Discovery of novel pleuromutilin derivatives as potent antibacterial agents

In the present study a series new 8-hydroxyquinoline-Benzimidazole hybrids (6a–l) were designed, synthesized (6a–l) by using conventional synthetic methods and assayed for their antimicrobial evaluation. The newly synthesized compounds (6a–l) were screened for their antibacterial activity against four strains i.e., E. coli, S. aureus, P. aeruginosa and B. subtilis and antifungal activity tested against A. niger and C. albicans. The compounds 6b, 6c, 6g, 6h, 6i, 6k and 6l are found to be active against all 4 bacterial strains. The compounds 6a, 6b, 6c, 6g, 6h, 6i, 6k and 6l are showing almost same antifungal activity when compared to the standard drug Voriconazole against A. niger. Whereas, In the case of C. albicans the compounds 6c, 6g, 6h, 6i, 6j, 6k and 6l are showing good antifungal activity. The MIC studies revealed that these compounds were showing the MIC values between 3.9 and 62.5 μg/ml for all the four bacterial strains. Among all the compounds, the compound 6g was showing the 3.9 μg/ml MIC value for E. coli and P. aeruginosa and found to be most potent compound antibacterial agent. From the results of the MIC studies exhibit that these compounds were good antifungal agents and showing the MIC values ranging between 19.2 and 500 μg/ml for both A. niger and C. albicans. The compound 6f was emerged as most potent antifungal agent by exhibiting the 22.3 μg/ml MIC value for A. niger and 19.2 μg/ml MIC value for C. albicans. Thus it is anticipated that these compounds will emerged as potential antibacterial as well antifungal agents on further exploration.

Antioxidant, antibacterial, and cytotoxic activities of cimemoxin derivatives and their molecular docking studies

DNA gyrase and topoisomerase IV enzymes are promising candidates for dual targeting with novel antibacterial agents, lowering the risk of bacterial resistance development. A new series of methylene disalicylic acid/1,3,4-oxadiazole hybrids (5a-l) was developed as dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity. The structures of the novel compounds were validated using 1H NMR, 13C NMR, and elemental microanalysis. Compounds 5a-l were tested for their inhibitory effect against E. coli DNA gyrase. Compounds 5g, 5h, 5j, and 5l exhibited the highest inhibitory activity against E. coli DNA gyrase, with IC50 values ranging from 164 to 179nM. Compound 5h has the highest potency as an E. coli DNA gyrase inhibitor with an IC50 value of 164nM, representing an enhanced potency compared to reference novobiocin. Compounds 5g, 5h, 5j, and 5l were tested against S. aureus DNA gyrase, E. coli, and S. aureus topoisomerase IV. The findings indicated that 5g, 5h, 5j, and 5l activities on DNA gyrase from S. aureus were predominantly less effective than those on E. coli gyrase, with IC50 values ranging from 44 to 56nM. Compound 5h was the most efficient inhibitor of E. coli and S. aureus topoisomerase IV. Compound 5h showed significant antibacterial effectiveness against the multi-drug resistant (MDR) VRE-12201 and MRSA (EMRSA-15) strains, outperforming the reference drugs vancomycin and amoxicillin. This study used molecular docking to analyze compound 5h with E. coli DNA gyrase B. ADME analysis highlighted enhanced lipophilicity, making it a promising candidate for further optimization as a Gyrase B inhibitor.

A novel series of urea Schiff base derivatives were synthesized via the condensation of o-phenylenediamine, naphthyl isocyanate and appropriate aryl aldehyde. The results of the in vitro cytotoxic activities of compounds 5a–h against cancer cells lines PC3, SKOV-3 and HeLa, revealed that almost all compounds exhibited good to moderate activities Compound 5g owing bromine atom at p-position displayed higher activity compared to homolog 5b possessing chlorine atom due to adequate diameter of bromine which is more favourable than chlorine for the inhibition activity. In addition, compound 5h is the best candidate of this series exhibiting excellent activity for three cancer cells lines. Compound 5h demonstrated also an excellent activity with IC50 value of 0.6±0.3μg/mL for prostate cancer cell line PC3 and it is considered more effective than the standard drug doxorubicin Dox (IC50 = 2.6±0.03μg/mL). The most active compound 5h displayed the best activity against ovarian cancer cell line SKOV3 with IC50 = 1.8±0.2μg/mL. This results are higher than clinically used drug Dox (IC50. 2.2±0.02μg/mL). The results of screening activities cytotoxic effect toward cervix cancer cell line HeLa, affirm that compound 5h manifest an activity with IC50 value of 2.2±0.4μg/mL comparable to Dox (IC50. 1.9±0.04μg/mL). In the current study, in vivo acute oral toxicity assessment of urea Schiff base hybrid compounds 5a – h indicated that there was no mortality on treated female mice during 14 days assessment test compared with the vehicle-treated group confirming the safety with LD50 greater than 2000 mg/kg. In the actual study, the results affirmed that compounds 5a–h manifested in vivo no toxicity to saint cells, the compounds 5b, 5g and 5h presented higher anticancer activities against three cancer cells which authorizes promoters to use them as candidate anticancer agents.

Herein, a series of N'-benzylidene-3,4-dimethoxybenzohydrazide derivatives were designed and synthesised to target the multidrug efflux pump (MATE). The antibacterial activities were screened against S. aureus, Acinetobacter, S. typhi, E. coli, and P. aeruginosa, whereas their antifungal activities were screened against C. albicans. Compounds 4a, 4h, and 4i showed the most promising antibacterial and antifungal activities. Moreover, compounds 4h and 4i being the broader and superior members regarding their antimicrobial effects were selected to be further evaluated via in vivo testing using biochemical analysis and liver/kidney histological examination. Additionally, molecular docking was carried out to attain further deep insights into the synthesised compounds' binding modes. Also, ADMET studies were performed to investigate the physicochemical/pharmacokinetics features and toxicity parameters of the synthesised derivatives. Finally, a structure-antimicrobial activity relationship study was established to facilitate further structural modifications in the future. Highlights A series of new N'-benzylidene-3,4-dimethoxybenzohydrazide derivatives were designed and synthesised targeting the multidrug efflux pump (MATE) guided by the pharmacophoric features of the co-crystallized native inhibitor of the target protein. The newly synthesised compounds were assessed through in vitro, in vivo, and in silico approaches. Using the agar well diffusion assay, the antibacterial activities of the synthesised compounds were screened against S. aureus, Acinetobacter, S. typhi, E. coli, and P. aeruginosa, whereas, their antifungal activities were screened against C. albicans. The minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC) of the synthesised compounds were investigated on variable microbial species. Compounds (4h and 4i) -as the broader and superior members regarding their antimicrobial effects- were further evaluated via in vivo testing using bio-chemical analysis and liver/kidney histological examination. A molecular docking study and ADMET in silico studies were performed. A structure-antimicrobial activity relationship study was established to facilitate further structural modifications in the future.

In search of better antibacterial and anticancer agents, this report presents a series of novel N-[3-fluoro-4-(morpholin-4-yl)aryl]thiazol-2-amine derivatives (6a–6l) that were synthesized and evaluated for their antibacterial and anticancer activity in vitro. Antibacterial activity against three G+ bacterial strains and anticancer activity against MCF-7 and A-549 was evaluated. Among all the tested compounds, 6i and 6j exhibited potent antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis bacterial strains. Biofilm profiles for the potent compounds and it was observed from the results that the active derivatives 6i and 6j were not only potent antibacterial agents but also efficient inhibitors of S. aureus and S. epidermidis biofilm growth. Compared to the standard drug, erlotinib, the anticancer activity screening results of 6h and 6k demonstrated high cytotoxic activity against the A-549 cancer cell line. Later, the results of the inhibitory assay of potent compounds 6h and 6k against the tyrosine kinase EGFR revealed that compound 6k showed ≈1.5 fold potency of the reference drug erlotinib. Finally, compounds 6h, 6i, 6j, and 6k did not show AMES toxicity and followed the rules of Lipinski, Ghose, Veber, Egan, and Muegge rules without any deviation.

Synthesis, characterization and carbonic anhydrase I and II inhibitory evaluation of new sulfonamide derivatives bearing dithiocarbamate

Novel sulphonamide-azaheterocycle conjugates and their anti-cancer, anti-inflammatory, anti-diabetic, anti-angiogenesis activity and molecular docking studies

Study of antimicrobial and antioxidant activities of pyrrole-chalcones

In this work, a series of curcumin derivatives (1a-1h, 2a-2g, and 3a-3c) were synthesized for the suppression of castration-resistant prostate cancer cells. All synthesized compounds were characterized by 1H NMR, 13C NMR, HRMS, and melting point. The invitro cytotoxicity study shows that compounds 1a, 1e, 1f, 1h, 2g, 3a, and 3c display similar or enhanced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9, other synthesized compounds display reduced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9. Molecular docking simulation was performed to study the binding affinity and probable binding modes of the synthesized compounds with androgen receptor. The results show that all synthesized compounds exhibit higher cdocker interaction energies as compared to ASC-J9. Compounds 1h, 2g, and 3c not only show strong cytotoxicity against 22Rv1 and C4-2 cells but also exhibit high binding affinity with androgen receptor. In androgen receptor suppression study, compounds 1f and 2g show similar androgen receptor suppression effect as compared to ASC-J9 on C4-2 cells, compound 3c displays significantly enhanced AR suppression effect as compared to ASC-J9, 1f and 2g. Compounds 1a, 1e, 1f, 1h, 2g, 3a and 3c prepared in this work have significant potential for castration-resistant prostate cancer therapy.

Novel pleuromutilin derivatives with substituted 6-methylpyrimidine: Design, synthesis and antibacterial evaluation.

This study focused on the design and synthesis of a novel series of 5-ethylsulfonyl-indazole-3-carboxamides (8a–l) as dual inhibitors of VEGFR-2 and EGFR. Compounds 8g and 8h emerged as the most efficient derivatives among all evaluated compounds against breast (MCF-7) and colorectal (HCT-116) cancer cell lines, exhibiting IC50 values of 24 and 28 nM for HCT-116 and MCF-7 cell lines, respectively, for 8g, and 23 and 25 nM for the same cell lines for 8h. Compounds 8g and 8h exhibited a promising safety margin against normal cells (WI-38) (IC50 values > 150 nM). In vitro enzyme assays demonstrated that compounds 8g and 8h exhibited potent inhibition of VEGFR-2 and EGFR. Furthermore, compounds 8g and 8h induced apoptosis by activating Bax, p53, caspase-3, 8, and 9, as well as down-regulating Bcl-2. Compounds 8g and 8h reduced TNF-α and IL-6 levels compared to dexamethasone. The computational investigation of compound 8h, a novel indazole-based urea derivative, was undertaken to rationalize its potent dual inhibition of EGFR and VEGFR-2. Molecular docking studies revealed a high binding affinity and a favorable interaction profile with key kinase residues, particularly hinge-region contacts with Met769 (EGFR) and Glu885/Asp1046 (VEGFR-2). Follow-up molecular dynamics (MD) simulations confirmed the stability of the 8h–EGFR complex over 150 ns, characterized by persistent hydrogen bonding, low RMSF in the binding site, and consistent radius of gyration. Quantum mechanical (QM) analyses, including DFT and MEP mapping, revealed a HOMO–LUMO gap of 4.55 eV, high dipole moment (9.3 D), and distinct electron-rich/hydrogen-bonding regions, supporting strong molecular interactions. Additionally, SwissADME profiling demonstrated acceptable drug-likeness, moderate solubility, and a low CYP-inhibition profile, suggesting favorable pharmacokinetics compared to the reference inhibitor erlotinib. These integrated computational findings align with experimental data on antiproliferative effects and kinase inhibition, reinforcing compound 8h as a promising dual-target anticancer candidate.

Targeting melanoma resistance: Novel oxindole and non-oxindole-based benzimidazole derivatives as potent dual inhibitors of BRAFV600E and ABL2 kinases.

A novel tetrazole analogue of resveratrol is a potent anticancer agent

The DNA topoisomerase (topo) II of chloroquine-sensitive and chloroquine-resistant strains of the rodent malaria parasite P. berghei were utilized as a target for testing of antimalarial compounds. Compounds belonging to the bischalcone and chalcone series significantly inhibited enzyme activity and percentage parasitaemia of chloroquine-sensitive and chloroquine-resistant strains of P. berghei. Compounds 1a, 1b, 2a, 2b, and 2c showed 100% inhibition while compounds 2h and 2i showed 60% and 63% inhibition of topoisomerase II activity of the chloroquine-sensitive strain, respectively. Compounds 2a, 2b, and 2d significantly inhibited the topo II activity of chloroquine-resistant strain. Compounds 2g and 2e specifically inhibited the topo II activity of the chloroquine-resistant strain of P. berghei with no effect on the chloroquine-sensitive strain. The in vitro topo II inhibition by chalcone and bischalcone analogs can be correlated with their in vivo antimalarial activity, as compounds 2c and 2h inhibited both in vitro activity of topo II and in vivo parasitaemia of the chloroquine-sensitive strain of P. berghei. In the chloroquine-resistant strain, compounds 2c, 2e, 2g, and 2i inhibited activity against both in vitro topo II and parasitaemia in vivo. The significant inhibition of topo II in the chloroquine-resistant strain by some of the analogs suggests the utilization of these structures for the synthesis of compounds active against chloroquine-resistant malarial parasites.