3e showed excellent absorption, consistent with its strong GIT absorption.

In the present investigation, it was of interest to synthesized some new derivatives of pyrimidine- 2,4,6(1H,3H,5H)-trione moiety incorporated with different biologically active pharmacophores such as thiazolidin-4- one, barbitone and 2-chloroquinoline-3-carbaldehyde. The structures of synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, and mass spectral data. Antimicrobial screening of title compounds were examined against Grampositive bacteria (Staphylococcus aureus and Streptococcus pyogenes), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and three fungal species (Candida albicans, Aspergillus niger, and Aspergillus clavatus) by serial broth dilution method. Compounds 6b, 6e, 6f and 6h were associated with considerably higher antibacterial and antifungal activities. Keywords: Barbitone, Quinoline, Thiazolidin-4-one

Cytotoxicity of η6-areneruthenium-based molecules to glioblastoma cells and their recognition by multidrug ABC transporters

(E)-3-(thiophen-2-yl)-1-(4-methylphenyl)-prop-2-en-1-one 1 was obtained from the reaction of thiophene-2-aldehyde with p-methyl acetophenone. The treatment of 1 with guanidine nitrate produced 4-thiophen-2-yl-6-(4-methylphenyl)-pyrimidin-2-ylamine 2. The synthesis of N-substituted benzylidine-4-(4-methylphenyl)-6-(thiophen-2-yl) pyrimidin-2-amines 3a–j was performed by the treatment of compound 2 with the corresponding aromatic aldehydes. The reaction of 3a–j with thioglycolic acid and thiolactic acid formed the corresponding 3-[4-(4-methyl-phenyl)-6-thiophen-2-yl-pyrimidin-2-yl]-2-(substituted-phenyl)-thiazolidin-4-ones 4a–j and 3-[4-(4-methyl-phenyl)-6-thiophen-2-yl-pyrimidin-2-yl]-2-(substituted-phenyl)-5-methyl-thiazolidin-4-ones 5a–j and with chloroacetylchloride, it gives 3-chloro-1-[4-(4-methyl-phenyl)-6-thiophen-2-yl-pyrimidin-2-yl]-4-(substituted-phenyl)-azetidin-2-ones 6a–j. Newer analogues were characterized by infrared spectrum, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance spectroscopy and elemental analyses. The newly synthesized analogues were then examined for their antimicrobial activity against some bacterial and fungal strains as two Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), two Gram-positive bacteria (Staphylococcus aureus, Streptococcus pyogenes) and two fungal species (Candida albicans, Aspergillus niger, Aspergillus Clavatus) to develop a novel class of antimicrobial agents.

This study evaluates the potential of green-synthesized zinc oxide nanoparticles (ZnO-NPs) derived from the fruit extract of Balanites aegyptiaca as an antimicrobial and larvicidal agent. The synthesised nanoparticles were characterized using a UV-Visible spectrophotometer, FTIR, XRD and SEM analysis. The antimicrobial potentials of the ZnO-NPs were evaluated against two Gram-positive bacteria (Staphylococcus aureus, Streptococcus pyogenes), two Gram-negative bacteria (Salmonella typhi, Klebsiella pneumoniae), and two fungal species (Candida albicans, Aspergillus niger). The ZnO-NPs have demonstrated moderate activity across Gram-positive, Gram-negative and fungal strains at the highest concentration (30 µg/ml). The larvicidal efficacy of the synthesized ZnO-NPs was tested against Anopheles mosquito larvae at concentrations of 40, 50, and 60 mg/L. The ZnO-NPs caused 100% mortality in third and fourth instar larvae, with LC₅₀ values ranging from 35.30 to 59.47 mg/L across instars. These findings underscore the potent larvicidal and antimicrobial properties of ZnO-NPs synthesized from the fruit extract of Balanites aegyptiaca, with dose-dependent effects and notable efficiency against disease vectors and pathogens. The study supports the development of eco-friendly nanobiopesticides and therapeutics from medicinal plants.

Drug-resistant bacteria pose an increasingly serious threat to mankind all over the world. However, the currently available clinical treatments do not meet the urgent demand. Therefore, it is desirable to find new targets and inhibitors to overcome the problems of antibiotic resistance. Dihydrofolate reductase (DHFR) is an important enzyme required to maintain bacterial growth, and hence inhibitors of DHFR have been proven as effective agents for treating bacterial infections. In the present work, we have designed some methyl 2-(1H-pyrazol-4-ylthio)-1,2,3,4-tetrahydro-6-methylpyrimidine-5-carboxylate derivatives as potential DHFR inhibitors through rational drug design approach. The designed derivatives were screened through Lipinski rule, Veber’s rule, ADMET analysis, drug-likeness properties, and molecular docking. All the compounds demonstrated more potent activity than Ampicillin against both gram-positive and gram-negative bacteria. Most of the compounds were more or equipotent than Chloramphenicol and Ciprofloxacin. Compound A7 was sensitive at 25 µg/mL against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus whereas compound A20 was sensitive to all gram +ve and –ve bacteria at same concentration. Compound A16 was sensitive at 50 µg/mL against all the bacteria. In antifungal activity, compound A7 exhibited MFCs of 100 µg/mL against Candida albicans, Aspergillus niger, and Aspergillus clavatus which is same as Nystatin.

Pyridine is a nitrogen bearing heterocyclic scaffold that shows a wide range of biological activities. The pyridine nucleus has become an interesting target for medicinal chemistry researchers worldwide. Several pyridine derivatives exhibited good anticancer effects against diverse cell lines. Therefore, to explore new anticancer pyridine entities, novel pyridine derivatives were designed and synthesized and evaluated for their anticancer abilities in vitro and in vivo. All of the target compounds were evaluated against three different human cancer cell lines (Huh-7, A549 and MCF-7) via MTT assay. Most of the compounds exhibited significant cytotoxic activities. Compounds 3a, 3b, 5a and 5b showed superior antiproliferative activities to Taxol. Where, compound 3b showed IC50 values of 6.54, 15.54 and 6.13 μM compared to Taxol (6.68, 38.05, 12.32 μM) against Huh-7, A549 and MCF-7, respectively. Also, tubulin polymerization assay was carried out. The most potent compounds 3a, 3b, 5a and 5b could significantly inhibit tubulin polymerization with IC50 values of 15.6, 4.03, 6.06 and 12.61 μM, respectively. Compound 3b exhibited the highest tubulin polymerization inhibitory effect with an IC50 value of 4.03 μM compared to combretastatin (A-4) (1.64 μM). Molecular modeling studies of the designed compounds confirmed that most of the compounds made the essential binding interactions compared to the reference compound which assisted in the prediction of the structure requirements for the detected anticancer activity. Finally, in vivo studies showed that compound 3b could significantly inhibit breast cancer.

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a major role in the development of Rheumatoid Arthritis (RA). In the present study, benzimidazole and benzene sulfonyl scaffold were identified as pharmacophore by analysis of literature reports and novel small molecule IL-6 inhibitors were designed. These were screened via docking with IL-6 (PDB: 1ALU), then and through Lipinski's rule of 5. Based on docking score, 10 best compounds (4a-4e and 7a-7e) were selected for synthesis and evaluated for IL-6 inhibitory activity invitro. Compounds 4b and 7b showed the maximum inhibition of IL-6 (87.55% and 82.75%, respectively). These compounds were further explored for anti-arthritic activity invivo using the Incomplete Freund's Adjuvant Model and by morphological and histopathological studies of the inflamed paw. Compound 4b was significantly more active than compound 7b and both were found to be slightly less active than methotrexate. These findings indicate that a benzimidazole nucleus linked to a benzene sulphonyl moiety may prove to be a useful template for the development of new chemical moieties against RA.

Novel dithioic acid derivatives have been synthesized from 3 different natural acids having marked anti-inflammatory activities including ferulic acid, cinnamic acid and salicylic acid. The structures of the new compounds were established on the basis of IR, 1H NMR and mass spectral data. In silico molecular analysis of different dithioic acid analogues of natural acids were done, and the compounds which obeyed Lipinski's rule of five were taken for computing molecular descriptors. Docking studies were carried out against target, human TNF-? converting enzyme (TACE). Out of the seventeen analogues docked, compound 1b, 2b and 3b exhibited minimum glide score and were taken out for wet laboratory synthesis and validations. Compound 1b ({5-[(E)-2-(4-hydroxy-3-methoxyphenyl) ethenyl]-1, 3, 4-thiadiazol-2-yl}carbamodithioic acid) was screened for in vitro anti-TNF-? study, and compounds 1b, 2b and 3b for in vivo anti-inflammatory activity. In vitro specific TNF-? inhibitory activity of the ferulic acid analogue (1b) was evaluated using Reverse transcriptase- polymerized chain reaction. In vitro and in vivo anti-inflammatory activity was also evaluated using the HRBC membrane stabilization method and carrageenan induced rat paw edema method and compared with standard drug (diclofenac sodium). Among all derivatives 1b (ferulic acid derivative) showed maximum percentage inhibition (60.09%) while the remaining compounds showed moderate inhibition.