Compounds 4l Research Articles

Design, synthesis, and cytotoxic activity of 2-amino-1,4-naphthoquinone-benzamide derivatives as apoptosis inducers

A new series of 2-amino-1,4-naphthoquinone-benzamides 5a-n was designed based on previously reported potent cytotoxic agents. These compounds were synthesized from the reaction of 1,4-naphthoquinone, 4-aminobenzoic acid, and appropriate amine derivatives in good yields. Cytotoxic activities of the target compounds 5a-n were evaluated against three cancer cell lines MDA-MB-231, SUIT-2, and HT-29 by MTT assay and the obtained in vitro data. All newly synthesized compounds were more potent than positive control cisplatin against MDA-MB-231 cell line and less potent than this control against SUIT-2 cell line. Moreover, most of the synthesized compounds were more potent than cisplatin against HT-29 cell line. Among the synthesized compounds, compound 5e was the most potent cytotoxic agent against all the three evaluated cell lines. Moreover, cell cycle analysis showed that derivatives 5f and 5l dose-dependently increase the percentage of sub-G1 cells. Induction of apoptosis as an important mechanism of anti-cancer drugs was confirmed morphologically in the most potent new compounds 5e, 5f, 5g, and 5l by Hoechst 33,258 staining.

Synthesis of Novel 3,4-Dihydropyrimidine Derivatives, Cytotoxic Activity Evaluation, Apoptosis, Molecular Docking Studies, and MD Simulations.

In this study, twelve 3,4-dihydropyrimidines derivatives were synthesized through Biginelli multi-component reaction. The efficacy of these compounds against MCF-7, A549, and HeLa cells was evaluated using the MTT method. The results showed that designed derivatives were more effective against A549 cancer cells than MCF-7 and HeLa cells. Compound 5l (bearing 4-Cl-phenyl at C4 of 3, 4-dihydropyrimidin-2(1H)-one ring) was the most potent analogue (A549: 18.65±1.87 μM, HeLa: 26.59±2.71 μM, MCF-7: 31.82±2.64 μM). The presence of an electron-withdrawing group with optimum lipophilicity at the C4 position of the phenyl ring increased the cytotoxic effect. The flow cytometry findings indicated that compound 5l induced apoptosis in A549 cancer cells in a dose-dependent manner. Eg5 and AKT1 were selected as molecular modeling target by applying pharmacology network analyses. The molecular docking results indicated that both enantiomers of compound 5l had significant interactions with key residues in both Eg5 (Gly117 and Glu116) and AKT1 (Ala123 and Glu121) active sites. However, MD simulation revealed that the R enantiomer had a more stable complex and a higher binding affinity to the Eg5 enzyme active site than the S-enantiomer. The affinity of 5l (R enantiomer) to Eg5 was predicted more than AKT1.

Synthesis of Paracetamol‐Appended Bis 1,2,3‐Triazole Analogues as Anti‐Inflammatory Agents

AbstractParacetamol‐based bis 1,2,3‐triazole analogues were synthesized involving copper‐catalyzed click chemistry protocol. The new compounds were characterized by 1H NMR, 13C NMR, and mass spectral techniques. All the compounds were evaluated for their in vitro anti‐inflammatory properties using diclofenac as standard reference. The compound 6b with chlorine and fluorine functions displayed outstanding activity with IC50 values of 7.34 ± 0.45 µM and 7.84 ± 0.47 µM, respectively. Compound 6g with methyl and fluorine functions displayed best activity with IC50 values of 9.34 ± 0.22 µM and 9.40 ± 0.35 µM, respectively. Compound 6i, 6k, 6f, 6a, 6e, 6h, 6j, and 6l exhibited promising activity with respect to diclofenac. Using PyRx tool, the molecular docking study against crystal structure of COX‐2 proved the binding efficacies with notable binding interactions.

Facile synthesis of substituted 2-styrylnaphthyridine and its derivatives via sp3C-H functionalization under mild conditions and their antimicrobial activity and Electrochemical properties.

Metal-free, synthetic approach for the Efficient synthesis of pyrazole, imidazopyridine based substituted 2-styryl-1,8-naphthyridines has developed via sp3 C-H activation of substituted 7-methyl-1,8-naphthyridines, with various aromatic/heteroaromatic aldehydes through knoevenagel condensation under mild basic (Piperidine) conditions. Further, the synthesized titled molecules tested their absorption and emission spectra, interestingly compound 3d was found to be that inspiring emission spectra at 626 nm (red shift) with impressive stokes shift 133 nm. Moreover, some of the best resultant conjugate scaffolds (compounds 3c, 3d, 3e, and 4e) analysed their electrochemical properties, thus, 3c, 3d, 3e, and 4e molecules respectively displaying medium to good redox potentials (compound 3e displays 0.3, -1.71 V respectively) and tested scanning rate (from 50 to 500 mV s−1) also. Furtherly, all synthsized derivatives analysed their biological activity, i.e., antifungal and antifungal. Among that, the compounds 3c, 3d, 3e, 3i, 3k, 3l, 5c, 5d and 5f were established excellent inhibition zone of activity against standard drugs.

Synthesis, Aromatase Inhibition, Cytotoxicity and Molecular Docking Studies of New Fluorinated and Non-fluorinated Thiourea Derivatives of Desloratadine.

Aromatase inhibitors are among the most effective treatment of the breast cancer. Aromatase catalyzes estrogen biosynthesis, which is a long-term cause of breast cancer. Current study describes the synthesis, purification of 26 new fluorinated and non-fluorinated thiourea derivatives of desloratadine (5), and their aromatase inhibition activity, cytotoxicity against cancer cell line (MDA-MB-231). Compounds 7v and 7l exhibited a significant anti-aromatase activity, while compounds 7a, 7g-h, 7m and 7u were also significant active against MDA-MB-231 cell line. Furthermore, the molecular docking studies revealed that active compounds form key interactions with the crucial amino acid of aromatase active site including TRP224, LEU477, CYS437, ALA438, MET374, ARG115, ILE305, and PHE221, which are responsible for the binding interaction of aromatase. All analogues were new, except 7b and 7k and also lacked cytotoxicity BJ human fibroblasts, with the exception of 5 and 7x. This selectivity makes this series particularly interesting for further studies.

In-vitro and in-silico studies based discovery of 2-aryl-N-(4-morpholinophenyl)thiazol-4-amines as promising DNA gyrase inhibitors

Background: DNA gyrase is an important enzyme for the survival of bacteria. Many DNA gyrase inhibitors are in clinical practice. However, these inhibitors also encompass certain toxic and drug/food interactions. This warrants the development of a new template as DNA gyrase inhibitors. Therefore, this study aimed to deliver morpholine-based thiazoles (5a-5l) as safer DNA gyrase inhibitors.Methods: The 5a-5l were prepared by reacting compound 3 with various aryl thioamides. The structures of 5a-5l were ascertained by their spectral records. The 5a-5l were subjected to their antibacterial activity potential (serial plate dilution method), DNA gyrase inhibiting activity, and toxicity analysis (MTT assay) against HepG2 & Vero cell lines. The in-silico studies (pharmacokinetic parameters and molecular docking) of 5a-5l were likewise performed.Results: It was surprisingly observed that the MIC values of 5a-5l were equal to the MIC values of ciprofloxacin (12.5 µg/ml) against the tested bacteria, whereas the DNA gyrase inhibitory activity (IC50 in µg/ml) of 5h (3.52), 5g (3.76), 5f (3.88), 5e (4.08), 5l (4.11), 5b (4.28), 5k (4.28), 5i (4.30), and 5d (4.32) was equal/better than ciprofloxacin (4.32). The MTT assay also implied the non-cytotoxic nature of 5a-5l against HepG2 & Vero cell lines up to 200 µg/ml concentration. The docking outcomes indicated a similar binding pattern of 5a-5l and ciprofloxacin at the active site of DNA gyrase, wherein 5a-5l displayed a better binding affinity for the active site. The in-silico toxicity data employing the ProTox-II web server indicated no hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, or cytotoxic effect of 5a-5l. Also, the SwissADME software supported the drug-likeliness properties and high gastrointestinal absorption of 5a-5l.Conclusion: Compounds 5h, 5g, 5f, 5e, 5l, 5b, 5k, 5i, and 5d are potent DNA gyrase inhibitors with promising safety profiles.Keywords: Discovery; Morpholine; Thiazole; DNA gyrase; MTT assay; Docking

Pharmacophore‐Based Modeling, Synthesis, and Biological Evaluation of Novel Quinazoline/Quinoline Derivatives: Discovery of EGFR Inhibitors with Low Nanomolar Activity

AbstractThe main aim of this study is to obtain novel molecules that are more selective on cancer cells compared to healthy cells. For this purpose, four hit molecules are identified using 11 new pharmacophore hypotheses followed by scanning the in‐house database. Then, based on those hit molecules, the synthesis and analysis of four different series (three quinazolines and one quinoline series) are carried out, and their anticancer activity is investigated. Finally, by using molecular docking and dynamics simulation methods, binding mode and structure–activity relationship are examined. Among the quinazolin‐4(3H)‐one derivatives, those containing halogen atom are found to be potentially effective, while the best epidermal growth factor receptor (EGFR) inhibition and apoptosis induction are displayed by compounds containing 4‐amino‐1,2,4‐triazole moiety. Notably, four compounds (4h, 8d, 8l, and 8m) show EGFR inhibition activity at 5.298 ± 0.164, 5.46 ± 0.221, 2.670 ± 0.124, and 2.191 ± 0.908 × 10−9 m, their inhibitory activity is similar to or stronger than gefitinib (IC50: 4.169 ± 0.156 × 10−9 m). In addition, EGFR inhibitor concentration of 4g, 8e, and 8o is determined as 27588 ± 6.945, 52.41 ± 2.312, and 33657 ± 8.512 × 10−9 m. These findings indicate that generated pharmacophore hypotheses successfully determine new EGFR inhibitors. In conclusion, four novel compounds, more active than gefitinib with fewer side effects, are reached, and the structure–activity relationships are clarified.

Design, Synthesis, and 3D-QASR of Oxazoline Derivatives Containing an S-S Moiety as Potential Acaricide.

To mitigate the detrimental effects of agricultural pest mites on crop yield, an active substructure splicing strategy was employed to modify etoxazole by introducing an S-S moiety. The target products were obtained efficiently via a bilateral disulfurating reagent (DSMO), which was developed by our group. The leaf dip method was used to evaluate the activities of the designed target compounds against the eggs and larvae of the spider mite (Tetranychus cinnabarinus). Most of the target compounds exhibited good efficacy in controlling the larvae and eggs of T. cinnabarinus. Based on these results, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established to guide the construction of compound 7l. Notably, compound 7l exhibited a better activity against T. cinnabarinus eggs (LC50 = 0.0035 mg/L) compared to etoxazole (LC50 = 0.2990 mg/L). Greenhouse bioassays indicated that compound 7l exhibits excellent acaricidal activity against egg of T. cinnabarinus, which is better than the etoxazole at 1.0 mg/L. Additionally, some of the compounds showed inhibitory effects against Dickeya zeae (D. zeae), Xanthomonas campestris pv campestris (Xcc), Xanthomonas oryzae pvoryza (Xoo), and Xanthomonas oryzae pvoryzicola (Xoc). Furthermore, compounds 7l not only exhibited relatively potent against Plutella xylostella activities (LC50 = 24.0 mg/L) but also had low toxicity (LC50 > 11.0 μg/bee) to Apis mellifera. In conclusion, the current experimental results suggest that oxazoline derivatives containing an S-S moiety have the potential to serve as lead compounds for the development of novel acaricide agents.

One-pot synthesis of fused isoxazolo[4′,5′:4,5]thiopyrano[2,3-d]pyrimidines as potent EGFR targeting anti-lung cancer agents

The requirement for scaffolds has prompted synthetic chemists to devise simple and effective methods for optimal synthesis, which are critical in the medical industry. Under comparatively optimized conditions, a click followed by a CC bond coupling reaction between iodoalkyne (4) and substituted nitrile oxide was utilized to explore the synthesis of fused isoxazoles containing thiopyrano[2,3-d]pyrimidine under microwave irradiation. The synthesized compounds were tested for their anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H460 and A549). The compounds 6i and 6l have shown more potent activity against both cancer cell lines as compared to standard drugs doxorubicin and erlotinib. And also compounds 6e, 6j, and 6k have shown more potent activity as compared to Doxorubicin and moderate activity compared to erlotinib. Later, in vitro EGFR results of more potent compounds revealed that compounds 6l and 6k have shown potent EGFR activity compared to standard erlotinib. To evaluate the molecular interactions of more potent compounds with the human epidermal growth factor receptor. It was observed that all the potent compounds exhibited greater binding energies in comparison to the standard drug erlotinib.

Screening of synthesized perimidine compounds for the assessment of antimicrobial potential: in-vitro and in-silico molecular docking and molecular dynamics simulation studies

Presently, antimicrobial resistance is a major and worldwide concern due to high rate of mutation in microorganisms, widespread use, lack of efficacy of drugs, and low drug discovery rate. Considering the importance of N-heterocycles as antibiotics, perimidine derivatives 3(a–v) have been synthesized via cyclocondensation reaction of 1,8-diaminonaphthalene and aryl aldehydes. Further, the synthesized perimidines 3(a–v) were screened as potent antimicrobial agents via in-vitro, in-silico, ADME and MD simulation studies. All 22 derivatives 3(a–v) were studied against two-gram +ve (E. coli and P. aeruginosa), two-gram −ve (S. aureus and B. subtilis), and two fungal (A. niger and S. cerevisiae) strains using ciprofloxacin and fluconazole as reference drugs. The in-vitro study results showed that compounds 3e, 3h, 3l, and 3m were the most potent against S. aureus and 3(a–d), 3(g–i), and 3s were the most active against B. subtilis as compared to the standard. Furthermore, molecular docking studies were performed against Dihydrofolate reductase (PDB Id: 3SRW) from S. aureus, DNA gyrase (PDB Id: 4DUH) from E. coli, and ERG11 gene (PDB Id: 4LXJ). Compounds 3f, 3f/3m, and 3o were found to bind efficiently with the highest binding energy − 10.6, − 9.6, and − 11.3kcal/mol depicting the potential inhibitor of 3SRW, 4DUH, and 4LXJ receptor protein, respectively. The drug-likeness properties of compounds were studied using SwissADME program. To further validate these findings, molecular dynamics simulations were conducted to evaluate their binding stability. From simulation studies, it was observed that all the shortlisted compounds displayed stable binding within the active site of the selected proteins.Graphical abstract

A promising class of Antiprotozoal agents, design and synthesis of novel Pyrimidine–Cinnamoyl Hybrids

Malaria, caused by parasitic protozoans of the Plasmodium genus, continues to be one of the greatest global health crises, especially in Africa. The emergence of antimalarial drug resistance continues to be a health problem necessitating an urgent need for alternative and cost-effective antimalarials. Using a molecular hybridization approach, we report the design and synthesis of an efficacious novel class of antiprotozoal agents; (E)-1-(4-(4,6-diphenylpyrimidin-2-yl)piperazin-1-yl)-3-phenyl prop-2-en-1-one derivatives (8a-r). The in vitro inhibitory activity of the synthesized compounds was evaluated against the NF54 chloroquine-sensitive strain of Plasmodium falciparum. From the antiprotozoal screening, three compounds displayed propitious activity with IC50 values (0.18-0.21μM), using quinine and chloroquine as standard antimalarials. Compounds 8o and 8l emerged as the most potent candidates with IC50 values of 0.18 ± 0.02 μM and 0.21 ± 0.001 μM with an associated good safety index of 18.59 and 16.75 to human kidney epithelial (HEK293) cells, respectively. The synthesized analogues present a new chemical architecture structurally unrelated to the current regime of antimalarial drugs, representing a valid strategy to combat resistance in P. falciparum species to current commercial drugs. We further investigated the binding affinities of the compounds against recombinant forms of two P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z, both of which are essential and promising druggable candidates. Compound 8l exhibited the highest binding affinity for both PfHsp70s. Furthermore, molecular docking revealed that compounds 8k, 8l, 8m, and 8o exhibited better fitness to PfHsp70-1, with compounds 8l and 8o showing the highest binding affinity of 10.5 kcal/mol and 10.1 kcal/mol, respectively. Therefore, it can be speculated that PfHsp70-1 may be a possible target of some of the inhibitors tested in this study. The presence of electron-donating groups on the phenyl ring of 4,6-pyrimidine moiety and cinnamoyl group demonstrated a positive correlation between the observed computational data and the biological activity. Taken together, this paper demonstrates the importance of using the molecular hybridization approach in the development of newer cinnamoyl clubbed with 4,6-diphenyl pyrimidine hybrids as potential antiprotozoal agents.

Microwave expedited Cu(I) catalyzed regioselective 1,2,3-triazoles as Mycobacterium Tuberculosis H37Rv inhibitors, in vitro α-amylase and α-glucosidase inhibition, in silico studies

In the present study, an efficient and convenient synthesis of novel 1,2,3-triazoles (8i-t) incorporated quinoline and coumarin cores has been reported. Microwave-assisted Huisgen 1,3-dipolar cycloaddition reaction of azide and alkyne resulted in high yields (88–94 %) of the title compounds. Regioselective single-product formation both under conventional and microwave methods is the foremost supremacy of this work. All the molecules were subjected to in vitro antibacterial assessment wherein the compounds 8i, 8k, 8l, 8n, and 8r demonstrated very good antibacterial activity against other bacterial strains tested. Compounds 8i, 8k, 8l, 8n, 8o, 8q, and 8r demonstrated excellent antitubercular activity with MICs in the range 1.60–6.25 µg/mL in comparison to the standard drugs (Isoniazid-1.60 µg/mL, Ciprofloxacin-3.25 µg/mL, Pyrazinamide-6.25 µg/mL). Compounds 8i, 8n, and 8r also exhibited inhibitory effects against α-amylase and α-glucosidase and thus, also showed anti-diabetic activity. The significantly active compounds were subjected to molecular docking and molecular dynamics simulation studies to study the putative binding pattern as well as the stability of the docked complexes, respectively. In silico ADME profiles of the titled compounds were also predicted to access the drug-likeness properties of the designed compounds. Titled compounds showed potential effectiveness as antibacterial and antidiabetic agents.

Phytotoxic and Cytogenetic Assessment of Glycerol Triazole Derivatives in Model Plants and Weeds.

Weed invasion represents a challenge for farmers, who typically manage it with herbicides. However, this approach raises concerns about environmental and human health, as well as increasing resistance in these plants with continued use. Therefore, exploring alternative methods, such as heterocyclic compounds, triazoles, is essential due to their biological and environmental relevance. This study aimed to evaluate the effects of twelve 1,2,3-triazoles on the germination and early development of Lactuca sativa, Bidens pilosa, and Lolium multiflorum, as well as their impact on cell division in the cells of L. sativa. Triazole derivatives 4a, 4b, 4c, 4g, 4h, 4i, 4k, and 4l exhibited phytotoxicity, showing varying levels of inhibition in germination, germination speed index, and root growth. Chlorinated compounds were the most detrimental to lettuce development. B. pilosa was notably affected by compounds 4h, 4i, 4k, and 4l, while L. multiflorum responded most to triazoles 4c and 4l, with effectiveness comparable to that of the herbicide glyphosate. All derivatives, except 4l, exhibited aneugenic mechanisms of action, and 4a, 4b, 4c, 4e, 4f, and 4g showed clastogenic effects. This study demonstrated the potential of triazoles as effective agents against weed growth, with mechanisms that warrant further investigation for agricultural applications.

Hybrid Analogues of Hydrazone and Phthalimide: Design, Synthesis, In vivo, In vitro, and In silico Evaluation as Analgesic Agents.

Based on the anti-inflammatory and analgesic activity of hydrazone and phthalimide, a new series of hybrid hydrazone and phthalimide pharmacophores was prepared and evaluated as analgesic agents. The designed ligands were synthesized by reaction of the appropriate aldehydes and 2- aminophthalimide. Analgesic, cyclooxygenase inhibitory, and cytostatic activity of prepared compounds were measured. All the tested ligands demonstrated significant analgesic activity. Moreover, compounds 3i and 3h were the most potent ligands in the formalin and writhing tests, respectively. Compounds 3g, 3j, and 3l were the most COX-2 selective ligands and ligand 3e was the most potent COX inhibitor with a 0.79 of COX-2 selectivity ratio. The presence of electron-withdrawing moieties with hydrogen bonding ability at the meta position was found to affect the selectivity efficiently, in which compounds 3g, 3l, and 3k showed high COX-2 selectivity, and compound 3k was the most potent one. The cytostatic activity of selected ligands demonstrated that compounds 3e, 3f, 3h, 3k, and 3m showed good analgesic and COX inhibitory activity and were less toxic than the reference drug. High therapeutic index of these ligands is one of the valuable advantages of these compounds.

Design and synthesis of new coumarin-1,2,3-triazole hybrids as new antidiabetic agents: In vitro α-amylase, α-glucosidase inhibition, anti-inflammatory, and docking study

The current study focuses on the synthesis of coumarin-triazole hybrids (7i-t) starting from 4-hydroxy benzaldehyde or 4-hydroxyacetophenone (1a-b) and propargyl bromide. On the other hand, coumarin derivatives (5c-h) were prepared by Pechmann cyclization and treated with sodium azide to give the corresponding 3-azido methyl coumarins (6c-h). Finally, 1,3-dipolar cycloaddition between compounds 6c-h and terminal alkyne 2a-b produces coumarin-triazole hybrids (7i-t) utilizing click chemistry approaches that are high yielding, wide in scope and simple to perform. The structural proofs of the newly synthesized coumarin-triazole hybrids (7i-t) are proved by various spectroscopic techniques, including IR, 1H NMR, 13C NMR, and LC-MS. The synthesized new coumarin triazole hybrids (7i-t) were explored for their antihyperglycemic potential and therefore evaluated for α-glucosidase and α-amylase inhibitory activities along with anti-inflammatory. The results suggest that among the series, compound 7l showed excellent activity with an IC50 value of 0.67±0.014 mg/mL and 0.72±0.012 mg/mL for α-amylase, and α-glucosidase inhibitory potential while compound 7o showed promising anti-inflammatory activity with IC50 value of 0.54±0.003 mg/mL. To support the above findings, molecular docking studies were performed, which confirmed the interaction of the synthesized molecules 7i-t with an effective binding energy of -9.0 to -10.6 kcal/mol at the active site of the enzyme human pancreatic α-amylase (PDB ID: 1B2Y). Therefore, these scaffolds have the potential to function as lead candidates for antidiabetic and anti-inflammatory activities.

Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations

In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful “multitarget-directed drug” for cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects.

Synthesis, cytotoxic evaluation, and in silico studies of novel benzenesulfonamide-thiazolidinone derivatives against colorectal carcinoma

Thirteen new benzenesulfonamide derivatives containing 4-thiazolidinone were synthesized. Their cytotoxic properties were tested on colorectal carcinoma (HT-29, DLD-1, COLO-205) and normal colon fibroblast (CCD-986Sk) cell lines. Compounds 3l (IC50=114.62 µM), 3a (IC50=25.82 µM), 3k (IC50=30.99 µM), and 3i (IC50=62.94 µM) showed the highest cytotoxicity on HT-29, DLD-1, COLO-205, and CCD-986Sk cell lines, respectively. Compound 3e (IC50=1075.4 µM) exhibited the least cytotoxicity against CCD-986Sk. The apoptosis profile of 5-FU at 5 µM was similar to that of compound 3e at 30 µM. Molecular docking and MD simulations showed stable interactions for compounds 3i and 3e. Molecular docking and MD simulations revealed that compounds 3i and 3e exhibit stable interactions with key cancer-related protein targets, particularly TGFβ2. These interactions suggest their potential as therapeutic agents. The predicted ADME parameters further highlighted compounds 3e and 3i for their favorable lipophilicity, solubility, permeability, and oral absorption profiles, supporting their promise as candidates for future drug development.

Synthesis and in silico studies of some new pyrrolylbenzamide derivatives as antitubercular and antimicrobial agents

Eighteen new pyrrolylbenzamide derivatives (6a-6r) were synthesized by reacting N-(2,5-dimethyl- 1H-pyrrol-1-yl)-4-(2-hydrazineyl-2-oxoethoxy)benzamide (4) with substituted benzoic acids (5a-5r) in the presence of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, diisopropyl ethylamine and dimethyl formamide. The produced compounds were subjected to molecular docking studies against the dihydrofolate reductase (DHFR) and InhA mycobacterial enzymes. The compounds were biologically screened for antimycobacterial, and antibacterial activities along with InhA and DHFR enzyme inhibition studies. The compounds were also analyzed for ADMET parameters. The compounds 6j, 6l, 6q, and 6r exhibited good antitubercular activity, and compounds 6j, 6l, 6q, and 6r were effective against the Gram-negative Escherichia coli strain. The compounds 6b, 6f, 6j, 6l, and 6q showed good InhA inhibition and compounds 6b, 6c, 6j, 6l, and 6q were effective against DHFR enzyme. Among the synthesized compounds 6j and 6l exhibited promising antitubercular, antibacterial, and effective InhA and DHFR enzyme inhibition values.. KEYWORDS :Benzamide, Dimethylpyrrole, Antimycobacterial activity, Antibacterial activity.

Assessing β-Carboline Analogues As Antibiotic Agent Using In Vitro Studies

The mortality rate caused by bacterial diseases and bacterial antimicrobial resistance (AMR) is a significant concern in global public health. There is an urgent demand for new therapeutic agents that not only offer improved efficiency but also entail fewer secondary effects, addressing the challenges posed by the currently available drugs used in clinical practice. In this study, 40 analogues of β-carboline were subjected to solubility tests to determine their solubility. Among them, 22 analogues proved to be soluble and were subsequently tested for in vitro antibacterial activity using the agar disc diffusion method against S. aureus and E. coli to evaluate their effectiveness. The results of the in vitro antibacterial studies revealed that compounds 1h, 7d, and 1l displayed appreciable growth-inhibitory effects against E. coli, while compounds 1a, 1f, 1l, and 1j exhibited appreciable growth-inhibitory effects against S. aureus. Notably, compounds 1j and 1l displayed the highest growth-inhibitory potency against S. aureus and E. coli, respectively, out of the 22 compounds tested. Of all the analogues examined, 1l and 1j demonstrated the most substantial growth-inhibitory effects against E. coli and S. aureus, respectively, underscoring their potential as inhibitors.

Green One-Pot Synthesis of Thiazole Scaffolds Catalyzed by Reusable NiFe2O4 Nanoparticles: In Silico Binding Affinity and In Vitro Anticancer Activity Studies.

A facile, green, one-pot multicomponent synthesis strategy was employed to fabricate novel thiazole scaffolds incorporating phthalazine, pyridazine, and pyrido-pyridazine derivatives (4a-4o). This synthetic route entailed the reaction of an α-halo carbonyl compound (1) with thiosemicarbazide (2) and various anhydrides (3a-3o), utilizing NiFe2O4 nanoparticles as a reusable catalyst in an ethanol:water (1:1) solvent system. The cytotoxicity of the synthesized compounds was meticulously assessed against three cancer cell lines, A375, HeLa, and MCF-7, employing IC50 values (μM) as the benchmark, and compared to the reference drug erlotinib. Compound 4n displayed remarkable efficacy against A375 (0.87 ± 0.31 μM), HeLa (1.38 ± 1.24 μM), and MCF-7 (1.13 ± 0.96 μM) cell lines, significantly surpassing erlotinib's IC50 values. Additionally, compounds 4k, 4l, 4m, and 4o demonstrated notable cytotoxicity across all tested cell lines, indicating their potential as effective anticancer agents. In silico docking studies against Hsp82 and Hsp90 proteins indicated that ligands 4k, 4m, 4c, 4j, 4o, and 4l had superior binding affinities compared to erlotinib. ADME analysis showed that compounds 4n, 4j, 4l, 4m, and 4o had favorable pharmacokinetic profiles, including nontoxicity, high human intestinal absorption, and low CYP inhibitory promiscuity. Structure-activity relationship analysis revealed that cyano and benzylidene substitutions significantly enhanced anticancer activity. Overall, the synthesized compounds, particularly 4n, demonstrated high efficacy, favorable binding interactions, and promising pharmacokinetic profiles, making them strong candidates for further development as anticancer agents.