A screen of repurposed drugs identifies AMHR2/MISR2 agonists as potential contraceptives.

We identified the anti-Mullerian hormone (also known as Müllerian inhibiting substance or MIS) as an inhibitory hormone that induces long-term contraception in mammals. The type II receptor to this hormone, AMHR2 (also known as MISR2), represents a promising druggable target for the modulation of female reproduction with a mechanism of action distinct from steroidal contraceptives. We designed an in vitro platform to screen and validate small molecules that can activate MISR2 signaling and suppress ovarian folliculogenesis. Using a bone morphogenesis protein (BMP)­response element luciferase reporter cell­based assay, we screened 5,440 compounds from a repurposed drug library. Positive hits in this screen were tested for specificity and potency in luciferase dose­response assays, and biological activity was tested in ex vivo Mullerian duct regression bioassays. Selected candidates were further evaluated in ex vivo follicle/ovary culture assays and in vivo in mice and rats. Here, we report that SP600125, CYC-116, gandotinib, and ruxolitinib can specifically inhibit primordial follicle activation and repress folliculogenesis by stimulating the MISR2 pathway.

Identification of a novel antifungal backbone of naphthalimide thiazoles with synergistic potential for chemical and dynamic treatment.

Aim: The high incidence and prevalence of fungal infections call for new antifungal drugs. This work was to develop naphthalimide thiazoles as potential antifungal agents. Results & methodology: These compounds showed significant antifungal potency toward some tested fungi. Especially, naphthalimide thiazole 4h with excellent anti-Candida tropicalis efficacy possessed good hemolysis level, low toxicity and no obvious resistance. Deciphering the mechanism showed that 4h interacted with DNA and disrupted the antioxidant defense system of C. tropicalis. Compound 4h also triggered membrane depolarization, leakage of cytoplasmic contents and LDH inhibition. Simultaneously, 4h rendered metabolic inactivation and eradicated the formed biofilms of C. tropicalis. Conclusion: The multifaceted synergistic effect initiated by naphthalimide thiazoles is a reasonable treatment window for prospective development.

In vivo screening and toxicity studies of indolinone incorporated thiosemicarbazone, thiazole and piperidinosulfonyl moieties as anticonvulsant agents.

Based on the biological importance of the thiazole nucleus, we decided to prepare and evaluate the biological activity of some new isatin derivatives containing thiazole moiety. The 5-(piperidin-1-ylsulfonyl)indoline-2,3-dione (1) was prepared and used as a starting material in the synthesis of many isatin derivatives for anticonvulsant evaluation. All the newly synthesized thiazlidino/thiosemicarbazide-indolin-2-one derivatives screened in vivo for their anticonvulsant activity against pentylenetetrazole-induced convulsions in mice. The results were compared with phenobarbitone sodium as a standard anticonvulsant drug. Most of the tested compounds exhibited anticonvulsant activity with relative potency ranging from 0.02 to 0.2 in comparison to standard drug phenobarbitone. The most active compounds 3, 6a, 6c and 8, were exposed to further investigations in rats to evaluate the effect of most active derivatives on the haematological, liver, kidney functions as well as histopathological studies of the liver and kidney tissues. Finally, the most potent compounds 3, 6a, 6c and 8 observed good toxic properties for both liver and kidney function with mild variability changes on RBCs, WBCs, Platelets, Hb, AST, ALT, and creatinine level, as well as kidney and liver tissue and these good results obtained rather than used low dose from phenobarbitone.

Evaluating the Antioxidants, Whitening and Antiaging Properties of Rice Protein Hydrolysates.

Plant-derived protein hydrolysates have potential applications in nutrition. Rice protein hydrolysates (RPHs), an excellent source of proteins, have attracted attention for the development of cosmeceuticals. However, few studies have reported the potential application of RPH in analysis, and this study examined their antioxidant activities and the inhibitory activities of skin aging enzymes. The results indicated that the total phenolic and flavonoid concentrations were 2.06 ± 0.13 mg gallic acid equivalent/g RPHs and 25.96 ± 0.52 µg quercetin equivalent/g RPHs, respectively. RPHs demonstrated dose-dependent activity for scavenging free radicals from 1,1-diphenyl-2-picrylhydrazyl [half-maximal inhibitory concentration (IC50) = 42.58 ± 2.1 mg/g RPHs] and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (IC50 = 2.11 ± 0.88 mg/g RPHs), dose-dependent reduction capacity (6.95 ± 1.40 mg vitamin C equivalent/g RPHs) and oxygen radical absorbance capacity (473 µmol Trolox equivalent/g RPHs). The concentrations of the RPH solution required to achieve 50% inhibition of hyaluronidase and tyrosinase activities were determined to be 8.91 and 107.6 mg/mL, respectively. This study demonstrated that RPHs have antioxidant, antihyaluronidase, and antityrosinase activities for future cosmetic applications.

Comparative study of two isothiazolinone biocides, 1,2-benzisothiazolin-3-one (BIT) and 4,5-dichloro-2-n-octyl-isothiazolin-3-one (DCOIT), on barrier function and mitochondrial bioenergetics using murine brain endothelial cell line (bEND.3).

Isothiazolinone (IT) biocides are potent antibacterial substances used as preservatives and disinfectants. These biocides exert differing biocidal effects and display environmental stability based upon chemical structure. In agreement with our recent study reporting that 2-n-octyl-4-isothiazolin-3-one (OIT) induced dysfunction of the blood-brain barrier (BBB), the potential adverse health effects of two IT biocides 1,2-benzisothiazolin-3-one (BIT) and 4,5-dichloro-2-n-octyl-isothiazolin-3-one (DCOIT) were compared using brain endothelial cells (ECs) derived from murine brain endothelial cell line (bEND.3). BIT possesses an unchlorinated IT ring structure and used as a preservative in cleaning products. DCOIT contains a chlorinated IT ring structure and employed as an antifouling agent in paints. Data demonstrated that DCOIT altered cellular metabolism at a lower concentration than BIT. Both BIT and DCOIT increased reactive oxygen species (ROS) generation at the mitochondrial and cellular levels. However, the effect of DCOIT on glutathione (GSH) levels appeared to be greater than BIT. While mitochondrial membrane potential (MMP) was decreased in both BIT- and DCOIT-exposed cells, direct disturbance in mitochondrial bioenergetic flux was only observed in BIT-treated ECs. Taken together, IT biocides produced toxicity in brain EC and barrier dysfunction, but at different concentration ranges suggesting distinct differing mechanisms related to chemical structure.

Antimutagenic, Cytoprotective and Antioxidant Properties of Ficus deltoidea Aqueous Extract In Vitro.

Ficus deltoidea var. deltoidea is used as traditional medicine for diabetes, inflammation, and nociception. However, the antimutagenic potential and cytoprotective effects of this plant remain unknown. In this study, the mutagenic and antimutagenic activities of F. deltoidea aqueous extract (FDD) on both Salmonella typhimurium TA 98 and TA 100 strains were assessed using Salmonella mutagenicity assay (Ames test). Then, the cytoprotective potential of FDD on menadione-induced oxidative stress was determined in a V79 mouse lung fibroblast cell line. The ferric-reducing antioxidant power (FRAP) assay was conducted to evaluate FDD antioxidant capacity. Results showed that FDD (up to 50 mg/mL) did not exhibit a mutagenic effect on either TA 98 or TA 100 strains. Notably, FDD decreased the revertant colony count induced by 2-aminoanthracene in both strains in the presence of metabolic activation (p < 0.05). Additionally, pretreatment of FDD (50 and 100 µg/mL) demonstrated remarkable protection against menadione-induced oxidative stress in V79 cells significantly by decreasing superoxide anion level (p < 0.05). FDD at all concentrations tested (12.5-100 µg/mL) exhibited antioxidant power, suggesting the cytoprotective effect of FDD could be partly attributed to its antioxidant properties. This report highlights that F. deltoidea may provide a chemopreventive effect on mutagenic and oxidative stress inducers.

Identification of Thiazoyl Guanidine Derivatives as Novel Antifungal Agents Inhibiting Ergosterol Biosynthesis for Treatment of Invasive Fungal Infections.

Invasive fungal infections (IFIs) are fatal infections, but treatment options are limited. The clinical efficacies of existing drugs are unsatisfactory because of side effects, drug-drug interaction, unfavorable pharmacokinetic profiles, and emerging drug-resistant fungi. Therefore, the development of antifungal drugs with a new mechanism is an urgent issue. Herein, we report novel aryl guanidine antifungal agents, which inhibit a novel target enzyme in the ergosterol biosynthesis pathway. Structure-activity relationship development and property optimization by reducing lipophilicity led to the discovery of 6h, which showed potent antifungal activity against Aspergillus fumigatus in the presence of serum, improved metabolic stability, and PK properties. In the murine systemic A. fumigatus infection model, 6h exhibited antifungal efficacy equivalent to voriconazole (1e). Furthermore, owing to the inhibition of a novel target in the ergosterol biosynthesis pathway, 6h showed antifungal activity against azole-resistant A. fumigatus.

Discovery of 4-Arylindolines Containing a Thiazole Moiety as Potential Antitumor Agents Inhibiting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction.

Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30 exhibited outstanding biochemical activity, with an IC50 of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30 significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30 showed favorable in vivo antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30 potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30 inhibited tumor growth by activating the immune microenvironment. We concluded that A30 is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.

Discovery of New Imidazo[2,1-b]thiazole Derivatives as Potent Pan-RAF Inhibitors with Promising In Vitro and In Vivo Anti-melanoma Activity.

BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1-b]thiazol-5-yl)pyrimidine derivatives possessing a terminal sulfonamide moiety were synthesized. Pan-RAF inhibitory effect of the new series was investigated, and structure-activity relationship is discussed. Antiproliferative activity of the target compounds was tested against the NCI-60 cell line panel. The most active compounds were further tested to obtain their IC50 values against cancer cells. Compound 27c with terminal open chain sulfonamide and 38a with a cyclic sulfamide moiety showed the highest activity in enzymatic and cellular assay, and both compounds were able to inhibit phosphorylation of MEK and ERK. Compound 38a was selected for testing its in vivo activity against melanoma. Cellular and animal activities are reported.

Discovery of selective fragment-sized immunoproteasome inhibitors.

Proteasomes contribute to maintaining protein homeostasis and their inhibition is beneficial in certain types of cancer and in autoimmune diseases. However, the inhibition of the proteasomes in healthy cells leads to unwanted side-effects and significant effort has been made to identify inhibitors specific for the immunoproteasome, especially to treat diseases which manifest increased levels and activity of this proteasome isoform. Here, we report our efforts to discover fragment-sized inhibitors of the human immunoproteasome. The screening of an in-house library of structurally diverse fragments resulted in the identification of benzo[d]oxazole-2(3H)-thiones, benzo[d]thiazole-2(3H)-thiones, benzo[d]imidazole-2(3H)-thiones, and 1-methylbenzo[d]imidazole-2(3H)-thiones (with a general term benzoXazole-2(3H)-thiones) as inhibitors of the chymotrypsin-like (ß5i) subunit of the immunoproteasome. A subsequent structure-activity relationship study provided us with an insight regarding growing vectors. Binding to the ß5i subunit was shown and selectivity against the ß5 subunit of the constitutive proteasome was determined. Thorough characterization of these compounds suggested that they inhibit the immunoproteasome by forming a disulfide bond with the Cys48 available specifically in the ß5i active site. To obtain fragments with biologically more tractable covalent interactions, we performed a warhead scan, which yielded benzoXazole-2-carbonitriles as promising starting points for the development of selective immunoproteasome inhibitors with non-peptidic scaffolds.

Magnetic cobalt oxide nanosheets: green synthesis and in vitro cytotoxicity.

Cobalt oxide nanoparticles were prepared via green chemistry route and fully characterized by Field Emission Scanning Electron Microscope (FESEM), Energy-dispersive X-ray spectroscopy (EDAX), X-ray diffraction (XRD), High-resolution transmission electron microscopy (HRTEM) and Transmission electron microscopy (TEM) analyses; the CoO and Co3O4 nanoparticles, in sheet-shaped cobalt oxide form, ensued simultaneously in one step. The varying concentrations of NPs were analyzed via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test on the cancer cell line (U87) which revealed that with increasing concentration of cobalt oxide nanoparticles, the survival rate of U87 tumor cells decreases; IC50 of nanoparticles being ~ 55 µg/ml-1.

Core size optimized silver coated gold nanoparticles for rapid screening of tricyclazole and thiram residues in pear extracts using SERS.

Silver-coated gold nanoparticles (Au@AgNPs) were optimized with different gold (Au) core sizes and modified surface with mercaptooctane (MCO) to determine fungicide residues in pear fruit extracts. The developed MCO/Au@AgNPs with a gold core size of 28 nm and silver shell thickness of 6 nm exhibited high sensitivity and significant enhancement of Raman scattering in detecting tricyclazole (TCZ) and thiram fungicides in standard and pear fruit samples. The detection limits for TCZ and thiram in the pear fruit extracts were 0.005 and 0.003 ppm with coefficients of determination of (R2) of 0.9984 and 0.9971, percent recovery ranging from 82.7 to 107.4% and 80.7 to 109.8%, and relative standard deviation (RSD) of 1.5 to 7.9% and 3.7 to 9.5%, respectively. Results showed that this easily prepared method could be employed as SERS active platforms for the rapid assessment of trace contaminants of agrochemicals in agriculture production.

Microwave-Assisted Rapid Green Synthesis of Gold Nanoparticles Using Seed Extract of Trachyspermum ammi: ROS Mediated Biofilm Inhibition and Anticancer Activity.

Green synthesis of metal nanoparticles using plant extracts as capping and reducing agents for the biomedical applications has received considerable attention. Moreover, emergence and spread of multidrug resistance among bacterial pathogens has become a major health concern and lookout for novel alternative effective drugs has gained momentum. In current study, we synthesized gold nanoparticles using the seed extract of Trachyspermum ammi (TA-AuNPs), assessed its efficacy against drug resistant biofilms of Listeria monocytogenes and Serratia marcescens, and evaluated its anticancer potential against HepG2 cancer cell lines. Microwave-assisted green synthesis of gold nanoparticles was carried out and characterization was done using UV-vis spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM), and dynamic light scattering (DLS). Most nanoparticles were observed as spherical and spheroidal with few anisotropies with an average crystalline size of 16.63 nm. Synthesized TA-AuNPs demonstrated significant biofilm inhibitory activity against L. monocytogenes (73%) as well as S. marcescens (81%). Exopolysaccharide (EPS), motility, and CSH, key elements that facilitate the formation and maintenance of biofilm were also inhibited significantly at the tested sub-minimum inhibitory concentrations (sub-MICs). Further, TA-AuNPs effectively obliterated preformed mature biofilms of S. marcescens and L. monocytogenes by 64% and 58%, respectively. Induction of intracellular ROS production in TA-AuNPs treated bacterial cells could be the plausible mechanism for the reduced biofilm formation in test pathogens. Administration of TA-AuNPs resulted in the arrest of cellular proliferation in a concentration-dependent manner. TA-AuNPs decrease the intracellular GSH in HepG2 cancer cell lines, cells become more prone to ROS generation, hence induce apoptosis. Thus, this work proposes a new eco-friendly and rapid approach for fabricating NPs which can be exploited for multifarious biomedical applications.

Defective transition metal hydroxide-based nanoagents with hypoxia relief for photothermal-enhanced photodynamic therapy.

Recently, phototherapy has attracted much attention due to its negligible invasiveness, insignificant toxicity and excellent applicability. The construction of a newly proposed nanosystem with synergistic photothermal and photodynamic tumor-eliminating properties requires a delicate structure design. In this work, a novel therapeutic nanoplatform (denoted as BCS-Ce6) based on defective cobalt hydroxide nanosheets was developed, which realized hypoxia-relieved photothermal-enhanced photodynamic therapy against cancer. Defective cobalt hydroxide exhibited high photothermal conversion efficacy at the near-infrared region (49.49% at 808 nm) as well as enhanced catalase-like activity to produce oxygen and greatly boost the singlet oxygen generation by a photosensitizer, Ce6, realizing efficacious dual-modal phototherapy. In vivo and in vitro experiments revealed that BCS-Ce6 can almost completely extinguish implanted tumors in a mouse model and present satisfactory biocompatibility during the treatment. This work sets a new angle of preparing photothermal agents and constructing comprehensive therapeutic nanosystems with the ability to modulate the hypoxic tumor microenvironment for efficient cancer therapy.

One-pot enantioselective synthesis of (S)-spirobrassinin and non-natural (S)-methylspirobrassinin from amino acids using a turnip enzyme.

The enantioselective synthesis of (S)-(-)-spirobrassinin, which features a unique sulfur-containing spirooxindole skeleton, was achieved by focusing on the phytoalexin generation in Brassicaceae plants. Specifically, (S)-(-)-spirobrassinin was obtained in a one-pot fashion from L-tryptophan through a reaction involving S-spirocyclization with various turnip enzymes and constituents, i.e., using the turnip as a reaction reagent, catalyst, and reaction vessel. Surprisingly, this strategy also enabled the one-pot enantioselective synthesis of the novel non-natural spirooxindole (S)-(-)-5-methylspirobrassinin from 5-methyl-DL-tryptophan.

Synthesis and Structure-activity Relationship of Aminoarylthiazole Derivatives as Potential Potentiators of the Chloride Transport Defect in Cystic Fibrosis.

BACKGROUND: Cystic fibrosis (CF) is the autosomal recessive disorder most common in Caucasian populations. It is caused by mutations in the cystic fibrosis transmembrane regulator protein (CFTR). CFTR is predominantly expressed at the apical plasma membranes of the epithelial cells lining several organs, and functions as a cAMP-regulated chloride/bicarbonate channel. To address the underlying causes of cystic fibrosis, two biomolecular activities are required, namely correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel. OBJECTIVE: In our previous data, we demonstrated that some aminoarylthiazoles (AATs) have peculiar activity acting as correctors and as potentiator-like molecules. Curiously, a compound called 1 has been shown to be markedly active as a potentiator. Now, we have further modified its scaffold at different portions, for the identification of molecules with improved potency and effectiveness on mutant CFTR. METHODS: Starting from this active compound, we synthesized a small library trying to improve the activity as potentiators. To extrapolate the contribution of a particular structural portion to bioactivity, we selectively modified one portion at a time. RESULTS: Our study has provided a structure-activity relationship (SAR) on AATs and led to the identification of some compounds, with a particular ability to act as CFTR potentiators. CONCLUSION: Two compounds 2 and 13 appear to be promising molecules and could be used for the future development of potentiators of the chloride transport defect in cystic fibrosis.

Biological evaluation of preceramic organosilicon polymers for various healthcare and biomedical engineering applications: A review.

Preceramic organosilicon materials combining the properties of a polymer and an inorganic ceramic phase are of great interest to scientists working in biomedical sciences. The interdisciplinary nature of organosilicon polymers and their molecular structures, as well as their diversity of applications have resulted in an unprecedented range of devices and synergies cutting across unrelated fields in medicine and engineering. Organosilicon materials, especially the polysiloxanes, have a long history of industrial and medical uses in many versatile aspects as they can be easily fabricated into complex-shaped products using a wide variety of computer-aided or polymer manufacturing techniques. Thus far, intensive research activities have been mainly devoted to the processing of preceramic organosilicon polymers toward magnetic, electronic, structural, optical, and not biological applications. Herein we present innovative research studies and recent developments of preceramic organosilicon polymers at the interface with biological systems, displaying the versatility and multi-functionality of these materials. This article reviews recent research on preceramic organosilicon polymers and corresponding composites for bone tissue regeneration and medical engineering implants, focusing on three particular topics: (a) surface modifications to create tailorable and bioactive surfaces with high corrosion resistance and improved biological properties; (b) biological evaluations for specific applications, such as in glaucoma drainage devices, orthopedic implants, bone tissue regeneration, wound dressing, drug delivery systems, and antibacterial activity; and (c) in vitro and in vivo studies for cytotoxicity, genotoxicity, and cell viability. The interest in organosilicon materials stems from the fact that a vast array of these materials have complementary attributes that, when integrated appropriately with functional fillers and carefully controlled conditions, could be exploited either as polymeric Si-based composites or as organosilicon polymer-derived Si-based ceramic composites to tailor and optimize properties of the Si-based materials for various proposed applications.

Discovery of thienothiazolocarboxamide analogues as novel anti-tubercular agent.

In order to identify anti-tubercular agents with a novel scaffold, commercial libraries of small organic compounds were screened against a fluorescent strain of Mycobacterium tuberculosis H37Rv, using a dual phenotypic assay. Compounds were assessed against bacteria replicating in broth medium, as well as inside macrophages, and thienothiazolocarboxamide (TTCA) scaffold was identified as hit in both assays, with submicromolar inhibitory concentrations. Derivatives of TTCA were further synthesized and evaluated for their inhibitory effects on M.tuberculosis H37Rv. In the present study we report the structure-activity relationship of these TTCA derivatives. Compounds 28, 32 and 42 displayed good anti-tubercular activities, as well as favorable ADME and PK properties. Compound 42 exhibited excellent oral bioavailability in mice with high distribution to lungs, within 1 h. It was found to be efficacious in a dose dependent manner in a murine model of M. tuberculosis infection. Hence, compound 42 is now under evaluation as a potential lead candidate for treatment of tuberculosis.

Anti-Inflammatory and Antioxidant Effects of Carpesium cernuum L. Methanolic Extract in LPS-Stimulated RAW 264.7 Macrophages.

A hypernomic reaction or an abnormal inflammatory process could cause a series of diseases, such as cardiovascular disease, neurodegeneration, and cancer. Additionally, oxidative stress has been identified to induce severe tissue injury and inflammation. Carpesium cernuum L. (C. cernuum) is a Chinese folk medicine used for its anti-inflammatory, analgesic, and detoxifying properties. However, the underlying molecular mechanism of C. cernuum in inflammatory and oxidative stress conditions remains largely unknown. The aim of this study was to examine the effects of a methanolic extract of C. cernuum (CLME) on lipopolysaccharide- (LPS-) induced RAW 264.7 mouse macrophages and a sepsis mouse model. The data presented in this study indicated that CLME inhibited LPS-induced production of proinflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7 cells. CLME treatment also reduced reactive oxygen species (ROS) generation and enhanced the expression of heme oxygenase-1 (HO-1) protein in a dose-dependent manner in the LPS-stimulated RAW 264.7 cells. Moreover, CLME treatment abolished the nuclear translocation of nuclear factor-κB (NF-κB), enhanced the activation of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), and reduced the expression of extracellular signal-related kinase (ERK) and ERK kinase (MEK) phosphorylation in LPS-stimulated RAW 264.7 cells. These outcomes implied that CLME could be a potential antioxidant and anti-inflammatory agent.

Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis.

Aim: Tryptophan hydroxylase 1 (TPH1) catalyzes serotonin synthesis in peripheral tissues. Selective TPH1 inhibitors may be useful for treating disorders related to serotonin dysregulation. Results & methodology: Screening using a thermal shift assay for TPH1 binders yielded Compound 1 (2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one), which showed high potency (50% inhibition at 98 ± 30 nM) and selectivity for inhibiting TPH over related aromatic amino acid hydroxylases in enzyme activity assays. Structure-activity relationships studies revealed several analogs of 1 showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of 1, with regards to tryptophan and tetrahydrobiopterin. Computational docking studies and live cell assays were also performed. Conclusion: This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin.