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5-Acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1 H )-ones 1 – 43 were synthesized in a “one-pot” three component reaction and structurally characterized by various spectroscopic techniques such as 1 H, 13 C NMR, EI-MS, HREI-MS, and IR. All compounds were evaluated for their in vitro urease inhibitory activity. It is worth mentioning that except derivatives 1 , 11 , 12 , and 14 , all were found to be more potent than the standard thiourea (IC 50  = 21.25 ± 0.15 µM) and showed their urease inhibitory potential in the range of IC 50  = 3.70 ± 0.5–20.14 ± 0.1 µM. Structure-activity relationship (SAR) was rationalized by looking at the varying structural features of the molecules. However, molecular modeling study was performed to confirm the binding interactions of the molecules (ligand) with the active site of enzyme. [ABSTRACT FROM AUTHOR]

Increased interest in ionic liquids (ILs) is due to their designable and tunable unique physicochemical properties, which are utilized for a wide variety of chemical and biotechnological applications. ILs containing the tris(pentafluoroethyl)trifluorophosphate ([FAP]) anion have been shown to have excellent hydrolytic, electrochemical and thermal stability and have been successfully used in various applications. In the present study the influence of the cation on the toxicity of the [FAP] anion was investigated. Due to the properties of [FAP] ILs, the IL-toxicity of seven cations with [FAP] compared to [Cl] was examined by determination of minimum inhibitory (MIC) and minimum bactericidal concentrations (MBC) on six Gram-positive and six Gram-negative clinically-relevant bacteria. For the first time, to our knowledge, the results provide evidence for a decrease in toxicity with increasing alkyl side-chain length, indicating that the combination of both ions is responsible for this ‘reverse side-chain effect’. These findings could portend development of new non-toxic ILs as green alternatives to conventional organic solvents. [ABSTRACT FROM AUTHOR]

Human sirtuin 5 ( SIRT5) is a protein deacylase regulating metabolic pathways and stress responses and is implicated in metabolism-related diseases. Small-molecule inhibitors for SIRT5 are sought as chemical tools and potential therapeutics. Herein, we proposed a customized virtual screening approach targeting catalytically important and unique residues Tyr102 and Arg105 of SIRT5. Of the 20 tested virtual screening hits, six compounds displayed marked inhibitory activities against SIRT5. For the hit compound 19, a series of newly synthesized ( E)-2-cyano-N-phenyl-3-(5-phenylfuran-2-yl)acrylamide derivatives/analogues were carried out structure-activity relationship analyses, resulting in new more potent inhibitors, among which 37 displayed the most potent inhibition to SIRT5 with an IC50 value of 5.59 ± 0.75 μM. The biochemical studies revealed that 37 likely acts via competitive inhibition with the succinyl-lysine substrate, rather than the NAD+ cofactor, and it manifested substantial selectivity for SIRT5 over SIRT2 and SIRT6. This study will aid further efforts to develop new selective SIRT5 inhibitors as tools and therapeutics. [ABSTRACT FROM AUTHOR]

Anthocyanins, the naturally occurring pigments responsible for most red to blue colours of flowers, fruits and vegetables, have also attracted interest because of their potential health effects. With the aim of contributing to major insights into their structure-activity relationship (SAR), we have evaluated the radical scavenging and biological activities of selected purified anthocyanin samples (PASs) from various anthocyanin-rich plant materials: two fruits (mahaleb cherry and blackcurrant) and two vegetables (black carrot and "Sun Black" tomato), differing in anthocyanin content (ranging from 4.9 to 38.5 mg/g DW) and molecular structure of the predominant anthocyanins. PASs from the abovementioned plant materials have been evaluated for their antioxidant capacity using Trolox Equivalent Antioxidant Capacity (TEAC) and Oxygen Radical Absorbance Capacity (ORAC) assays. In human endothelial cells, we analysed the anti-inflammatory activity of different PASs by measuring their effects on the expression of endothelial adhesion molecules VCAM-1 and ICAM-1. We demonstrated that all the different PASs showed biological activity. They exhibited antioxidant capacity of different magnitude, higher for samples containing non-acylated anthocyanins (typical for fruits) compared to samples containing more complex anthocyanins acylated with cinnamic acid derivatives (typical for vegetables), even though this order was slightly reversed when ORAC assay values were expressed on a molar basis. Concordantly, PASs containing non-acylated anthocyanins reduced the expression of endothelial inflammatory antigens more than samples with aromatic acylated anthocyanins, suggesting the potential beneficial effect of structurally diverse anthocyanins in cardiovascular protection. [ABSTRACT FROM AUTHOR]

In this study, phthalonitriles 6, 7 and their corresponding bromo derivatives 8, 9 were synthesized from 8- hydroxyquinoline to investigate antiproliferative and cytotoxic activities on C6 (rat brain tumor), HeLa (human cervix carcinoma) and HT29 (human colon carcinoma) cancer cell lines of these molecules. The antiproliferative and apoptotic effects of 7-bromo- and 5,7-dibromo-8-hydroxyquinoline derivatives (2 and 3) and phthalonitrile 6, 7 and their brominated derivatives 8, 9 were compared in terms of Structure Activity Relationship (SAR). Although bromohydroxyquinoline derivatives 2 and 3 exhibited high antiproliferative activity according to literature, it has been determined that phthalonitrile compounds 6, 7 and their brominated 8, 9 derivatives are significantly reduced in antiproliferative activity. The SAR of the quinoline core at C-8 revealed that OH group lead to antiproliferative and apoptotic activity. In addition, biological activity was decreased when alkyl or substituted cyclic groups bounded to OH of quinoline, and the bromination of these derivatives did not increase the antiproliferative activity. [ABSTRACT FROM AUTHOR]

N -acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that participates in the deactivation of fatty acid ethanolamides, such as palmitoylethanolamide (PEA). NAAA inhibition may provide a potential therapeutic strategy for the treatment of diseases in which higher PEA level is desired. In the present study, we reported the structure-activity relationship (SAR) studies for oxazolidone derivatives as NAAA inhibitors. A series of substituents or alkyl replacements for the terminal phenyl ring of oxazolidone derivatives were examined. The results showed that the inhibition potency of these oxazolidone derivatives towards NAAA depends on the sizes, flexibility, and lipophilicity of the terminal groups. SAR results suggested that small lipophilic 3-phenyl substituents or hydroxy-containing 4-phenyl substituents were preferable for optimal potency. Furthermore, the distal aliphatic replacement is also preferred for high inhibitory potency. Rapid dilution and kinetic analysis suggested that oxazolidone derivatives with different terminal phenyl moieties inhibited NAAA via different mechanisms. This study identified several highly potent NAAA inhibitors, including 1a (F215, IC 50 = 0.009 μM), 1o (IC 50 = 0.061 μM) and 2e (IC 50 = 0.092 μM), and also determined structural requirements of oxazolidone derivatives for potent inhibition against NAAA. [ABSTRACT FROM AUTHOR]

FISLE-412 is the first reported small molecule peptidomimetic that neutralizes anti-dsDNA autoantibodies associated with systemic lupus erythematosus (SLE) pathogenesis. FISLE-412 is a complex small molecule that involves a challenging synthesis scheme, but has attractive pharmacological activities as a potential small molecule therapeutic in lupus. Therefore, we initiated a Structure–Activity Relationship study to simplify the complexity of FISLE-412. We synthesized a small library of mimetopes around the FISLE-412 structure and identified several analogues which could neutralize anti-DNA lupus antibodies in vitro and ex vivo . Our strategies reduced the structural complexity of FISLE-412 and provide important information that may guide development of potential autoantibody-targeted lupus therapeutics. [ABSTRACT FROM AUTHOR]

A new library of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl ether derivatives ( 1 − 2 3 ) were synthesized and characterized by EI-MS and 1 H NMR, and screened for their α -amylase inhibitory activity. Out of twenty-three derivatives, two molecules 19 (IC 50 = 0.38 ± 0.82 µM) and 23 (IC 50 = 1.66 ± 0.14 µM), showed excellent activity whereas the remaining compounds, except 10 and 17 , showed good to moderate inhibition in the range of IC 50 = 1.77–2.98 µM when compared with the standard acarbose (IC 50 = 1.66 ± 0.1 µM). A plausible structure-activity relationship has also been presented. In addition, in silico studies was carried out in order to rationalize the binding interaction of compounds with the active site of enzyme. [ABSTRACT FROM AUTHOR]

Knoevenagel condensation was employed to generate a set of molecules potentially capable of inhibiting the RNA polymerase- σ 70 / σ A interaction in bacteria. Synthesis was achieved via reactions between a variety of indole-7-carbaldehydes and rhodanine, N -allylrhodanine, barbituric acid or thiobarbituric acid. A library of structurally diverse compounds was examined by enzyme-linked immunosorbent assay (ELISA) to assess the inhibition of the targeted protein–protein interaction. Inhibition of bacterial growth was also evaluated using Bacillus subtilis and Escherichia coli cultures. The structure–activity relationship studies demonstrated the significance of particular structural features of the synthesized molecules for RNA polymerase- σ 70 / σ A interaction inhibition and antibacterial activity. Docking was investigated as an in silico method for the further development of the compounds. [ABSTRACT FROM AUTHOR]

This Letter details the discovery and subsequent optimization of a novel M 4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M 4 PAM chemotypes. Optimized compounds in this series demonstrated improved M 4 PAM potency on both human and rat M 4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma K p = 5.3, K p,uu = 2.4; MDCK-MDR1 (P-gp) ER = 1.1). [ABSTRACT FROM AUTHOR]

To understand interaction of drugs with the prostaglandin transporter OATP2A1/ SLCO2A1 that regulates disposition of prostaglandins, we explored the impact of 636 drugs in an FDA-approved drug library on 6-carboxyfluorescein (6-CF) uptake by OATP2A1-expressing HEK293 cells (HEK/2A1). Fifty-one and 10 drugs were found to inhibit and enhance 6-CF uptake by more than 50%, respectively. Effect of the 51 drugs on 6-CF uptake was positively correlated with that on PGE 2 uptake (r = 0.64, p < 0.001). Among those, 5 drugs not structurally related to prostaglandins, suramin, pranlukast, zafirlukast, olmesartan medoxomil, and losartan potassium, exhibited more than 90% PGE 2 uptake inhibition. Inhibitory affinity of suramin to OATP2A1 was the highest (IC 50,2A1 of 0.17 μM), and its IC 50 values to MRP4-mediated PGE 2 transport (IC 50,MRP4 ) and PGE 2 synthesis in human U-937 cells treated with phorbol 12-myristate 13-acetate (IC 50,Syn ) were 73.6 and 336.7 times higher than IC 50,2A1 , respectively. Moreover, structure-activity relationship study in 29 nonsteroidal anti-inflammatory drugs contained in the library displayed inhibitory activities of anthranilic acid derivatives, but enhancing effects of propionic acid derivatives. These results demonstrate that suramin is a potent selective inhibitor of OATP2A1, providing a comprehensive information about drugs in clinical use that interact with OATP2A1. [ABSTRACT FROM AUTHOR]

A set of fused ring analogues of a new antitubercular agent, Q203, was designed and synthesized. To reduce the lipophilicity of Q203 caused by linearly extended side chains, shorter and heteroatoms containing fused rings were introduced into the side chain region. Antitubercular activity was tested against H37Rv-GFP replicating in liquid broth culture medium (extracellular) and within macrophages (intracellular). Many analogues showed potent extracellular activities as well as intracellular activities without cytotoxicity. Among them, compounds 18–21 displayed significant antitubercular activities with favorable metabolic stabilities. Representative compound 21 exhibited excellent in vivo pharmacokinetic values at high drug exposure levels in the plasma, which makes this compound promising candidate for a new antitubercular drug. [ABSTRACT FROM AUTHOR]

For the last three decades, metalloenzymes such as histone deacetylases (HDACs) and matrix metalloproteinases (MMPs) have been identified in promoting solid as well as hematological carcinogenesis. Histone deacetylase 8 (HDAC-8), a class I HDAC enzyme, may serve as ‘epigenetic player' that affects in the regulation of transcription factors and alters the structure of chromosome associated with tumorigenesis. It is established that the influence of MMP-2 in invasion, metastasis and angiogenenic events of hematological malignancies may be suppressed by HDAC inhibitors through reversion-inducing-cysteine-rich protein with kazal motifs (RECK) protein. Therefore, the isoform-specific HDAC-8 and MMP-2 inhibitors may provide synergistic medicinal benefit in leukemia. However, a paucity of articles is available on dual acting HDAC-8/MMP-2 inhibitors. In this circumstance, a lot of works are still necessary to identify novel dual HDAC-8/MMP-2 inhibitors and this review will surely provide an initial idea regarding the utility of designing such type of dual inhibitors. Here, the importance of MMP-2 and HDAC-8 inhibition in hematological malignancies are focussed for the first time as per our knowledge along with the structure-activity relationships (SARs) of a handful of molecules, some of which were synthesised in-house, have been highlighted that will inspire more interactions between the medicinal chemistry and biology community to harness their expertise in design and discovery of the better acting dual inhibitors in future. [ABSTRACT FROM AUTHOR]

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M 4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M 4 (hM 4 IC 50 s < 200 nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma K p = 2.1, K p,uu = 1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M 1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists. [ABSTRACT FROM AUTHOR]

Human microsomal prostaglandin $$\hbox {E}_{2}$$ synthase (mPGES)-1 is a promising drug target for inflammation and other diseases with inflammatory symptoms. In this work, we built classification models which were able to classify mPGES-1 inhibitors into two groups: highly active inhibitors and weakly active inhibitors. A dataset of 1910 mPGES-1 inhibitors was separated into a training set and a test set by two methods, by a Kohonen's self-organizing map or by random selection. The molecules were represented by different types of fingerprint descriptors including MACCS keys (MACCS), CDK fingerprints, Estate fingerprints, PubChem fingerprints, substructure fingerprints and 2D atom pairs fingerprint. First, we used a support vector machine (SVM) to build twelve models with six types of fingerprints and found that MACCS had some advantage over the other fingerprints in modeling. Next, we used naïve Bayes (NB), random forest (RF) and multilayer perceptron (MLP) methods to build six models with MACCS only and found that models using RF and MLP methods were better than NB. Finally, all the models with MACCS keys were used to make predictions on an external test set of 41 compounds. In summary, the models built with MACCS keys and using SVM, RF and MLP methods show good prediction performance on the test sets and the external test set. Furthermore, we made a structure-activity relationship analysis between mPGES-1 and its inhibitors based on the information gain of fingerprints and could pinpoint some key functional groups for mPGES-1 activity. It was found that highly active inhibitors usually contained an amide group, an aromatic ring or a nitrogen heterocyclic ring, and several heteroatoms substituents such as fluorine and chlorine. The carboxyl group and sulfur atom groups mainly appeared in weakly active inhibitors. [ABSTRACT FROM AUTHOR]

The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-pentacyclic triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with pentacyclic triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-pentacyclic triterpene conjugates. Their structures were confirmed by ESI-HRMS, 1H-NMR, and 13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 µM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 µM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 µM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 µM, ~20-30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold. [ABSTRACT FROM AUTHOR]

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M 4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M 4 (IC 50 s < 300 nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma K p,uu = 0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CL p = 5.37 mL/min/kg). Surprisingly, this series displayed pan -muscarinic antagonist activity across M 1–5 , despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan -muscarinic antagonist agents. [ABSTRACT FROM AUTHOR]

This letter describes the further chemical optimization of the 5-amino-thieno[2,3- c ]pyridazine series (VU0467154/VU0467485) of M 4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 ( 8p ). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson’s disease model has been reported with 8p , this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties. [ABSTRACT FROM AUTHOR]

The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many biological processes and physiological functions. A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids, and synthetic cannabinoids, have been discovered or developed over the past 20 years. In 2005, it was discovered that the CB1 receptor contains allosteric site(s) that can be recognized by small molecules or allosteric modulators. A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists. Given the psychoactive effects commonly associated with CB1 receptor agonists and antagonists/inverse agonists, allosteric modulation may offer an alternate approach to attain potential therapeutic benefits while avoiding inherent side effects of orthosteric ligands. This review details the complex pharmacological profiles of these allosteric modulators, their structure-activity relationships, and efforts in elucidating binding modes and mechanisms of actions of reported CB1 allosteric modulators. The ultimate development of CB1 receptor allosteric ligands could potentially lead to improved therapies for CB1-mediated neurological disorders. [ABSTRACT FROM AUTHOR]

The strong haemolytic toxicity of Pulsatilla saponin A (PSA) has hampered its clinical development as an injectable anticancer agent. To circumvent this challenge, twenty PSA derivatives with C ring or C-28 or C-3 modifications were synthesized and evaluated for cytotoxicity against seven selected human tumor lines, as well as for haemolytic toxicity. Structure-activity relationship (SAR) and structure-toxicity relationship (STR) correlations were also elucidated. Compared with PSA, compound 22 showed a better balance between haemolytic toxicity (HD 50 > 500 μM) and cytotoxicity toward lung cancer cells A549 (IC 50 = 4.68 μM). Molecular studies indicated that 22 was liked to lead to G1 cell cycle arrest and therefore, 22 may be a potent antitumor drug candidate. [ABSTRACT FROM AUTHOR]

Uncontrolled regulation of specific metalloenzymes plays important roles in several diseases like tumor metastasis and inflammation. Therefore, selective metalloenzyme inhibition may be a potential target for drug design and development. Matrix metalloproteinase inhibitors (MMPIs) opened up a new horizon as the possible treatment of arthritis, cancer, and emphysema. However, due to adverse effects and poor pharmacokinetics, first generation MMPIs failed in clinical trials. Therefore, development of potential and selective MMPIs is still in demand. Moreover, the flexibility of the enzyme S1′ pocket is variable in length and shape making the designing approach more challenging. In this article, arylsulfonamides have been highlighted as potential and selective MMP-2 inhibitors through structure-activity relationships study. It may be postulated that sulfonamide moiety may provide better direction to the associated aryl group to accommodate the deep hydrophobic S1′ pocket. Tetrahedral geometry of the sulfonyl function may be favorable than planar carboxyl function regarding the interaction between the aryl group and S1′ pocket. Hydroxamates may impart higher inhibition than corresponding carboxylates due to additional hydrogen bonding. Moreover, MMP-2 selectivity is not only dependent on zinc binders but also on the aryl functions directed towards S1 and S2′ pockets. Therefore, this review may help in designing potential and selective MMP-2 inhibitors. [ABSTRACT FROM AUTHOR]

This letter describes the continued optimization of M 5 NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375 has an excessively long elimination half-life in rat (t 1/2 = 80 h), which can be problematic in certain rodent addiction paradigms (e.g., reinstatement). Thus, we required an M 5 NAM of comparable potency to ML375, but with a rat t 1/2 of less than 4 h. Steep SAR plagued this chemotype, and here we detail aniline replacements that offered some improvements over ML375, but failed to advance. Ultimately, incorporation of a single methyl group to the 9 b -phenyl ring acted as a metabolic shunt, providing ( S )- 11 (VU6008667), an equipotent M 5 NAM, with high CNS penetration, excellent selectivity versus M 1–4 and the desired short half-life (t 1/2 = 2.3 h) in rat. [ABSTRACT FROM AUTHOR]

Starting from acylsufonamide HTS hit 2 , a novel series of para-N -acylaminomethylbenzoic acids was identified and developed as selective prostaglandin EP4 receptor antagonists. Structural modifications on lead compound 4a were explored with the aim of improving potency, physicochemical properties, and animal PK predictive of QD (once a day) dosing regimen in human. These efforts led to the discovery of the clinical candidate AAT-008 ( 4j ), which exhibited significantly improved pharmacological profiles over grapiprant ( 1 ). [ABSTRACT FROM AUTHOR]

[Display omitted] The c-MYC oncogene transcription factor has been implicated in cell cycle regulation controlling cell growth and proliferation. It is tightly regulated in normal cells, but has been shown to be deregulated in cancer cells, and is thus an attractive target for oncogenic therapies. Building upon previous SAR, a series of analogues containing benzimidazole core replacements were prepared and evaluated, leading to the identification of imidazopyridazine compounds that were shown to possess equivalent or improved c-MYC HTRF pEC 50 values, lipophilicity, solubility, and rat pharmacokinetics. The imidazopyridazine core was therefore determined to be superior to the original benzimidazole core and a viable alternate for continued lead optimization and medicinal chemistry campaigns. [ABSTRACT FROM AUTHOR]

• The recent progress of pyrrolidine derivatives for antibacterial activity is reviewed. • The corresponding structure-activity relationships are described. • The quinoline-based metronidazole derivatives illustrated the significance of the pyrrolidine ring by increasing antibacterial activity. • Spiro and dispirocompounds displayed concentration-dependent inhibition. • The addition of metal atoms to thiazole derivatives was found to be favourable for the net antibacterial activity of the derivatives. Bacterial infections are a major health problem globally with a continuous increase in death cases. The drug-resistance problem is associated with the available antibiotics making them ineffective against bacterial strains leading to more problems in curing bacterial infections. About 1.2 million deaths have been reported in 2019 as a consequence of infections caused by various antibiotic-resistant bacteria. Pyrrolidine compounds, a prominent family of synthetic and natural plant metabolites exhibit a wide range of pharmacological activities. Significant antibacterial activity has been demonstrated in a wide range of synthetic pyrrolidine derivatives with numerous derivatizations including quinoline, spiro, thiazole, thiourea and many other derivatives. In addition to being discovered as promising antibacterial drugs, pyrrolidine compounds have the fewest side effects. These compounds have demonstrated an extraordinary ability to modulate a wide range of targets to produce excellent in vitro antibacterial activity, primarily against Gram-positive and Gram-negative bacteria. The research examines the significance of pyrrolidine ring derivatives, the various substitution patterns on the ring site, stereo and specifically the structure-activity relationship (SAR) that influences the overall antibacterial activity of pyrrolidine-based hybrid compounds. [Display omitted] [ABSTRACT FROM AUTHOR]

Due to the widespread and increasing appearance of antibiotic resistance, a new strategy is needed for developing novel antibiotics. Especially, there are no specific antibiotics for Helicobacter pylori (H. pylori). H. pylori are bacteria that live in the stomach and are related to many serious gastric problems such as peptic ulcers, chronic gastritis, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Because of its importance as a human pathogen, it’s worth studying the structure and function of the proteins from H. pylori. After the sequencing of the H. pylori strain 26695 in 1997, more than 1,600 genes were identified from H. pylori. Until now, the structures of 334 proteins from H. pylori have been determined. Among them, 309 structures were determined by X-ray crystallography and 25 structures by Nuclear Magnetic Resonance (NMR), respectively. Overall, the structures of large proteins were determined by X-ray crystallography and those of small proteins by NMR. In our lab, we have studied the structural and functional characteristics of small proteins from H. pylori. In this review, 25 NMR structures of H. pylori proteins will be introduced and their structure-function relationships will be discussed.

Antimicrobial peptides (AMPs) have been considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and different mechanisms of action compared to conventional antibiotics. Although AMPs possess considerable benefits as new generation antibiotics, their clinical and commercial development still have some limitations, such as potential toxicity, susceptibility to proteases, and high cost of peptide production. In order to overcome those obstacles, extensive efforts have been carried out. For instance, unusual amino acids or peptido-mimetics are introduced to avoid the proteolytic degradation and the design of short peptides retaining antimicrobial activities is proposed as a solution for the cost issue. In this review, we focus on small peptides, especially those with less than twelve amino acids, and provide an overview of the relationships between their three-dimensional structures and antimicrobial activities. The efforts to develop highly active AMPs with shorter sequences are also described.

A series of N-3-substituted 7-aminopyrido[2,3-d]pyrimidin-6-carbonitrile derivatives was readily synthesized and their anti-proliferative activities on five types of tumor cells were evaluated through a cell-based phenotypic screening approach. Compound 3k was found to be potent on human colon cancer SW620 cells with an IC50 value of 12.5 mM. Structural optimization of compound 3k led to compound 4a with improved anti-proliferative potency on SW620 cells with an IC50 value of 6.9 mM. Further cell-cycle analyses suggested that compound 4a induced apoptosis of SW620 cells in a concentration-dependent manner.

For the first time, a novel series of tschimganin analogs were designed, synthesized, and evaluated for their insecticidal and fungicidal activities. Their structures were characterized by 1H-NMR, 13C-NMR and HRMS. Some of these compounds displayed excellent insecticidal and fungicidal activities, suggesting that they have potential to be used as bifunctional agrochemicals. Compound 3d and 3g with electron donating groups showed better inhibitory activity and growth inhibition activity towards Helicoverpa armigera (Hübner). The properties and positions of the substituents on the benzene ring have an important influence on the acaricidal activity of tschimganin analogs. Topomer comparative molecular field analysis (CoMFA) was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds against Tetranychus turkestani Ugarov et Nikolski. It was indicated that higher electronegativity was beneficial for acaricidal activity. Moreover, compound 3r having a 2-hydroxy-3,5- dinitrophenyl moiety displayed a fungicidal spectrum as broad as azoxystrobin against these phytopathogens.

Quantitative structure-activity relationship models were obtained by applying the Molecular Descriptor Family approach to eight ordnance compounds with different toxicity on five marine species (arbacia punctulata, dinophilus gyrociliatus, sciaenops ocellatus, opossum shrimp, and ulva fasciata). The selection of the best among molecular descriptors generated and calculated from the ordnance compounds structures lead to accurate monovariate models. The resulting models obtained for six endpoints proved to be accurate in estimation (the squared correlation coefficient varied from 0.8186 to 0.9997) and prediction (the correlation coefficient obtained in leave-one-out analysis varied from 0.7263 to 0.9984).

[Display omitted] Kir6.2/SUR1 is an ATP-regulated potassium channel that acts as an intracellular metabolic sensor, controlling insulin and appetite-stimulatory neuropeptides secretion. In this Letter, we present the SAR around a novel Kir6.2/SUR1 channel opener scaffold derived from an HTS screening campaign. New series of compounds with tractable SAR trends and favorable potencies are reported. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the biggest challenges for the scientific community in the 21st century. It is a well-recognized multifactorial health problem contributes significantly to high mortality rates by causing serious health complications mainly related to cardiovascular diseases, kidney damage and neuropathy. The inhibition of α -glucosidase (enzyme that catalyses starch hydrolysis in the intestine) is an effective therapeutic approach for controlling hyperglycemia associated with type-2 diabetes. However, the presently approved drugs/inhibitors such as acarbose, miglitol and voglibose have several undesirable gastrointestinal side effects impeding their applications. Therefore, search for novel and more effective inhibitors with reduced side effects and less cost remains a fascinating area of research. In this context, a large variety of α -glucosidase inhibitors have been identified in recent years that demands attention from drug development community. This review is therefore an effort to summarize and highlight the promising α -glucosidase inhibitors especially those which are primarily based on aromatic heterocyclic scaffolds such as coumarin, imidazole, isatin, pyrimidine, quinazoline, triazine, thiazole etc, having improved safety and pharmacological profiles. [Display omitted] • Managing diabetes mellitus is one of the biggest challenges in the 21st century. • Inhibition of α-glucosidase is an effective therapeutic approach. • Synthetic α-Glucosidase inhibitors based on aromatic heterocyclic scaffolds. • Structural activity relationship (SAR) analyses. • Summary of IC 50 values and kinetic studies of active inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] A series of Icariside II (ICS II) derivatives were synthesized, and their structure–activity relationships (SARs) were studied in this paper. The in vitro antitumor activities towards human breast cancer cell lines (MCF-7) were evaluated by Cell Counting Kit-8 (CCK-8 kit). Preliminary results showed that, compared with ICS II, most of the derivatives displayed good micromole level activities. Among the series of derivatives, the S27 , which totally acetylated hydroxyl of ICS II, possessed highest cytotoxicity, with IC 50 values of 0.70 ± 0.08 μM. Furthermore, compound S27 showed better selectivity than ICS II for cancer cells over normal cells. Our findings indicate that compound S27 may be a promising anticancer lead candidate drug. [ABSTRACT FROM AUTHOR]

Molecular-level investigations of the Central Nervous System have been revolutionized by the development of computational methods, computing power, and capacity advances. These techniques have enabled researchers to analyze large amounts of data from various sources, including genomics, in vivo, and in vitro drug tests. In this review, we explore how computational methods and informatics have contributed to our understanding of mental health disorders and the development of novel drugs for neurological diseases, with a special focus on the emerging field of psychedelics. In addition, the use of state-of-the-art computational methods to predict the potential of drug compounds and bioinformatic tools to integrate disparate data sources to create predictive models is also discussed. Furthermore, the challenges associated with these methods, such as the need for large datasets and the diversity of in vitro data, are explored. Overall, this review highlights the immense potential of computational methods and informatics in Central Nervous System research and underscores the need for continued development and refinement of these techniques and more inclusion of Quantitative Structure-Activity Relationships (QSARs).

The regulation of bile acid pathways has become a particularly promising therapeutic strategy for a variety of metabolic disorders, cancers, and diseases. However, the hydrophobicity of bile acids has been an obstacle to clinical efficacy due to off-target effects from rapid drug absorption. In this report, we explored a novel strategy to design new structure fragments based on lithocholic acid (LCA) with improved hydrophilicity by introducing a polar "oxygen atom" into the side chain of LCA, then (i) either retaining the carboxylic acid group or replacing the carboxylic acid group with (ii) a diol group or (iii) a vinyl group. These novel fragments were evaluated using luciferase-based reporter assays and the MTS assay. Compared to LCA, the result revealed that the two lead compounds 1a - 1b were well tolerated in vitro, maintaining similar potency and efficacy to LCA. The MTS assay results indicated that cell viability was not affected by dose dependence (under 25 µM). Additionally, computational model analysis demonstrated that compounds 1a - 1b formed more extensive hydrogen bond networks with Takeda G protein-coupled receptor 5 (TGR5) than LCA. This strategy displayed a potential approach to explore the development of novel endogenous bile acids fragments. Further evaluation on the biological activities of the two lead compounds is ongoing.

Background: K ATP channels have diverse roles, including regulation of insulin secretion and blood flow, and protection against biological stress responses and are excellent therapeutic targets. Different subclasses of K ATP channels exist in various tissue types due to the unique assemblies of specific pore-forming (Kir6.x) and accessory (SURx) subunits. The majority of pharmacological openers and blockers act by binding to SURx and are poorly selective against the various K ATP channel subclasses. Methods and Results: We used 3D models of the Kir6.2/SUR homotetramers based on existing cryo-EM structures of channels in both the open and closed states to identify a potential agonist binding pocket in a functionally critical area of the channel. Computational docking screens of this pocket with the Chembridge Core chemical library of 492,000 drug-like compounds yielded 15 top-ranked "hits", which were tested for activity against K ATP channels using patch clamping and thallium (Tl + ) flux assays with a Kir6.2/SUR2A HEK-293 stable cell line. Several of the compounds increased Tl + fluxes. One of them (CL-705G) opened Kir6.2/SUR2A channels with a similar potency as pinacidil (EC 50 of 9 µM and 11 μM, respectively). Remarkably, compound CL-705G had no or minimal effects on other Kir channels, including Kir6.1/SUR2B, Kir2.1, or Kir3.1/Kir3.4 channels, or Na + currents of TE671 medulloblastoma cells. CL-705G activated Kir6.2Δ36 in the presence of SUR2A, but not when expressed by itself. CL-705G activated Kir6.2/SUR2A channels even after PIP 2 depletion. The compound has cardioprotective effects in a cellular model of pharmacological preconditioning. It also partially rescued activity of the gating-defective Kir6.2-R301C mutant that is associated with congenital hyperinsulinism. Conclusion: CL-705G is a new Kir6.2 opener with little cross-reactivity with other channels tested, including the structurally similar Kir6.1. This, to our knowledge, is the first Kir-specific channel opener., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gando, Becerra Flores, Chen, Yang, Nakamura, Cardozo and Coetzee.)

Chemical structures bearing a combination of aggregation-induced emission enhancement (AIEE) and intramolecular charge transfer (ICT) properties attracted the attention of many researchers. Recently, there is an increasing demand to pose tunable AIEE and ICT fluorophores that could present their conformation changes-related emission colors by adjusting the medium polarity. In this study, we designed and synthesized a series of 4-alkoxyphenyl-substituted 1,8-naphthalic anhydride derivatives NAxC using the Suzuki coupling reaction to construct donor-acceptor (D-A)-type fluorophores with alkoxyl substituents of varying carbon chain lengths (x = 1, 2, 4, 6, 12 in NAxC). To explain the observation that molecules with longer carbon chains revealed unusual fluorescence enhancement in water, we study the optical properties and evaluate their locally excited (LE) and ICT states by solvent effects combined with Lippert-Mataga plots. Then, we explored the self-assembly abilities of these molecules in water-organic (W/O) mixed solutions and observed the morphology of its nanostructure using a fluorescence microscope and SEM. The results show that NAxC, x = 4, 6, 12 show different degrees of self-assembly behaviors and corresponding aggregation-induced emission enhancement (AIEE) progresses. At the same time, different nanostructures and corresponding spectral changes can be obtained by adjusting the water ratio in the mixed solution. That is, NAxC compounds present different transitions between LE, ICT and AIEE based on the polarity, water ratio and time changes. We designed NAxC as the structure-activity relationship (SAR) of the surfactant to demonstrate that AIEE comes from the formation of micelle-like nanoaggregates, which causes a restriction of the transfer from the LE state to the ICT state, and micelle formation results in a blue-shift in emission and enhances the intensity in the aggregate state. Among them, NA12C is most likely to form micelles and the most obvious fluorescence enhancement, which will switch over time due to the nano-aggregation transition.

In this paper, structure–activity relationship (SAR, classification) and quantitative structure–activity relationship (QSAR) models have been established to predict the bioactivity of human epidermal growth factor receptor-2 (HER2) inhibitors. For the SAR study, we established six SAR (or classification) models to distinguish highly and weakly active HER2 inhibitors. The dataset contained 868 HER2 inhibitors, which was split into a training set including 580 inhibitors and a test set including 288 inhibitors by a Kohonen’s self-organizing map (SOM), or a random method. The SAR models were performed using support vector machine (SVM), random forest (RF) and multilayer perceptron (MLP) methods. Among the six models, SVM models obtained superior results compared with other models. The prediction accuracy of the best model (model 1A) was 90.27% and the Matthews correlation coefficient (MCC) was 0.80 on the test set. For the QSAR study, we chose 286 HER2 inhibitors to establish six quantitative prediction models using MLR, SVM and MLP methods. The correlation coefficient (r) of the best model (model 4B) was 0.92 on the test set. The descriptors analysis showed that HAccN, lone pair electronegativity and π electronegativity were closely related to the bioactivity of HER2 inhibitors. [ABSTRACT FROM PUBLISHER]

5-Lipoxygenase (5-LOX) is a key enzyme in the inflammatory path. Inhibitors of 5-LOX are useful for the treatment of diseases like arthritis, cancer, and asthma. We have collected a dataset including 220 human 5-LOX inhibitors for classification. A self-organizing map (SOM), a support vector machine (SVM), and a multilayer perceptron (MLP) algorithm were used to build models with selected descriptors for classifying 5-LOX inhibitors into active and weakly active ones. MACCS fingerprints were used in this model building process. The accuracy (Q) and Matthews correlation coefficient (MCC) of the best SOM model (Model 1A) were 86.49% and 0.73 on the test set, respectively. The Q and MCC of the best SVM model (Model 2A) were 82.67% and 0.64 on the test set, respectively. The Q and MCC of the best MLP model (Model 3B) were 84.00% and 0.67 on the test set, respectively. In addition, 180 inhibitors with bioactivities measured by fluorescence method were further used for a quantitative prediction. Multiple linear regression (MLR) and SVM algorithms were used to build models to predict the $$\hbox {IC}_{50}$$ values. The correlation coefficients ( R) of the MLR model (Model Q1) and the SVM model (Model Q2) were 0.72 and 0.74 on the test set, respectively. [ABSTRACT FROM AUTHOR]

This letter describes the chemical optimization of a novel series of M 4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3- c ]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 ( 5 ). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration). [ABSTRACT FROM AUTHOR]

A series of fused ring derivatives of pyrrolidine and imidazolidinone were designed, synthesized, characterized and assayed against the DENV-2 NS2B-NS3 protease and wild-type DENV-2 virus. The linear dipeptide compound 1 and the non-peptidic fused ring compound 2 show comparable activities against DENV-2 NS2B-NS3 protease and wild-type DENV-2 virus in a viral replication assay. The preliminary SAR reveals that a substituent and its stereochemistry at C-3 position, substitution (X) at N-2 arene and a linker (Y) between C-3 position and its attached arene are important for the fused-ring scaffold of pyrrolidino [1,2- c ]imidazolidinone to block the active site of NS2B-NS3 protease. This promising structural core will facilitate the discovery of non-peptidic, potent NS2B-NS3 protease inhibitors to stop dengue virus infections. [ABSTRACT FROM AUTHOR]

The anti-tubercular activity of 6-chloro-2-ethyl- N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo [1,2- a ]pyridine-3-carboxamide ( Q203 ) is modified by varying its side chain. In this study, we synthesized Q203 analogues with different side chains and studied their effects on anti-tubercular activity. Many analogues showed good potency against M . tuberculosis replicating in liquid broth culture medium (extracellular activity) regardless of chain length and conformational changes. However, a polar character in the side chain region was unfavorable for anti-tubercular activity. The analogues, 25 , 28 , 35 , and 36 , displayed excellent activity against M . tuberculosis replicating inside macrophages (intracellular activity) and promising pharmacokinetic (PK) properties with high drug exposure level and long half-life. [ABSTRACT FROM AUTHOR]

A series of 1,1-diaryl tertiary alcohols and some of their dehydration derivatives were designed, synthesized and evaluated for their antifungal activities. Some compounds exhibited moderate inhibitory activities against seven plant pathogens at 50 μg/mL in vitro , compounds 5 g and 7 c displayed nearly the same or higher fungicidal activities against some certain plant pathogens compared with the lead compound pyrimorph. A qualitative structure-activity relationship (SAR) analysis revealed that the Cl substituent and its position at the pyridine ring were crucial for the compounds’ activities. Specially, several compounds displayed 100% protection effect against wheat powdery mildew or cucumber anthrax at 400 mg/mL in vivo , which suggested that these compounds might be potential fungicidal candidates for certain plant diseases. [ABSTRACT FROM AUTHOR]

The article reports on PI3Kγ enzyme inhibitor which are used for fighting the chronic inflammatory disorders. Topics discussed include use of aminimethyl propanol scaffold as PI3Kγ enzyme inhibitor; orientation of magenta and cyan as observed on docking with autodock vina in the P13Ky enzyme receptor; and experiments carried out on this behalf.

Aurora kinases have emerged as important anticancer targets so that there are several inhibitors have advanced into clinical study. Herein, we identified novel indazole derivatives as potent Aurora kinases inhibitors by utilizing in silico fragment-based approach and knowledge-based drug design. After intensive hit-to-lead optimization, compounds 17 (dual Aurora A and B), 21 (Aurora B selective) and 30 (Aurora A selective) possessed indazole privileged scaffold with different substituents, which provide sub-type kinase selectivity. Computational modeling helps in understanding that the isoform selectivity could be targeted specific residue in the Aurora kinase binding pocket in particular targeting residues Arg220, Thr217 or Glu177. [ABSTRACT FROM AUTHOR]

This letter describes the further deconstruction of the known PAR4 inhibitor chemotypes (MWs 490–525 and with high plasma protein binding) to identify a minimum PAR4 pharmacophore devoid of metabolic liabilities and improved properties. This exercise identified a greatly simplified 2-methoxy-6-arylimidazo[2,1- b ][1,3,4]thiadiazole scaffold that afforded nanomolar inhibition of both activating peptide and γ-thrombin mediated PAR4 stimulation, while reducing both molecular weight and the number of hydrogen bond donors/acceptors by ∼50%. This minimum PAR4 pharmacophore, with competitive inhibition, versus non-competitive of the larger chemotypes, allows an ideal starting point to incorporate desired functional groups to engender optimal DMPK properties towards a preclinical candidate. [ABSTRACT FROM AUTHOR]

Okadaic acid (OA) and the closely related dinophysistoxins (DTXs) are algal toxins that accumulate in shellfish and are known serine/threonine protein phosphatase (ser/thr PP) inhibitors. Phosphatases are important modulators of enzyme activity and cell signaling pathways. However, the interactions between the OA/DTX toxins and phosphatases are not fully understood. This study sought to identify phosphatase targets and characterize their structure-activity relationships (SAR) with these algal toxins using a combination of phosphatase activity and cytotoxicity assays. Preliminary screening of 21 human and yeast phosphatases indicated that only three ser/thr PPs (PP2a, PP1, PP5) were inhibited by physiologically saturating concentrations of DTX2 (200 nM). SAR studies employed naturally-isolated OA, DTX1, and DTX2, which vary in degree and/or position of methylation, in addition to synthetic 2-epi-DTX2. OA/DTX analogs induced cytotoxicity and inhibited PP activity with a relatively conserved order of potency: OA = DTX1 ⩾ DTX2 >> 2-epi-DTX. The PPs were also differentially inhibited with sensitivities of PP2a > PP5 > PP1. These findings demonstrate that small variations in OA/DTX toxin structures, particularly at the head region (i.e., C1/C2), result in significant changes in toxicological potency, whereas changes in methylation at C31 and C35 (tail region) only mildly affect potency. In addition to this being the first study to extensively test OA/DTX analogs' activities towards PP5, these data will be helpful for accurately determining toxic equivalence factors (TEFs), facilitating molecular modeling efforts, and developing highly selective phosphatase inhibitors. [ABSTRACT FROM AUTHOR]

This Letter describes the further lead optimization of the CHT inhibitor probe, ML352 (VU0476201), and the development of VU6001221, an improved in vivo tool. A multi-dimensional optimization effort encountered steep SAR, and ultimately, subtle tuning of the electronics of the central phenyl core provided VU6001221, a CHT inhibitor with comparable potency for choline uptake inhibition as ML352, yet improved PK and CNS penetration. Moreover, VU6001221 enabled evaluation, for the first time, of a CHT inhibitor in a standard preclinical rodent cognition model, novel object recognition (NOR). We observed VU6001221 to elicit a dose-responsive increase in NOR, raising the possibility of agonism of synaptic α7 nicotinic ACh receptors by elevated extracellular choline, that if confirmed would represent a novel molecular strategy to enhance cognition. [ABSTRACT FROM AUTHOR]