Compounds 3u Research Articles

Design, Synthesis, and Biological Activity Evaluation of Eco-Friendly Rosin-Diamide-Based Fungicides as Potential Succinate Dehydrogenase Inhibitors for Sustainable Crop Protection.

To develop novel succinate dehydrogenase (SDH) inhibitors for sustainable crop protection, a series of dehydroabietyl-diamide-based fungicides (a total of 21) were designed. In vitro fungicidal activity measurement showed that compound 3u exhibited excellent fungicidal activity against Valsa mali (half-maximal effective concentration, EC50 = 0.195 μg/mL), surpassing that of the positive control carbendazim (EC50 = 1.35 μg/mL). The in vivo fungicidal activity assessment suggested that 3u exhibited a protective effect on apple branches (69.7-48.1%) and apples (94.6-56.6%). Furthermore, biosafety evaluation indicated that 3u was significantly environmentally friendly toward zebrafish. Subsequently, morphology, physiology, and molecular docking were investigated to elucidate the mode of action of 3u against V. mali. Results demonstrated a strong binding between 3u and SDH, resulting in decreased SDH activity (half-maximal inhibitory concentration, IC50 = 11.7 μg/mL). Moreover, 3u disrupted the mycelial cell membrane and accelerated electrolyte leakage, ultimately resulting in the death of V. mali. These findings suggest that 3u could serve as a potent SDH inhibitor for sustainable crop protection.

Discovery of Novel Myristic Acid Derivatives as N-Myristoyltransferase Inhibitors: Design, Synthesis, Analysis, Computational Studies and Antifungal Activity.

In recent years, N-Myristoyltransferase (NMT) has been identified as a new target for the treatment of fungal infections. It is observed that at present, there are increased rates of morbidity and mortality due to fungal infections. Hence, a series of novel myristic acid derivatives were designed via molecular docking studies and ADMET studies by targeting NMT (N-Myristoyltransferase). The designed myristic acid derivatives were synthesized by converting myristic acid into myristoyl chloride and coupling it with aryl amines to yield corresponding myristic acid derivatives. The compounds were purified and characterized via FTIR, NMR and HRMS spectral analyses. In this study, we carried out a target NMT inhibition assay. In the NMT screening assay results, the compounds 3u, 3m and 3t showed better inhibition compared to the other myristic acid derivatives. In an in vitro antifungal evaluation, the myristic acid derivatives were assessed against Candida albicans and Aspergillus niger strains by determining their minimal inhibitory concentrations (MIC50). The compounds 3u, 3k, 3r and 3t displayed superior antifungal capabilities against Candida albicans, and the compounds 3u, 3m and 3r displayed superior antifungal capabilities against Aspergillus niger compared to the standard drug FLZ (fluconazole). Altogether, we identified a new series of antifungal agents.

Chemo- and Diastereoselective Cycloisomerization/[2 + 3] Cycloaddition of Enynamides: Synthesis of Spiropyrazolines as Potential Anticancer Reagents.

A silver-catalyzed one-pot cycloisomerization/[2 + 3] cycloaddition of enynamides with in situ generated nitrile imines has been developed. Unlike the well-established cycloisomerization/[4 + n] cycloadditions of enynamides, this strategy provides efficient access to a new type of spiropyrazolines, which exhibit an anti-proliferation effect on multiple tumor cell lines. The compound 3u exhibits obvious anticancer activity by inducing apoptosis in RKO cells. The combination of compound 3u and an autophagy inhibitor could improve its anti-proliferation capacities.

Identification of pyrrolo[3′,4’:3,4]cyclohepta[1,2-d][1,2]oxazoles as promising new candidates for the treatment of lymphomas

Unsatisfactory outcomes for relapsed/refractory lymphoma patients prompt continuing efforts to develop new therapeutic strategies. Our previous studies on pyrrole-based anti-lymphoma agents led us to synthesize a new series of twenty-six pyrrolo[3′,4':3,4]cyclohepta[1,2-d] [1,2]oxazole derivatives and study their antiproliferative effects against a panel of four non-Hodgkin lymphoma cell lines. Several candidates showed significant anti-proliferative effects, with IC50's reaching the sub-micromolar range in at least one cell line, with compound 3z demonstrating sub-micromolar growth inhibitory effects towards the entire panel. The VL51 cell line was the most sensitive, with an IC50 value of 0.10 μM for 3z.Our earlier studies had shown that tubulin was a prominent target of many of our oxazole derivatives. We therefore examined their effects on tubulin assembly and colchicine binding. While 3u and 3z did not appear to target tubulin, good activity was observed with 3d and 3p.Molecular docking and molecular dynamics simulations allowed us to rationalize the binding mode of the synthesized compounds toward tubulin. All ligands exhibited a better affinity for the colchicine site, confirming their specificity for this binding pocket. In particular, a better affinity and free energy of binding was observed for 3d and 3p. This result was confirmed by experimental data, indicating that, although both 3d and 3p significantly affected tubulin assembly, only 3d showed activity comparable to that of combretastatin A-4, while 3p was about 4-fold less active.Cell cycle analysis showed that compounds 3u and especially 3z induced a block in G2/M, a strong decrease in S phase even at low compound concentrations and apoptosis through the mitochondrial pathway. Thus, the mechanism of action of 3u and 3z remains to be elucidated.Very high selectivity toward cancer cells and low toxicity in human peripheral blood lymphocytes were observed, highlighting the good potential of these agents in cancer therapy and encouraging further exploration of this compound class to obtain new small molecules as effective lymphoma treatments.

Design, synthesis, and anticancer evaluation of nitrobenzoxadiazole-piperazine hybrids as potent pro-apoptotic agents

Inspired by antitumor drug 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), a series of novel nitrobenzoxadiazole-piperazine hybrids were designed, synthesized, and evaluated for their anticancer activities in vitro. The representative hybrids 3u, 3v, and 3w containing a chloromethyl substitution exhibited the most potent anticancer effects against MCF-7, HepG2, and A549 cells. Among the synthesized compounds, 3u was found to be the most active derivative possessing broad-spectrum cytotoxicity against HepG2 and A549 cells with the highest IC50 values of 3.50 and 4.73 μM, respectively. Mechanistic studies of anti-proliferative activity revealed that compound 3u triggered apoptosis in cancer cell lines through hydrolyzing of PARP by caspase 3, and effectively inhibited colony formation. These results suggested that compound 3u deserves further development as a promising lead compound for discovering novel antitumor agents.

Taking Advantage of the Renewable Forest Bioresource Turpentine to Prepare α,β-Unsaturated Compounds as Highly Efficient Fungicidal Candidates.

In a continuous study on the high-value-added exploration of a renewable forest bioresource turpentine in modern organic agriculture, two series of α-pinene derivatives containing amide and α,β-unsaturated ketone pharmacophores were prepared. Through an in-depth fungicidal activity study, the title compounds presented excellent inhibitory activity against common crop fungi, especially Sclerotinia sclerotiorum, and the notable EC50 values of α,β-unsaturated compounds 3u (funan containing) and 3v (thiophene containing) were 1.657 and 1.749 μg/mL, respectively. Further physiological and biochemical studies on S. sclerotiorum revealed that compounds 3u and 3v reduced the ergosterol content in the cell membrane and increased the permeability of the cell membrane. In combination with their effect on mycelial morphology, the title compounds might have inhibitory effects on the biosynthesis of ergosterol, which is a paramount component of the target cell membrane. Moreover, quantitative structure-activity relationship (QSAR) and SAR studies revealed that the charge distribution of α,β-unsaturated carbonyl ketone derivatives played an important role in the observed fungicidal activity. In summary, this study highlights the design and development of novel high-efficacy turpentine-based antifungal agents.

PdCl2-catalyzed synthesis of a new class of isocoumarin derivatives containing aminosulfonyl / aminocarboxamide moiety: First identification of a isocoumarin based PDE4 inhibitor.

While anti-inflammatory properties of isocoumarins are known their PDE4 inhibitory potential was not explored previously. In our effort the non-PDE4 inhibitor isocoumarins were transformed into the promising inhibitors via introducing an aminosulfonyl/aminocarboxamide moiety to the C-3 benzene ring attached to the isocoumarin framework. This new class of isocoumarins were synthesized via a PdCl2-catalyzed construction of the 4-allyl substituted 3-aryl isocoumarin ring starting from the appropriate 2-alkynyl benzamide derivative. Several compounds showed good inhibition of PDE4B invitro and the SAR indicated superiority of aminosulfonamide moiety over aminocarboxamide in terms of PDE4B inhibition. Two compounds 3q and 3u with PDE4B IC50=0.43±0.11 and 0.54±0.19μM and ≥ 2-fold selectivity over PDE4D emerged as initial hits. The participation of aminosulfonamide moiety in PDE4B inhibition and the reason for selectivity though moderate shown by 3q and 3u was revealed by the in silico docking studies. In view of potential usefulness of moderately selective PDE4B inhibitors the compound 3u (that showed PDE4 selectivity over other PDEs) was further evaluated in adjuvant induced arthritic rats. At an intraperitoneal dose of 30mg/kg the compound showed a significant reduction in paw swelling (in a dose dependent manner), inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels and increase in body weight. Moreover, besides its TNF-α inhibition and no significant toxicity in an MTT assay the compound did not show any adverse effects in a thorough toxicity studies e.g. teratogenicity, hepatotoxicity, cardiotoxicity and apoptosis in zebrafish. Thus, the isocoumarin 3u emerged as a new, safe and moderately selective PDE4B inhibitor could be useful for inflammatory diseases possibly including COVID-19.

Ultrasound-assisted synthesis of novel chalcone, heterochalcone and bis-chalcone derivatives and the evaluation of their antioxidant properties and as acetylcholinesterase inhibitors

The chalcone and bis-chalcone derivatives have been synthesized under sonication conditions via Claisen-Schmidt condensation with KOH in ethanol at room temperature (20–89%). The structures were established on the basis of NMR, IR, Single-crystal XRD, and MS. The best compound 3u had inhibitory activity (IC50 = 7.50 µM). The synthesis, the antioxidative properties, chemical reactivity descriptors supported in Density Functional Theory (DFT), acetylcholinesterase (AChE) inhibition and their potential binding modes, and affinity were predicted by molecular docking of a number of morpholine-chalcones and quinoline-chalcone. A series of bis-chalcones are also reported. Molecular docking and an enzyme kinetic study on compound 3u suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Moreover, the pharmacokinetic profile of these compounds was investigated using a computational method.

Binding pocket-based design, synthesis and biological evaluation of novel selective BRD4-BD1 inhibitors.

Bromodomain-containing protein 4 (BRD4), consisting of two tandem bromodomains (BD1 and BD2), is key epigenetic regulator in fibrosis and cancer, which has been reported that BD1 and BD2 have distinct roles in post-translational modification. But there are few selective inhibitors toward those two domains. Herein, this study designed and synthesized a series of novel selective BRD4-BD1 inhibitors, using computer-aided drug design (CADD) approach focused on exploring the difference of the binding pockets of BD1 and BD2, and finding the His437 a crucial way to achieve BRD4-BD1 selectivity. Our results revealed that the compound 3u is a potent selective BRD4-BD1 inhibitor with IC50 values of 0.56 μM for BD1 but >100 μM for BD2. The compound exhibited a broad spectrum of anti-proliferative activity against several human cancer and fibroblastic cell lines, which might be related to its capability of reducing the expression of c-Myc and collagen I. Furthermore, it could induce apoptosis in A375 cells. To the contrary, the selective BD2 inhibitor, RVX-208, did not indicate any of these activities. Our findings highlight that the function of BRD4-BD1 might be predominant in fibrosis and cancer. And it is rational to further develop novel selective BRD4-BD1 inhibitors.

A robust synthesis of functionalized 2H-indazoles via solid state melt reaction (SSMR) and their anti-tubercular activity

A facile and convenient approach has been developed for the synthesis of functionalized indazoles via solid state melt reaction using easily accessible starting materials under catalyst-free conditions. This transformation involves electrocyclization via a conjugated nitrene intermediate obtained under thermal conditions. Further anti-tubercular activity screening of the molecules was undertaken, among the compounds 3a-3x screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv, compound 3u (MIC: 4.20μM) was found to be most active and are superior over existing standard drugs ciprofloxacin and ethambutol. Compounds 3c and 3x were found to equally potent as ethambutol. Among most potent compounds in the series, four compounds (3n, 3o, 3p and 3u) showed lower cytotoxicity which could be promising drug candidates for further development.

Novel tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one: Design, synthesis, model and use as hMAO-B inhibitors

Based on our recently reported selective hMAO-A inhibitors, on which, the intramolecular cyclization led to a very interesting change of isoform selectivity. A series of selective hMAO-B inhibitors (3a–3u) with novel scaffold of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one were designed and synthesized. Compound 3u (IC50=221nM) exhibited the best inhibitory activity and isoform selectivity against hMAO-B, superior to selegiline (IC50=321nM), which is a commercial selective hMAO-B inhibitor used to Parkinson’s disease. Modeling study indicated that the selectivity of our compounds to hMAO-B is determined by at least two residues, i.e., Ile 199 and Cys 172 (or corresponded Phe 208 and Asn 181 of hMAO-A). These data support further studies to assess rational design of more efficiently selective hMAO-B inhibitors.

Synthesis and biological evaluation of quinoline–imidazole hybrids as potent telomerase inhibitors: a promising class of antitumor agents

A series of 1-isoquinoline-2-styryl-5-nitroimidazole derivatives has been synthesized and screened for telomerase inhibitory as well as antiproliferative properties on four variant cancer cell lines (U251, Hela, HepG-2 and A549). The bioassay results showed that most of the designed compounds exhibited moderate to potent in vitro inhibitory activity in the enzymatic and cellular assays, of which compounds 3u and 3v were revealed the most potent telomerase inhibitors, with IC50 values of 0.98 μM and 1.92 μM, respectively, compared to staurosporine. Docking simulation was performed to position compounds 3u and 3v into the telomerase active site to determine the probable binding pose. Twenty three compounds were scrutinized by the CoMFA and CoMSIA techniques of 3D Quantitative Structure–Activity Relationship (QSAR). These new findings along with molecular docking observations could provide important information that compounds 3u and 3v with potent inhibitory activity in tumor growth inhibition may be potential anticancer agents.