Series Of Analogues Research Articles

Synthesis of Novel Methylsulfonylacrylimidamide via Click Chemistry Approach, Computational Analysis and α‐ Glucosidase Inhibition Activity

AbstractA series of Novel Methylsulfonylacrylimidamide analogs (4 a–4 h) were designed, synthesized, and screened for their α‐glucosidase inhibitory activity. The results indicated that some of the synthesized derivatives displayed inhibitory activities against α‐glucosidase with IC50 values ranging from 10.35±0.15 to 60.39±1.77 μM when compared to standard drug acarbose (IC50 832.22±2.00 μM). Among the synthesized derivatives, compounds 4 f and 4 h with a Di cyclohexyl and dioctyl substitution in the acrylimidamide displayed the most significant inhibitory activity with the IC50 value of 14.54±0.19 μM and 10.35±0.15 μM. The inhibitory action of compounds 4 f and 4 h against α‐glucosidase was studied by enzyme kinetic and molecular docking. In vitro, cytotoxicity showed that 4 f and 4 h exhibited low cytotoxicity against human cell lines. The ADME study suggested that most compounds will likely be orally active as they obeyed Lipinski's rule of five. Our studies showed that these derivatives could be considered a new class of α‐glucosidase inhibitors.

Caffeic acid phenethyl ester analogues as selective inhibitors of 12-lipoxygenase product biosynthesis in human platelets.

The inflammatory response is an essential process for the host defence against pathogens. Lipid mediators are important in coordinating the pro-inflammatory and pro-resolution phases of the inflammatory process. However, unregulated production of these mediators has been associated with chronic inflammatory diseases such as arthritis, asthma, cardiovascular diseases, and several types of cancer. Therefore, it is not surprising that enzymes implicated in the production of these lipid mediators have been targeted for potential therapeutic approaches. Amongst these inflammatory molecules, the 12-hydroxyeicosatetraenoic acid (12(S)-HETE) is abundantly produced in several diseases and is primarily biosynthesized via the platelet's 12-lipoxygenase (12-LO) pathway. To this day, very few compounds selectively inhibit the 12-LO pathway, and most importantly, none are currently used in the clinical settings. In this study, we investigated a series of polyphenol analogues of natural polyphenols that inhibit the 12-LO pathway in human platelets without affecting other normal functions of the cell. Using an ex vivo approach, we found one compound that selectively inhibited the 12-LO pathway, with IC50 values as low as 0.11µM, with minimal inhibition of other lipoxygenase or cyclooxygenase pathways. More importantly, our data show that none of the compounds tested induced significant off-target effects on either the platelet's activation or its viability. In the continuous search for specific and better inhibitors targeting the regulation of inflammation, we characterized two novel inhibitors of the 12-LO pathway that could be promising for subsequent in vivo studies.

Structure-Activity Relationship Studies on Cell-Potent Nicotinamide N-Methyltransferase Bisubstrate Inhibitors.

Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme implicated in multiple diseases, making it a promising therapeutic target. Building upon our recently reported NNMT inhibitor II399, we systematically investigate the structure-activity relationship by designing and synthesizing a series of analogues. Among them, two top inhibitors II559 (Ki = 1.2 nM) and II802 (Ki = 1.6 nM) displayed over 5000-fold selectivity for NNMT over closely related methyltransferases. Moreover, II559 and II802 showed enhanced cellular inhibition, with a cellular IC50 value of approximately 150 nM, making them the most cell-potent bisubstrate inhibitors reported to date. Furthermore, both inhibitors reduced the cell viability with a GI50 value of ∼10 μM and suppressed the migration of aggressive clear cell renal cancer cell carcinoma cell lines. Overall, II559 and II802 would serve as valuable probes to investigate the enzymatic function of NNMT in health and diseases.

Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitro and In Vivo Antimalarial Activity.

The Plasmodium falciparum aspartic protease plasmepsin X (PMX) is essential for the egress of invasive merozoite forms of the parasite. PMX has therefore emerged as a new potential antimalarial target. Building on peptidic amino alcohols originating from a phenotypic screening hit, we have here developed a series of macrocyclic analogues as PMX inhibitors. Incorporation of an extended linker between the S1 phenyl group and S3 amide led to a lead compound that displayed a 10-fold improved PMX inhibitory potency and a 3-fold improved half-life in microsomal stability assays compared to the acyclic analogue. The lead compound was also the most potent of the new macrocyclic compounds in in vitro parasite growth inhibition. Inhibitor 7k cleared blood-stage P. falciparum in a dose-dependent manner when administered orally to infected humanized mice. Consequently, lead compound 7k represents a promising orally bioavailable molecule for further development as a PMX-targeting antimalarial drug.

Synthesis and Antibacterial Evaluation of Novel Vancomycin Derivatives Containing Quaternary Ammonium Moieties.

A series of novel vancomycin analogues with quaternary ammonium moieties have been designed and synthesized for fighting with clinically isolated drug-resistant bacteria. Partial target molecules exhibited potent activity against the tested strains. Among all of the compounds, a triazole quaternary ammonium vancomycin (QAV) derivative QAV-a1 exerted the best antibacterial activities. QAV-a1 was found to be 4- to 32-fold more efficacious than vancomycin against MRSA. Meanwhile, QAV-a1 showed a good pharmacokinetic profile with a half-life of 5.19 ± 0.10 h, which is longer than that of vancomycin (4.3 ± 1.9 h). These results provided guidance for the further exploitation of vancomycin derivatives against drug-resistant bacteria.

Design, Synthesis, and Insecticidal Evaluation of Neonicotinoids with Conjugated Diene.

Neonicotinoid insecticides acting on the insect nicotinic acetylcholine receptors (nAChRs) play an essential role in contemporary pest control. In the present study, a series of novel neonicotinoid analogues with conjugated diene were synthesized. Bioassays indicated that compounds A3 and A12 had LC50 values of 1.26 and 1.24 mg/L against Myzus persicae, respectively, which were comparable to that of imidacloprid (IMI, LC50 = 0.78 mg/L). Density functional theory (DFT) calculations were performed to explain the differences in the insecticidal activities of target compounds. Molecular docking results indicate that compounds A3 and A12 interact favorably with Lymnaea stagnalis AChBP. The hydrolysis experiments confirmed that the stability of compounds A3 and A12 was enhanced in water.

1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1.

A new series of nortopsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,3,4-oxadiazole or 1,3,4-thiadiazole moiety, was efficiently synthesized. The antiproliferative activity of all synthesized derivatives was evaluated against five pancreatic ductal adenocarcinoma (PDAC) cell lines, a primary culture and a gemcitabine-resistant variant. The five more potent compounds elicited EC50 values in the submicromolar-micromolar range, associated with a significant reduction in cell migration. Moreover, flow cytometric analysis after propidium iodide staining revealed an increase in the G2-M and a decrease in G1-phase, indicating cell cycle arrest, while a specific ELISA demonstrated the inhibition of CDK1 activity, a crucial regulator of cell cycle progression and cancer cell proliferation.

Targeting the binding pocket of the fluorophore 8-anilinonaphthalene-1-sulfonic acid in the bacterial enzyme MurA.

8-Anilinonaphthalene-1-sulfonic acid (ANS) has been extensively used as a fluorescent probe to detect conformational changes of proteins. It has been cocrystallized with several of the proteins it is used to monitor, including the bacterial cell wall synthesis enzyme MurA. MurA catalyzes the first committed step of peptidoglycan biosynthesis, converting UDP-N-acetylglucosamine (UDP-GlcNAc) into enolpyruvyl UDP-GlcNAc. It has been reported before that ANS binds to MurA from Enterobacter cloacae without inhibiting the enzyme's activity up to a concentration of 1 mM ANS. In this study, we present evidence that ANS inhibits the activity of several isoforms of MurA with IC50 values of 18, 22, and 31 µM against wild-type Escherichia coli, C115D E. coli, and E. cloacae MurA, respectively. This prompted us to test a larger series of structural analogs of ANS for the inhibition of these MurA enzymes, which led to the discovery of compound 26. This ANS analog showed enhanced inhibition of MurA (WT and C115D MurA from E. coli, and E. cloacae MurA) with IC50 values of 2.7, 10, and 14 µM, respectively. Based on our results, the ANS binding pocket was identified as a novel target site for the development of potential antibiotics.

Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer.

The androgen/androgen receptor (AR) signaling pathway plays an important role in castration-resistant prostate cancer (CRPC). Bifunctional agents that simultaneously degrade AR and inhibit androgen synthesis are expected to block the androgen/AR signaling pathway more thoroughly, demonstrating the promising therapeutic potential for CRPC, even enzalutamide-resistant CRPC. Herein, a series of steroid analogs were designed, synthesized, and identified as selective AR degraders, among which YXG-158 (23-h) was the most potent antitumor compound with dual functions of AR degradation and CYP17A1 inhibition. In addition, 23-h abrogated the hERG inhibition and exhibited excellent PK profiles. In vivo, 23-h effectively inhibited the growth of hormone-sensitive organs in the Hershberger assay and exhibited robust antitumor efficacy both in enzalutamide-sensitive (LNCaP/AR) and enzalutamide-resistant (C4-2b-ENZ) xenograft models. Thus, 23-h was chosen as a preclinical candidate for the treatment of enzalutamide-resistant prostate cancer.

Eucryphin analog's total synthesis, anti-inflammatory activity for DNFB-induced contact hypersensitivity and structure-activity relationship

Eucryphin, a natural product widely found in plants, has a variety of biological activities. In this work, a series of eucryphin analogs were designed, synthesized, characterized and the anti-inflammatory activity in vivo was evaluated comparing with eucryphin and its 7-O-glycosyl derivatives to study the structure-activity relationship. Eucryphin exhibited remarkable anti-inflammatory activity and minor side effects in 2,4-dinitrofluorobenzene (DNFB) induced mice auricle edema model. Glycosyl substitution at the position of C-3 was essential for the anti-inflammatory activity. Methyl substitution at C-2 and glycosylation at C-7 of eucryphin reduce anti-inflammatory activity.

Benzidine Derivatives: A Class of High Redox Potential Molecules for Aqueous Organic Flow Batteries.

The development of water-soluble redox-active molecules with high potentials is one of the effective ways to enhance the energy density of aqueous organic flow batteries (AOFBs). Herein, a series of promising N-substituted benzidine analogues as water-soluble catholyte candidates with controllable redox potentials (0.78-1.01 V vs. standard hydrogen electrode (SHE)) were obtained by the molecular engineering of aqueous irreversible benzidines. Theoretical calculations reveal that the redox potentials of these benzidine derivatives in acidic solution are determined by their electronic structure and alkalinity. Among these benzidine derivatives, N,N,N',N'-tetraethylbenzidine(TEB) shows both high redox potential (0.82 V vs. SHE) and good solubility (1.1 M). Pairing with H4 [Si(W3 O10 )4 ] anolyte, the cell displayed discharge capacity retention of 99.4 % per cycle and a high coulombic efficiency (CE) of ∼100 % over 1200 cycles. The stable discharge capacity of 41.8 Ah L-1 was achieved at the 1.0 M TEB catholyte with a CE of 97.2 % and energy efficiency (EE) of 91.2 %, demonstrating that N-substituted benzidines could be promising for AOFBs.

Innovative Strategy toward Mutant CFTR Rescue in Cystic Fibrosis: Design and Synthesis of Thiadiazole Inhibitors of the E3 Ligase RNF5.

In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the CF transmembrane conductance regulator (CFTR) is associated to misfolding and defective gating of the mutant channel. One of the most promising CF drug targets is the ubiquitin ligase RNF5, which promotes F508del-CFTR degradation. Recently, the first ever reported inhibitor of RNF5 was discovered, i.e., the 1,2,4-thiadiazol-5-ylidene inh-2. Here, we designed and synthesized a series of new analogues to explore the structure-activity relationships (SAR) of this class of compounds. SAR efforts ultimately led to compound 16, which showed a greater F508del-CFTR corrector activity than inh-2, good tolerability, and no toxic side effects. Analogue 16 increased the basal level of autophagy similar to what has been described with RNF5 silencing. Furthermore, co-treatment with 16 significantly improved the F508del-CFTR rescue induced by the triple combination elexacaftor/tezacaftor/ivacaftor in CFBE41o- cells. These findings validate the 1,2,4-thiadiazolylidene scaffold for the discovery of novel RNF5 inhibitors and provide evidence to pursue this unprecedented strategy for the treatment of CF.

Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity.

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 µM. The representative compound 37 displays improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model.

Fluorinated and N-Acryloyl-Modified 3,5-Di[(E)-benzylidene]piperidin-4-one Curcuminoids for the Treatment of Pancreatic Carcinoma.

Pancreatic carcinoma is a cancer disease with high mortality. Thus, new and efficient treatments for this disease are badly needed. Curcumin has previously shown promising effects in pancreatic cancer patients; however, this natural compound suffers from inadequate efficacy and bioavailability, preventing its clinical approval. The synthetic curcuminoid EF24 was developed with activities superior to curcumin against various cancer types. In this study, a series of analogs of EF24 were investigated for anticancer effects on pancreatic carcinoma models. A distinct activity boost was achieved by straightforward N-acrylation of EF24 analogs, in particular, of compounds bearing 3-fluoro-4-methoxybenzylidene, 3,4-difluorobenzylidene, and 4-trifluoromethylbenzylidene moieties, while no improvement was seen for N-acryloyl-modified EF24. Apoptosis induction and suppression of phospho-STAT3 levels were determined, the latter corroborated by docking of active curcuminoids into STAT3. Hence, promising new clues for the development of efficient and superior curcuminoids as valuable treatment options for one of the most lethal cancer diseases were discovered in this study.

Synthesis of 1-(4-(dimethylamino)phenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione analogues and their anti-inflammatory activities in lipopolysaccharide-induced BV2 cells

A series of thalidomide analogues, where the fused benzene ring in the phthalimide moiety was converted into two separated diphenyl rings in maleimide moiety and N-aminoglutarimide moiety was replaced by substituted phenyl moiety, were synthesized and evaluated for their NO inhibitory activities on BV2 cells stimulated with lipopolysaccharide (LPS). Among the synthesized compounds, the dimethylaminophenyl analogue 1s (IC50 = 7.1 μM) showed significantly higher inhibitory activity than the glutarimide analogue 1a (IC50 > 50 μM) and suppressed NO production dose-dependently without cytotoxicity. In addition, 1s inhibited the production of pro-inflammatory cytokines and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by blocking nuclear factor-kappa B (NF-κB) and p38 MAPK pathways. These results demonstrated that 1s showed good anti-inflammatory activity and could become a leading compound for the treatment of neuroinflammatory diseases.

Prussian blue analogs as catalysts for the fixation of CO2 to glycidol to produce glycerol carbonate and multibranched polycarbonate polyols

A series of Prussian blue analogs (PBAs) having a range of crystal structures and compositions was investigated as heterogeneous catalysts for the fixation of carbon dioxide (CO2) to glycidol. The morphology of PBAs was modified, as confirmed by structural characterization, by varying the precipitation method. Of the prepared catalysts, the cubic Zn(II)-Co(III) PBA exhibited the highest catalytic activity (turn-over frequency up to 763 h−1), selectivity (up to 94%), and recyclability for the cycloaddition of CO2 to glycidol. In addition, branched polycarbonate polyols having tunable branching degree (0.15–0.61) and linear polycarbonates of relatively high carbonate content (up to 64.2%) were produced via ring-opening (multibranching) copolymerization of CO2 and various epoxides using a highly amorphous Zn(II)-Co(III) double metal cyanide catalyst. Mechanistic pathways have been proposed by combining experimental results with computational studies.

Structure-Activity Relationships for a Recently Controlled Synthetic Cathinone Dopamine Transporter Reuptake Inhibitor: α-Pyrrolidinohexiophenone (α-PHP).

α-Pyrrolidinohexiophenone (α-PHP) is the one-carbon unit α-extended homolog of the better-known and widely abused synthetic cathinone central stimulant α-PVP ("flakka"); both are now U.S. Schedule I controlled substances. Structurally, α-PVP and α-PHP possess a common terminal N-pyrrolidine moiety and differ only with respect to the length of their α-alkyl chain. Using a synaptosomal assay, we previously reported that α-PHP is at least as potent as α-PVP as a dopamine transporter (DAT) reuptake inhibitor. A systematic structure-activity study of synthetic cathinones (e.g., α-PHP) as DAT reuptake inhibitors (i.e., transport blockers), a mechanism thought responsible for their abuse liability, has yet to be conducted. Here, we examined a series of 4-substituted α-PHP analogues and found that, with one exception, all behaved as relatively (28- to >300-fold) selective DAT versus serotonin transporter (SERT) reuptake inhibitors with DAT inhibition potencies of most falling within a very narrow (i.e., <3-fold) range. The 4-CF3 analogue of α-PHP was a confirmed "outlier" in that it was at least 80-fold less potent than the other analogues and displayed reduced (i.e., no) DAT vs SERT selectivity. Consideration of various physicochemical properties of the CF3 group, relative to that of the other substituents involved here, provided relatively little insight. Unlike with DAT-releasing agents, as previously reported by us, a QSAR study was precluded because of the limited range of empirical results (with the exception of the 4-CF3 analogue) for DAT reuptake inhibition.

Design, synthesis, and biological evaluation of a series of new anthraquinone derivatives as anti-ZIKV agents

The major severe complications linked to Zika virus (ZIKV) cause the global public health problems, including microcephaly and other congenital abnormalities in newborns, and Guillain-Barré syndrome, meningoencephalitis, multi-organ failure in adults. However, neither approved vaccines nor drugs are available for ZIKV. In this study, we describe the design, synthesis and the anti-ZIKV activities of a series of anthraquinone analogs. Most of the newly synthesized compounds demonstrated moderate to excellent potency against ZIKV. Among all, compound 22, showed the most potent anti-ZIKV activity (EC50 value from 1.33 μM to 5.72 μM) with low cytotoxicity (CC50＞50 μM) in multiple cellular model. Importantly, 22 significantly improved the survival of ZIKV-infected mice (Ifnar1−/−), alleviated ZIKV-associated pathological damages and suppressed the excessive inflammatory response and pyroptosis induced by ZIKV in vivo and in vitro. Furthermore, the molecular docking simulation analysis and the surface plasmon resonance results demonstrated the direct binding between 22 and ZIKV RdRp, and the mechanistic study revealed that 22 suppressed viral RNA synthesis by ZIKV NS5 in cells. Taken together, this study highlights that 22 may be a novel anti-ZIKV drug candidate and provides treatment options for ZIKV-associated diseases.

Palladium-Catalyzed C-H Olefination for Nucleic Acid Production.

The palladium-catalyzed direct C-H olefination of unprotected uridine, 2'-deoxyuridine, uridine monophosphate, and uridine analogues are described here. This protocol provides an efficient, atom-economical, and environmentally friendly method for the introduction of an alkenyl group at the C5 position of the uracil without pre-functionalization. A series of C5-alkenylated uridine analogues, including some biologically significant compounds and potential pharmaceutical candidates, were synthesized with exposed hydroxyl groups on the ribose. © 2023 Wiley Periodicals LLC. Basic Protocol 1: The reaction of uridine, 2'-deoxyuridine, and sofosbuvir for the C-H olefination with methyl acrylate Basic Protocol 2: The reaction of uridine and 2'-deoxyuridine for the C-H olefination with styrene.

Discovery of ecnoglutide – A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog

ObjectiveGlucagon-like peptide (GLP)-1 is an incretin hormone that acts after food intake to stimulate insulin production, enhance satiety, and promote weight loss. Here we describe the discovery and characterization of ecnoglutide (XW003), a novel GLP-1 analog. MethodsWe engineered a series of GLP-1 peptide analogs with an alanine to valine substitution (Ala8Val) and a γGlu-2xAEEA linked C18 diacid fatty acid at various positions. Ecnoglutide was selected and characterized in GLP-1 receptor signaling assays in vitro, as well as in db/db mice and a diet induced obese (DIO) rat model. A Phase 1, double-blind, randomized, placebo-controlled, single (SAD) and multiple ascending dose (MAD) study was conducted to evaluate the safety, tolerability, and pharmacokinetics of subcutaneous ecnoglutide injection in healthy participants. SAD doses ranged from 0.03 to 1.0 mg; MAD doses ranged from 0.2 to 0.6 mg once weekly for 6 weeks (ClinicalTrials.gov Identifier: NCT04389775). ResultsIn vitro, ecnoglutide potently induced cAMP (EC50 = 0.018 nM) but not GLP-1 receptor internalization (EC50 > 10 μM), suggesting a desirable signaling bias. In rodent models, ecnoglutide significantly reduced blood glucose, promoted insulin induction, and led to more pronounced body weight reduction compared to semaglutide. In a Phase 1 trial, ecnoglutide was generally safe and well tolerated as a once-weekly injection for up to 6 weeks. Adverse events included decreased appetite, nausea, and headache. The half-life at steady state ranged from 124 to 138 h, supporting once-weekly dosing. ConclusionsEcnoglutide showed a favorable potency, pharmacokinetic, and tolerability profile, as well as a simplified manufacturing process. These results support the continued development of ecnoglutide for the treatment of type 2 diabetes and obesity.