Compounds 4k Research Articles

The antibacterial and anti-biofilm effects of novel synthetized nitroimidazole compounds against methicillin-resistant Staphylococcus aureus and carbapenem-resistant Escherichia coli and Klebsiella pneumonia in vitro and in silico

The antibiotic resistance and biofilm formation by bacterial pathogens has led to failure in infections elimination. This study aimed to assess the antibacterial and anti-biofilm properties of novel synthesized nitroimidazole compounds (8a–8o). In this study, nitroimidazole compounds were synthesized via the A3 coupling reaction of sample substrates in the presence of copper-doped silica cuprous sulfate (CDSCS). Fifteen and two carbapenemase producing Escherichia coli and Klebsiella pneumonia (CP-E. coli and CP-K. pneumonia, respectively) and one methicillin-resistant Staphylococcus aureus (MRSA) and one methicillin-susceptible S. aureus (MSSA) plus standard strain of each isolate were included. The antibacterial effects of these compounds demonstrated that the lowest minimum inhibitory and bactericidal concentrations (MIC/MBC, respectively) levels corresponded to compound 8g against S. aureus (1/2 µg/mL) and K. pneumonia (8/32 µg/mL) standard and clinical strains and confirmed by in silico assessment. This was comparable to those of metronidazole being 32–128 µg/mL against K. pneumonia and 32–64 µg/mL against S. aureus. In comparison to metronidazole, against CP-E. coli, compounds 8i and 8m had significantly higher antibacterial effects (p < 0.001) and against CP-K. pneumonia, compounds 8a–8j and 8l–8o had significantly higher (p < 0.0001) antibacterial effects. Compound 8g exhibited significantly higher antibacterial effects against MSSA and compounds 8b (p < 0.001), 8c (p < 0.001), 8d (p < 0.001), 8e (p < 0.001) and 8g (p < 0.0001) exerted significantly higher antibacterial effects than metronidazole against MRSA. Moreover, potential anti-biofilm effects was corresponded to compounds 8a, 8b, 8c, 8e, 8f, 8g, 8i, 8k, 8m and 8n. Considering the antibacterial and anti-biofilm effects of novel synthesized compounds evaluated in this study, further assessments is warranted to verify their properties in vivo and clinical trials in the future.

Investigating the C2 modulation of the imidazo[1,2-a]pyrazine-based hit compound CTN1122: synthesis, in vitro antileishmanial activity, cytotoxicity and casein kinase 1 inhibition.

Our research group previously discovered CTN1122, an imidazo[1,2-a]pyrazine compound with promising antileishmanial activity against intramacrophage amastigotes of Leishmania major and L. donovani strains. CTN1122 effectively targets Leishmania casein kinase 1 (L-CK1.2) and exhibits a favorable safety profile. To further explore its chemical space, we developed a convergent strategy to modify the C2 position of the imidazo[1,2-a]pyrazine core using Suzuki-Miyaura coupling of the corresponding triflate intermediate. Among 15 newly synthesized analogs, seven derivatives featuring variously substituted phenyl rings at C2 demonstrated L-CK1.2 inhibition within micromolar to submicromolar ranges and antileishmanial activity in vitro with low cytotoxicity in macrophages. Compounds 7d and 7l were particularly potent, with IC50 values of 1.25 µM and 0.92 µM against L. major, and 1.44 µM and 2.34 µM against L. donovani, respectively. They showed IC50 L-CK1.2 = 0.3 μM and 0.57 µM with enhanced selectivity indices (SI = 3.8 and 1.6) over the human CK1ε ortholog. Additionally, four C2 analogs and two C5 isomers exhibited notable antiparasitic effects without strongly inhibiting L-CK1.2, indicating a possible alternative mechanism of action. Compound 7k displayed the highest general activity, with IC50 values of 0.31 µM on L. major and 0.27 µM on L. donovani, coupled with favorable selectivity indexes.

Synthesis of dolutegravir derivatives modified by 1,2,3-triazole structure and their anti-inflammatory activity in LPS-induced BV2 cells.

Given the promising anti-inflammatory activity of the HIV integrase inhibitor dolutegravir and the widespread use of the 1,2,3-triazole structure in anti-inflammatory drug development, this study aimed to enhance dolutegravir's efficacy by introducing a 1,2,3-triazole group. As a result, four series of dolutegravir derivatives were synthesized. Screening these derivatives for anti-inflammatory activity in microglial cells revealed that compound 6k demonstrated the most potent anti-inflammatory effect without significant cytotoxicity. Specifically, 6k significantly reduced the transcription levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Additionally, 6k decreased the LPS-induced overproduction of inflammatory mediators such as nitric oxide (NO), IL-6, and TNF-α. Further investigation into the upstream inflammatory enzymes iNOS and COX-2 showed that 6k markedly reduced their transcription and protein levels. To elucidate the mechanism underlying the anti-inflammatory effects of dolutegravir derivatives, it was found that compound 6k modulates microglial inflammation by inhibiting the phosphorylation and nuclear translocation of signal transducer and activator of transcription 1/3 (STAT1/3). Moreover, acute toxicity testing in mice indicated that compound 6k exhibited low toxicity, suggesting its potential as a lead compound for the treatment of neuroinflammation.

1,3-Naphthoxazine derivatives: Synthesis, in silico pharmacokinetic studies, antioxidant and photoprotective properties

Investigation into the interactions between photoprotective agents and skin can offer a precise understanding of their biological behaviors in vitro and in vivo, providing crucial insights for generating new substances. For this purpose, we designed and synthesized a series of naphthoxazine derivatives and examined their photoprotective properties. 1,3-naphthoxazine derivatives were synthesized through the multi-component reaction of 2-naphthol, arylamines and aromatic aldehydes in the presence of copper(II) trifluoromethanesulfonate (Cu(OTf)2) and (±)-Camphor-10-sulfonic acid ((±)-CSA) catalyst system under sonication. The potential of these synthesized 1,3-naphthoxazine derivatives as antioxidants and viable organic structural-based sunscreen ingredients has been investigated. Sun protection factor (SPF) assay results showed that especially compounds 4i, 4c, 4k, 4d, 4r, and 4h had remarkably high activity (23.65, 23.57, 23.04, 21.94, 20.80, and 20.26, respectively at 900 µg/mL concentration). Additionally, antioxidant activity of the synthesized compounds was evaluated and compounds 4h, 4e, 4b, and 4j exhibited the highest activities in DPPH scavenging activity assay (86.46 %, 82.83 %, 80.78 %, and 80.65 % respectively at 400 µg/mL concentration). The synthesized compounds exhibit promising characteristics for effective UV radiation absorption, suggesting their suitability for inclusion in sunscreen formulations. Cytotoxic activity of compound 4k against normal human fibroblast cell line (MRC-5) was determined by CVDK-8 method. The results revealed that the compound provided remarkable viability (87.55 %) of MRC-5 cells at concentration of 100 µM. The study explores their efficacy in providing broad-spectrum protection against UVA and UVB rays, degradation and photostability, ADMET profile, and other pharmacokinetic properties.

Novel Hydrazide-Hydrazones Bearing a Benzimidazole Ring: Design, Synthesis, and Evaluation of Inhibitor Properties Against CA I and CA II Isozymes.

In this study, we propose identifying potential novel compounds targeting carbonic anhydrase I and II. Herein, we have designed and synthesized new benzimidazole-hydrazide-hydrazones derivatives (4a-4r) to investigate the effects of these synthesized compounds on CA isoenzymes. The compounds' 1H NMR, 13C NMR, and HRMS spectra were used to confirm their chemical structures. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase I and II by invitro assay. These compounds have IC50 values of 3.727-1.493 μM (hCA I) and 3.892-1.547 μM (hCA II). Inhibition types and Ki values of the compounds were determined. The Ki values of the compounds were 3.006 ± 0.17 μM-0.356 ± 0.0 μM (hCA I) and 2.923 ± 0.15 μM-0.346 ± 0.0 μM (hCA II). Acetazolamide (AAZ) was used as the reference in the study. The most potent derivatives, a 4-methoxy derivative (compound 4k) and 4-(trifluoromethyl) derivative (compound 4g), than AAZ (IC50 = 2.26 μM) and their IC50 values were found as 1.493 μM and 1.675 μM, respectively. Compared to AAZ, the other derivatives having more effect on hCA I were compounds 4b, 4e, 4l, 4m, 4n, and 4o. The compounds gave IC50 values of 1.743, 1.789, 1.933, 1.966, 1.983, and 1.986 μM, respectively. Compounds 4a-4r found no more effective inhibitory activity against hCA II isozyme than AAZ (IC50 = 1.17 μM). According to the invitro test results, detailed protein-ligand interactions of the compounds 4b and 4k exhibited considerably low binding energies, suggesting strong interaction affinities against hCA I. In addition, the cytotoxic effects of the compounds on the L929 healthy cell line were evaluated.

Novel Pyrrolo-Pyrimidine Derivatives Bearing Amide Functionality as Potential Anticancer Agents: Synthesis and Molecular Docking Studies

Current investigation presents the synthesis, molecular docking and anticancer evaluation of novel pyrrolo-pyrimidine derivatives designed to target Janus kinase 1 (JAK1), Janus kinase 2 (JAK2) and cyclin-dependent kinase 4 (CDK4). The synthesis route commenced with 2-amino-4,6-dichloropyrimidine-5-carbaldehyde, proceeding through sequential steps involving intermediate formations and coupling reactions to yield a diverse array of pyrrolo-pyrimidine derivatives. Characterization using spectroscopic techniques (1H NMR, 13C NMR and HRMS) confirmed the chemical structures of the synthesized compounds. Molecular docking studies against JAK1, JAK2 and CDK4 demonstrated substantial binding affinities, remarkably compounds 7k, 7l and 7d, which displayed promising interactions within the active sites of the proteins. Anticancer evaluation against breast cancer (MCF-7), chronic myeloid leukemia (SET-2), colorectal carcinoma (HCT-116) and HEK-293 cell lines revealed diverse cytotoxic profiles. Specifically, compounds 7k and 7f exhibited potent activity against breast cancer (MCF-7), 7k and 7f showed efficacy against chronic myeloid leukemia (SET-2) and compounds 7k and 7l demonstrated effectiveness against colorectal carcinoma (HCT-116). These findings underscore the potential of these pyrrolo-pyrimidine derivatives as selective and effective anticancer agents, prompting further exploration for therapeutic development.

Microwave‐Assisted Fe3O4 Nanoparticles Catalyzed Cascade Synthesis of 3‐(1,4,5‐Triaryl‐1H‐imidazol‐2yl)quinolin‐2‐amines as COX‐1, COX‐2 Inhibitors and Antioxidant Agents

ABSTRACTA proficient Fe3O4 nanoparticle catalyzed cascade multicomponent synthetic protocol has been established to synthesize the title compounds. 2‐Chloroquinoline‐3‐carbaldehydes, aniline, and substituted benzils were subjected to cascade coupling to produce novel 3‐(1,4,5‐triaryl‐1H‐imidazol‐2‐yl)quinolin‐2‐amine 5k–z under microwave irradiation using Fe3O4 NPs. According to the biological data and the computational analysis, the compounds were found to bind COX‐2 enzyme superior than the COX‐1 enzyme. The molecular docked positions of the compounds (PDB ID: 4O1Z and PDB ID: 5IKR; A chain) were examined, and the results showed that these configurations are similar to those of the highly selective COX‐1 and COX‐2 inhibitors. Compared to mefenamic acid (1.318 μg), the compounds 5k, 5l, 5n, 5p, 5q, 5r, 5s, 5t, 5v, 5x, and 5z Showed IC50 values of 1.172, 1.136, 1.508, 1.0373, 1.186, 1.017, 1.827, 1.008, 1.504, 1.217, 1.440, and 1.832, respectively, making them the most effective and selective COX‐1 and COX‐2 inhibitors. For every significantly active molecule, a selectivity index was calculated. Interestingly, these molecules that worked as COX inhibitors also functioned well and showed promising results for antioxidant activity.

Design and evaluation of novel N-substituent diphenylamine derivatives as tubulin colchicine binding site inhibitors

Novel N-substituent diphenylamine derivatives as tubulin inhibitors targeting colchicine-binding site have been designed based on structural simplification and structural fusing strategy. Most designed compounds exhibited the moderate or potent antiproliferative activities against five cancer cell lines. Among them, compound 4k displayed the significant selectivity for osteosarcoma cells MG-63 and U2OS with the IC50 value of 0.08–0.14 μM. Further investigations verified 4k could inhibit tubulin polymerization by targeting colchicine binding site. Meanwhile, compound 4k not only effectively induced tumor cell cycle arrest at the G2/M phase, but also slightly induced cell apoptosis. These results indicated that N-substituent of diphenylamine derivatives are deserved for further development as tubulin colchicine binding site inhibitors.

Natural Products-Based Anticancer Agents: Synthesis and Anticancer Activities of Funtumine Amide/Sulfonamide Derivatives.

Funtumine is a pregnene-type steroidal alkaloid exhibiting moderate anticancer activity. To discover novel natural product-based anticancer drugs, a series of novel funtumine amide/sulfonamide derivatives were papered and identified using spectroscopic techniques. Additionally, the structures of compounds 2j, 3a, and 4k were further confirmed through X-ray diffraction analysis. Biological activity experiments conducted against three cancer cell lines revealed that several of the synthesized compounds demonstrated inhibition activities comparable to or exceeding those of the commercial anticancer agent, 5-Fluorouracil. Especially compound 4i demonstrated a notably strong growth inhibitory effect on HePG2 (IC50=14.89 μM) and HCT116 (IC50=15.67 μM) cell lines, while exhibiting minimal cytotoxicity towards human normal BEAS-2B cells. Preliminary structure-activity relationships (SARs) analysis indicated that the conversion of the carbonyl group at the C-20 position of funtumine to a hydroxyl group could yield more potent compounds.

Discovery of novel fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile

As an important part of anti-AIDS therapy, HIV-1 non-nucleoside reverse transcriptase inhibitors are plagued by resistance and toxicity issues. Taking our reported XJ-18b1 as lead compound, we designed a series of novel diarypyrimidine derivatives by employing a scaffold hopping strategy to discover potent NNRTIs with improved anti-resistance properties and drug-like profiles. The most active compound 3k exhibited prominent inhibitory activity against wild-type HIV-1 (EC50 = 0.0019 μM) and common mutant strains including K103 N (EC50 = 0.0019 μM), L100I (EC50 = 0.0087 μM), E138K (EC50 = 0.011 μM), along with low cytotoxicity and high selectivity index (CC50 = 21.95 μM, SI = 11478). Additionally, compound 3k demonstrated antiviral activity against HIV-2 with EC50 value of 6.14 μM. The enzyme-linked immunosorbent assay validated that 3k could significantly inhibit the activity of HIV-1 reverse transcriptase (IC50 = 0.025 μM). Furthermore, molecular dynamics simulation studies were performed to illustrate the potential binding mode and binding free energy of the RT-3k complex, and in silico prediction revealed that 3k possessed favorable drug-like profiles. Collectively, 3k proved to be a promising lead compound for further optimization to obtain anti-HIV drug candidates.

Design, synthesis and antitumor activity of triphenylphosphonium-linked derivatives of quinazolinone

Cancer is the leading cause of human death. Quinazolinone heterocyclic compounds have a variety of biological activities and have been extensively studied in recent years, especially for their potential anticancer activity. The triphenylphosphonium moiety (TPP+) has become a very important lipophilic cation, especially concerning its application the development of anticancer agents. In this work, we designed and synthesised 24 new TPP+ -conjugated quinazolinone derivatives, which have alkylated TPP+ at the N-3 position and different small group substitutions at the C-6 position, and their antiproliferative activity was evaluated in three cancer cell lines (human alveolar adenocarcinoma cells (A549), human hepatoblastoma cells (HepG2) and human breast cancer cells (MCF-7)) and human normal liver cells (QSG-7701). The cytotoxicity screening results showed that some derivatives exhibited effective inhibitory effects in cancer cells. Among them, the compound 5k–o showed better antiproliferative activity than the positive control drug gefitinib on MCF-7 and A549 cells. The most active compounds being 5o, with IC50 values of 6.56, 14.52 and 7.51 µM in MCF-7 cells, HepG2 cells and A549 cells, respectively. Compound 5o may be a promising compound for cancer treatment worthy of further study.

Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2

Pseudokinase TRIB2, a member of the CAMK Ser/Thr protein kinase family, regulates various cellular processes through phosphorylation-independent mechanisms. Dysregulation of TRIB2 has been implicated in promoting tumor growth, metastasis, and therapy resistance, making it a promising target for cancer treatment. In this study, we designed and synthesized a series of TRIB2 PROTAC degraders by conjugating a TRIB2 binder 1 with VHL or CRBN ligands via linkers of varying lengths and compositions. Among these compounds, 5k demonstrated potent TRIB2 degradation with a DC50 value of 16.84 nM (95 % CI: 13.66–20.64 nM) in prostate cancer PC3 cells. Mechanistic studies revealed that 5k directly interacted with TRIB2, selectively inducing its degradation through a CRBN-dependent ubiquitin-proteasomal pathway. Moreover, 5k outperformed the TRIB2 binder alone in inhibiting cell proliferation and inducing apoptosis, confirming that TRIB2 protein degradation could be a promising therapeutic strategy for TRIB2-associated cancers. Additionally, compound 5k also serves as an effective tool for probing TRIB2 biology.

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 derivatives via sp3 C-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 CH 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) were 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 respectively were established excellent inhibition zone of activity against standard drugs.

Ionic Liquid Assisted Green Synthesis of Quinoxaline Based Bisspirooxindoles: Anticancer Evaluation and Molecular Dynamics

AbstractIn this study, we have synthesized a series of novel quinoxaline based bisspirooxindoles through green protocol using ionic liquid [Bmim]BF4. All the compounds were well characterized by spectroscopic methods like FT‐IR, 1H NMR, 13C NMR, mass and finally the structures were authenticated by single crystal X‐ray diffraction (SCXRD) (4e). The target compounds were evaluated for their anticancer activity with different cancer cell lines like MDAMB‐231, MCF‐7, MCF‐10A, HCC‐1395, Molt‐4, and FaDU. The compounds 4d, 4g, 4m, and 4n showed 42.0%, 43.3%, 52.7%, and 56.0 percentage of growth inhibition respectively with the T cell acute lymphoblastic Molt‐4 cell line. The compounds 4b, 4c, 4 h, 4k, and 4m have shown 30%–39% of growth inhibition against FaDU cell line. Further, anticancer activity was validated with in silico molecular docking and molecular dynamics simulations. The outcomes of dynamics simulations exclusively emphasize that the compounds bind to HIS862 and TYR896 residues which are among the catalytic triad of PARP1. Finally, the results of ADME is also used to assess the drug likeness, which clearly shows that our target compounds are adaptable as potential drug pathways for medicinal chemists.

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.

Rationale design and synthesis of new roflumilast analogues as preferential selective and potent PDE-4B inhibitors

In this study, we designed and synthesized novel analogues of roflumilast that exhibit selective inhibition of PDE-4B. To accomplish this target; synthesis of novel series (4a-u, 5a-i, and 6) was done, aiming at obtaining new PDE-4B inhibitors hits based on the proposed pharmacophore, 1-(cyclopropylmethoxy)-2-(difluoromethoxy) benzene moiety. Enzyme assay was used to measure the IC50 values for the PDE-4B inhibition of all the synthesized compounds along with roflumilast as a reference drug. The results demonstrated that most of the examined candidates exhibited considerable inhibitory activity against the PDE-4B enzyme. The four compounds (4i, 4k, 4p, and 4q) exhibited the highest potency (IC50 = 7.25, 7.15, 5.50, 7.19 nM, respectively) with no significant inhibition difference from roflumilast (no statistical difference at p < 0.05). Interestingly, compound 4p with 3-OH and 4-OCH3 substituents was found to be the most potent against PDE-4B enzyme (IC50 = 5.50 nM), compared to that of roflumilast (IC50 = 2.36 nM). Moreover, the most potent derivatives 4i, 4k, 4p, and 4q were further tested for PDE-4D inhibitory activity to investigate their PDE-4D/PDE-4B selectivity ratio. Compound 4k showed the highest selectivity towards PDE-4B isozyme more than the reference drug roflumilast (PDE-4D/4B IC50 ratio for compound 4k and roflumilast = 3.22 and 3.02, respectively). Additionally, compound 4p was chosen to test its selectivity for PDE-4B over PDE-8A, PDE-11A, and PDE-1B compared to thereference drug roflumilast. Compound 4p showed approximately 6-fold selectivity for PDE-4B over PDE-8A, about 5-fold selectivity for PDE-4B over PDE-11A, and about 11-fold selectivity of PDE-4B over PDE-1B. Compound 4p showed a higher selectivity towards PDE-4B than PDE-1B, more than the reference compound roflumilast. Furthermore, the most potent compounds (4i, 4k, 4p, 4q) were subjected to further investigation, and their effects on the cAMP level and percentage of inhibition of tumor necrosis factor-alpha (TNF-α) were studied and compared with reference drug roflumilast. Compound 4q showed the highest increase in the level of intracellular cAMP (6.55 ± 0.37 pmol/mL) and compound 4i showed the highest % of TNF-α inhibition (77.22 %). On the other side, a molecular docking study against PDE-4B clarified that all the examined candidates achieved nearly similar binding modes with similar orientations to that of the native roflumilast ligand and showed higher docking scores than roflumilast.

Synthesis of novel meta-diamide compounds containing pyrazole moiety and their insecticidal evaluation

Abstract A novel series of meta-diamide compounds incorporating a pyrazole moiety (2a–2v) were designed and synthesized based on cyproflanilide. Their structures were validated through 1H NMR, 13C NMR, and HRMS analyses. These compounds were evaluated for their insecticidal activity against Plutella xylostella, Mythimna separate, Tetranychus cinnabarinus, and Nilaparvata lugens. Most of the title compounds exhibited good activity against N. lugens at 400 mg/L. Compound 2k demonstrated potential for further optimization as an insecticidal lead, thereby extending the application of meta-diamide compounds in the field of sucking mouthparts.

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 &amp; 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 &amp; 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

Discovery and Development of Caffeic Acid Analogs as Versatile Therapeutic Agents

Caffeic acid (CA) is a polyphenolic acid compound widely distributed in plant seeds. As natural compounds with high research interest, caffeic acid and its derivatives show good activity in the treatment of tumors and inflammation and have antibacterial properties. In recent years, caffeic acid derivatives have been studied extensively, and these derivatives fall roughly into three categories: (1) caffeic acid ester derivatives, (2) caffeic acid amide derivatives, (3) caffeic acid hybrids. These caffeic acid analogues exert mainly antibacterial and antioxidant activities. Among the caffeic acid analogues summarized in this paper, compounds 1g and CAP10 have good activity against Candida albicans, and their MIC50 is 32 µg/mL and 13 μM, respectively. In a DPPH assay, compounds 3k, 5a, CS2, Phellinsin A and 8j showed strong antioxidant activity, and their IC50 values are 18.6 μM, 67.85 μM, 40.29 μM, 0.29 ± 0.004 mM, 4774.37 ± 137.20 μM, respectively. Overall, compound CAP10 had the best antibacterial activity and compound 3k had the best antioxidant activity. This paper mainly summarizes and discusses some representative caffeic acid analogs, hoping to provide better drug design strategies for the subsequent development of caffeic acid analogs.