Covalent inhibitors: An ambitious approach for the discovery of newer oncotherapeutics.

Covalent inhibitors have been used to treat several diseases for over a century. However, strategic approaches for the rational design of covalent drugs have taken a definitive shape in recent times. Since the first appearance of covalent inhibitors in the late 18th century, the field has grown tremendously and around 30% of marketed drugs are covalent inhibitors especially, for oncology indications. However, the off-target toxicity and safety concerns can be significant issues related to the covalent drugs. Covalent kinase inhibitor (CKI) targeted oncotherapeutics has advanced dramatically over the last two decades since the discovery of afatinib (Gilotrif®), an EGFR inhibitor. Since then, US FDA has approved 10 CKIs for diverse cancer targets. The present review broadly summarizes the ongoing development in the discovery of newer CKIs from 2016 till the end of 2022. We believe that these efforts will assist the modern medicinal chemist actively working in the field of CKI discovery for varied indications.

Hit discovery of novel 2-phenyl-substituted 4-amino-6,7-dihydro-5H-cyclopenta[d]pyrimidines as potential anti-glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening.

Glioblastoma multiforme (GBM) is a highly-aggressive, dreadful disease with poor prognosis and disappointing clinical success. There is an unmet medical need of molecularly-targeted therapeutics for GBM treatment. In the present work, a series of novel 2-phenyl-substituted 4-amino-6,7-dihydro-5H-cyclopenta[d]pyrimidines was designed, synthesized, purified, characterized, and evaluated for cytotoxicity against glioblastoma cell line U87-MG. The design process (virtual library enumeration around the core, physicochemical and molecular property prediction/calculation of the designs, filtering the undesirable ones, and the diversity analyses of the lead-like designs), was carefully curated so as to obtain a set of structurally-diverse, novel molecules (total 20), with a particular focus on the relatively unexplored core structure, 6,7-dihydro-5H-cyclopenta[d]pyrimidine. The preliminary screening was done using MTT assay at 10 and 100 µM concentrations of the title compounds F1 -F20 and positive control cisplatin, which yielded six hits (% inhibition at 10 µM: ~50%)-F2 , F3 , F5 , F7 , F15 , and F20 , which were taken up for IC50 determination. The top hits F2 and F7 (IC50 < 10 µM) were further used for computational studies such as target prediction, followed by their molecular docking in the binding sites of the top-3 predicted targets (epidermal growth factor receptor kinase domain, cyclin-dependent kinase 2 [CDK2]) /cyclin E, and anaplastic lymphoma kinase [ALK]). The docking pose analyses revealed interesting trends. The relatively planar core structure, presence of favorable hinge-binding substructures, basic groups, all added up, and culminated in appreciable cytotoxicity against GBM cell line.

Anxiolytic activity of Psidium guajava in mice subjected to chronic restraint stress and effect on neurotransmitters in brain.

The anxiolytic activity of Psidium guajava L. leaf ethanolic extract (PLE) and its effect on neurotransmitter systems was investigated. PLE, extracted using Soxhlet apparatus, was subjected to preliminary qualitative and quantitative (flavonoids and phenols) analyses. The anxiolytic activity at 100, 200, and 400 mg/Kg doses were assessed in mice using elevated plus maze (EPM) and light/dark transition (LDT) test models on days 1 and 16. Neurotransmitters such as monoamines (serotonin, norepinephrine, and dopamine), γ-aminobutyric acid (GABA), and glutamate were estimated in different regions of the brain (cortex, hippocampus, and cerebellum and brain stem). Phytoconstituents identified using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry were analyzed in silico to evaluate their potential binding mode(s) to GABAA and 5-HT1A receptors. Phytochemical studies showed the presence of alkaloids, tannins, flavonoids, saponins, anthraquinone glycosides, carbohydrates, and proteins, whereas total flavonoid and phenol contents were estimated to be 64.96 ± 0.95 and 206.58 ± 1.60 mg/g of dried extract, respectively. PLE treatment significantly enhanced exploratory activity of mice in EPM and LDT models with significant effects on monoamines, GABA and glutamate levels in the brain. The in silico studies suggested the interaction(s) of PLE component(s) with GABAA /5-HT1A receptors as a potential mechanism of its anxiolytic activity.

Crocetin and related oxygen diffusion-enhancing compounds: Review of chemical synthesis, pharmacology, clinical development, and novel therapeutic applications.

The current pandemic forced us to introspect and revisit our armamentarium of medicinal agents which could be life-saving in emergency situations. Oxygen diffusion-enhancing compounds represent one such class of potential therapeutic agents, particularly in ischemic conditions. As rewarding as the name suggests, these agents, represented by the most advanced and first-in-class molecule, trans-sodium crocetinate (TSC), are the subject of intense clinical investigation, including Phase 1b/2b clinical trials for COVID-19. Being a successor of a natural product, crocetin, TSC is being investigated for various cancers as a radiosensitizer owing to its oxygen diffusion enhancement capability. The unique properties of TSC make it a promising therapeutic agent for various ailments such as hemorrhagic shock, stroke, heart attack, among others. The present review outlines various (bio)synthetic strategies, pharmacological aspects, clinical overview and potential therapeutic benefits of crocetin and related compounds including TSC. The recent literature focusing on the delivery aspects of these compounds is covered as well to paint the complete picture to the curious reader. Given the potential TSC holds as a first-in-class agent, small- and/or macromolecular therapeutics based on the core concept of improved oxygen diffusion from blood to the surrounding tissues where it is needed the most, will be developed in future and satisfy the unmet medical need for many diseases and disorders.

A novel series of substituted 1,2,3-triazoles as cancer stem cell inhibitors: Synthesis and biological evaluation.

An alarming increase in global death toll resulting from cancer incidents, particularly due to multidrug resistance and reduced efficacy as a consequence of target mutations, has compelled us to look for novel anticancer agents. Cancer stem cells (CSCs), contributing majorly to the chemoresistance and tumor relapse, seem to the main culprits. In the present investigation, new chemical entities (NCEs) belonging to four novel chemical series (A: 4'-allyl-2'-methoxyphenoxymethyl-1,2,3-triazoles; B: 4'-acetamidophenoxymethyl-1,2,3-triazoles; C: naphthalene-1'-yloxymethyl-1,2,3-triazoles, and D: naphthalene-2'-yloxymethyl-1,2,3-triazoles) were synthesized via Copper (I)-catalyzed alkyne-azide cycloaddition reaction and evaluated for in vitro anticancer activity. A total of 30 NCEs (39-68) were screened at 10 µM concentration in cell viability assay against cancer cell lines such as breast (MDA-MB-231), prostate (PC-3), glioma (U87 MG), along with cervical (SiHa) and lung (A549). The NCEs from Series C (56-60) and D (61-68) were more potent than those in Series A (39-45) and Series B (46-55) at the tested concentration. Furthermore, NCEs with >80% inhibition at 10 µM were evaluated for dose response. A total of five NCEs, 48, 56, 61, 65 and 66, were further assessed in soft-agar assay and found to be relatively potent (IC50 < 10 µM). Finally, the hits were screened in sphere assay to identify potential CSC inhibitors against mammospheres (MDA-MB-231) and prostatospheres (PC-3). More so, the hits were also evaluated to understand in vitro cytotoxicity against normal cells using mouse embryonic fibroblast cell line (NIH/3T3) and human peripheral blood mononuclear cells (hPBMCs). Overall, hits 56 and 61 exhibited potent anticancer as well as CSC inhibitory activities with notably less toxicity toward NIH/3T3 and hPBMCs. On the whole, our arduous study led to the identification of potential hits with anticancer and CSC inhibitory activities, with minimal or no toxicity to normal cells.

Egg White Protein Carrier-Assisted Development of Solid Dispersion for Improved Aqueous Solubility and Permeability of Poorly Water Soluble Hydrochlorothiazide.

Hydrochlorothiazide (HTZ) is a first-line drug used in the treatment of hypertension suffered from low oral bioavailability due to poor aqueous solubility and permeability. Hence, lyophilized egg white protein-based solid dispersion (HTZ-EWP SD) was developed to explore its feasibility as a solid dispersion carrier for enhanced aqueous solubility and permeability of HTZ. The HTZ-EWP SD was prepared using the kneading method. HTZ-EWP SD was characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transforms infrared spectroscopy (FT-IR), powder X-ray diffractometer (PXRD), solubility, in vitro dissolution, and ex vivo permeation studies. The physico-chemical evaluation suggested the formation of the solid dispersion. Optimized HTZ-EWP SD4 drastically enhanced (~32-fold) aqueous solubility (~16.12 ± 0.08 mg/mL) over to pure HTZ (~ 0.51 ± 0.03 mg/mL). The dissolution study in phosphate buffer media (pH 6.8) revealed that HTZ-EWP SD4 significantly enhanced the release rate of HTZ (~ 87 %) over to HTZ (~ 25 %). The permeation rate of HTZ from optimized HTZ-EWP SD4 was enhanced significantly (~ 84 %) compared to pure HTZ (~ 24 %). Optimized HTZ-EWP-SD4 enhanced the rate of HTZ dissolution (~ 86 %) in FeSSIF (fed state simulated intestinal fluid), compared to a low dissolution rate (~ 72 %) in FaSSIF (fasted state simulated intestinal fluid) state after 2-h study. Obtained results conclude that lyophilized egg white protein can be utilized as an alternative solid dispersion carrier for enhancing the solubility and permeability of HTZ.

Substituted chloroacetamides as potential cancer stem cell inhibitors: Synthesis and biological evaluation.

Cancer kills, irrespective of geographical and cultural origin. Novel modalities for treating cancer are desperately needed. Cancer stem cells (CSCs), main culprits behind chemoresistance and tumor relapse, are one of the few logical choices. Herein, we report the synthesis and biological evaluation of small molecules with chloroacetamide war-head. These molecules were screened for viability against various breast, prostate, and oral cancer cell lines using MTT and soft-agar assays. Further, promising hits were screened in sphere-forming assay with the aim of discovering potential anti-CSC agents. Our optimism yielded four hits inhibiting self-renewal of cancer cells with stem-like characters in vitro. Finally, the hits were evaluated for in vitro toxicity against human peripheral blood mononuclear cells and mouse embryonic fibroblast cell line. Overall, these preliminary investigations yielded three hits exhibiting promising anti-CSC potential with little or no toxicity against normal cells.

An outlook on procedures of conjugating folate to (co)polymers and drugs for effective cancer targeting.

Folate receptors (FRs) are expressed in vast majority of cancers. Selective targeting of the FRs is, therefore, one of the most popular and sought-after strategies for improving the efficacy of cancer therapeutics. Variety of approaches involving folate conjugation to several well-known and novel, nontoxic, biodegradable, and biocompatible (co)polymers have been attempted and successfully applied to a large number of nanoparticulate drug delivery systems (micelles, liposomes, nanoparticles, quantum dots, mesoporous silica-based materials, and others) in the last decade-and-a-half. Standard and novel synthetic approaches were utilized for the conjugation, followed by the formulation of the drug delivery modality. In most of the cases, the targeted system lived up to its reputation, validating its usefulness in targeted cancer therapeutics. The present review summarizes the progress and state-of-the-art synthetic methodologies for folate conjugation to (co)polymers, drugs, and nucleic acids. The limitations of the FR targeting are discussed in brief to give the reader the other side of the story. Finally, the information on marketed folic acid conjugates highlight their industrial applications.

Design, synthesis and biological evaluation of Helicobacter pylori inosine 5'-monophosphate dehydrogenase (HpIMPDH) inhibitors. Further optimization of selectivity towards HpIMPDH over human IMPDH2.

Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes a crucial step in guanine nucleotide biosynthesis, thereby governing cell proliferation. In contrast to mammalian IMPDHs, microbial IMPDHs are relatively less explored as potential targets for antimicrobial drug discovery. In continuation with our previous work, here we report the discovery of moderately potent and highly selective Helicobacter pylori IMPDH (HpIMPDH) inhibitors. The present study is mainly focused around our previously identified, modestly potent and relatively nonselective (for HpIMPDH over human IMPDH2) hit molecule IX (16i). In an attempt to optimize the selectivity for the bacterial enzyme, we screened a set of 48 redesigned new chemical entities (NCEs) belonging to 5-aminoisobenzofuran-1(3H)-one series for their in vitro HpIMPDH and human IMPDH2 inhibition. A total of 12 compounds (hits) demonstrated ≥70% HpIMPDH inhibition at 10 µM concentration; none of the hits were active against hIMPDH2. Compound 24 was found to be the most potent and selective molecule (HpIMPDH IC50 = 2.21 µM) in the series. The study reaffirmed the utility of 5-aminoisobenzofuran-1(3H)-one as a promising scaffold with great potential for further development of potent and selective HpIMPDH inhibitors.

Study of degradation behavior of besifloxacin, characterization of its degradation products by LC-ESI-QTOF-MS and their in silico toxicity prediction.

Knowledge and understanding of the stability profile of a drug is important as it affects its safety and efficacy. In the present work, besifloxacin, a new, fourth-generation fluoroquinolone antibiotic, was subjected to different forced-degradation conditions as per International Conference on Harmonization (ICH) guidelines such as hydrolysis (acid, base and neutral), oxidation, thermal and photolysis. The drug degraded under acidic, basic, oxidative and photolytic conditions while it was found to be stable under dry heat and neutral hydrolytic conditions. In total, five degradation products (DPs) were formed under different conditions-DP1 and DP2 (photolysis), DP3 (oxidation), DP4 (acidic), DP3 and DP5 (basic). The chromatographic separation of besifloxacin and its degradation products was achieved on a Sunfire C18 (250 mm × 4.6 mm, 5 µm) column with 0.1% aqueous formic acid-acetonitrile as a mobile phase. The gradient RP-HPLC method was developed and validated as per ICH guidelines. The degradation products were characterized with the help of LC-ESI-QTOF mass spectrometric studies and the most likely degradation pathway of the drug was proposed. In silico toxicity assessment of the drug and its degradation products was carried out, which indicated that DP3 and DP4 carry a mutagenicity alert.

Design, synthesis, and biological evaluation of Helicobacter pylori inosine 5'-monophosphate dehydrogenase (HpIMPDH) inhibitors.

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of guanine nucleotides. Being a validated target for immunosuppressive, antiviral, and anticancer drug development, lately it has been exploited as a promising target for antimicrobial therapy. Extending our previous work on Mycobacterium tuberculosis IMPDH, GuaB2, inhibitor development, we screened a set of 23 new chemical entities (NCEs) with substituted flavone (Series 1) and 1,2,3-triazole (Series 2) core structures for their in vitro Helicobacter pylori IMPDH (HpIMPDH) and human IMPDH2 (hIMPDH2) inhibitory activities. All the NCEs possessed acceptable molecular, physicochemical, and toxicity property profiles. The ranges for HpIMPDH and hIMPDH2 inhibition were 9-99.9% and 16-57%, respectively, at 10 µM concentration. The most potent HpIMPDH inhibitor, 25c, exhibited IC50 value of 1.27 µM with no hIMPDH2 inhibitory activity. The moderately potent, structurally novel hit molecule, 25c, may serve as a lead for further design and development of highly potent HpIMPDH inhibitors.

Novel analogs of sulfasalazine as system xc- antiporter inhibitors: Insights from the molecular modeling studies.

System xc- (Sxc- ), a cystine-glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sxc- . However, its pharmacological inhibition with novel and potent agents is still very much required due to potential issues, for example, potency, bioavailability, and blood-brain barrier (BBB) permeability, with the current lead molecules such as SSZ. Therefore, in this study, we report the synthesis and structure-activity relationships (SAR) of SSZ derivatives along with molecular docking and dynamics simulations using the developed homology model of xCT chain of Sxc- antiporter. The generated homology model attempted to address the limitations of previously reported comparative protein models, thereby increasing the confidence in the computational modeling studies. The main objective of the present study was to derive a suitable lead structure from SSZ eliminating its potential issues for the treatment of glioblastoma multiforme (GBM), a deadly and malignant grade IV astrocytoma. The designed compounds with favorable Sxc- inhibitory activity following in vitro Sxc- inhibition studies, showed moderately potent cytotoxicity in patient-derived human glioblastoma cells, thereby generating potential interest in these compounds. The xCT-ligand model can be further optimized in search of potent lead molecules for novel drug discovery and development studies.

Hit discovery of Mycobacterium tuberculosis inosine 5'-monophosphate dehydrogenase, GuaB2, inhibitors.

Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5'-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent.

Newer human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents.

Human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure-activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for hIMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines. Few title compounds exhibited cellular activity profile better than MPA itself. The observed differences in the overall biological profile could be attributed to improved structural and physicochemical properties of the analogues over MPA. This is the first report of the activity of MPA derivatives in glioblastoma, the most aggressive brain cancer.

Attenuation of quorum sensing-regulated behaviour by Tinospora cordifolia extract & identification of its active constituents.

BACKGROUND & OBJECTIVES: The pathogenicity of the nosocomial pathogens, Pseudomonas aeruginosa and Acinetobacter baumannii is regulated by their quorum sensing (QS) systems. The objective of the present study was to examine the effect of the cold ethyl acetate extract of Tinospora cordifolia stem on virulence and biofilm development in the wild type and clinical strains of P. aeruginosa and A. baumannii. The study was further aimed to identify the probable active constituents in the plant extract. METHODS: P. aeruginosa virulence factors viz., LasA protease, LasB elastase and pyocyanin production were analyzed spectrophotometrically. Biofilm formation was studied using crystal violet staining-microtitre plate assay. The plant extract was fractionated using silica gel column chromatography and the most active fraction was derivatized using silylation and analyzed by gas chromatography-mass spectrometry (GC-MS). In silico testing of the molecules identified in GC-MS was performed, for binding to the P. aeruginosa LasI and LasR proteins, to predict the QS inhibitory molecules. RESULTS: The plant extract inhibited three major virulence factors in P. aeruginosa; it exhibited enhanced biofilm formation in P. aeruginosa while decreased biofilm development in A. baumannii. The most active fraction obtained from column chromatography, exhibited suppression of virulence as well as biofilm in both the organisms. Docking scores were calculated for all the molecules identified in GC-MS, and high docking scores were obtained for 2,3,4-triacetyloxybutyl acetate, methyl 16-methyl heptadecanoate, 2-(5-ethenyl-5-methyloxolan-2-yl)propan-2-ol, methyl hexadecanoate and 2-methoxy-4-vinyl phenol. INTERPRETATION & CONCLUSIONS: The compounds showing high docking scores could probably be the QS inhibitors. These molecules can be screened further for the development of new anti-infective drugs.

Emerging roles of system [Formula: see text] antiporter and its inhibition in CNS disorders.

System [Formula: see text] is an antiporter belonging to the hetero(di)meric amino acid transporter family. It is located on astrocytes as well as on blood-brain barrier within the CNS. It plays a pivotal role in free radical neutralization as well as neuronal signalling by regulating the glutathione production which occurs via the exchange of intracellular glutamate with extracellular cystine at 1:1 molar ratio. Understandably, it is a vital component responsible for the maintenance of neuronal homeostasis (e.g. redox state). Hence, it could be postulated that any perturbation in system [Formula: see text] function may contribute, directly or indirectly, to the pathophysiology of a variety of CNS disorders like Alzheimer's disease, schizophrenia, drug addiction, depression, multiple sclerosis, hypoglycemic neuronal cell death, glioma, and excitotoxicity, making system [Formula: see text] a promising target for treating CNS disorders. In recent times, recognizing the potential of this target, variety of inhibitors has been synthesized by modifying commercially available potent inhibitors including sulfasalazine, erastin, and sorafenib. Although, they have demonstrated efficacy, the in-depth data is still lacking to warrant their use for the treatment of aforementioned CNS disorders. In this review, we discuss the in-depth role of system [Formula: see text] transporter in maintaining normal physiology as well as in the pathophysiology of CNS diseases. Additionally, we have also listed some of the potent inhibitors of system [Formula: see text]. In conclusion, the critical role of system [Formula: see text] in multiple CNS disorders and advanced research on its inhibitors have promising future prospects for better management of the CNS ailments.

In situ allicin generation using targeted alliinase delivery for inhibition of MIA PaCa-2 cells via epigenetic changes, oxidative stress and cyclin-dependent kinase inhibitor (CDKI) expression.

Allicin, an extremely active constituent of freshly crushed garlic, is produced upon reaction of substrate alliin with the enzyme alliinase (EC 4.4.1.4). Allicin has been shown to be toxic to several mammalian cells in vitro in a dose-dependent manner. In the present study this cytotoxicity was taken to advantage to develop a novel approach to cancer treatment, based on site directed generation of allicin. Alliinase was chemically conjugated to a monoclonal antibody (mAb) which was directed against a specific pancreatic cancer marker, CA19-9. After the CA19-9 mAb-alliinase conjugate was bound to targeted pancreatic cancer cells (MIA PaCa-2 cells), on addition of alliin, the cancer cell-localized alliinase produced allicin, which effectively induced apoptosis in MIA PaCa-2 cells. Specificity of anticancer activity of in situ generated allicin was demonstrated using a novel in vitro system-integrated discrete multiple organ co-culture technique. Further, allicin-induced caspase-3 expression, DNA fragmentation, cell cycle arrest, p21(Waf1/Cip1) cyclin-dependent kinase inhibitor expression, ROS generation, GSH depletion, and led to various epigenetic modifications which resulted in stimulation of apoptosis. This approach offers a new therapeutic strategy, wherein alliin and alliinase-bound antibody work together to produce allicin at targeted locations which would reverse gene silencing and suppress cancer cell growth, suggesting that combination of these targeted agents may improve pancreatic cancer therapy.

Inhibition of carbonic anhydrase isoforms I, II, IX and XII with Schiff's bases incorporating iminoureido moieties.

A series of new Schiff's bases was obtained from the sulfanilamide semicarbazone (4-aminosulfonylphenyl semicarbazide) and aromatic/heterocyclic aldehydes. The new compounds were designed to incorporate moieties known to induce effective inhibitory activity against carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in crucial physiologic or pathologic processes such as the cytosolic CA I and II or the transmembrane, tumor-associated CA IX and XII: the compounds were medium potency - weak CA I inhibitors, highly effective, low nanomolar CA II inhibitors, but few of them inhibited effectively CA IX and XII. This may probably due to the long spacer between the sulfamoylphenyl and imine fragments of the molecules, which probably induces a highly flexible conformation of the inhibitor bound to the active site of the enzyme, with destabilizing effects for the adduct. The detailed structure activity relationship for this class of inhibitors is discussed.

Design, synthesis and biological evaluation of novel inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitors.

This study is based on our attempts to further explore the structure-activity relationship (SAR) of VX-148 (3) in an attempt to identify inosine 5'-mono-phosphate dehydrogenase (IMPDH) inhibitors superior to mycophenolic acid. A five-point pharmacophore developed using structurally diverse, known IMPDH inhibitors guided further design of novel analogs of 3. Several conventional as well as novel medicinal chemistry strategies were tried. The combined structure- and ligand-based approaches culminated in a few analogs with either retained or slightly higher potency. The compounds which retained the potency were also checked for their ability to inhibit human peripheral blood mononuclear cells proliferation. This study illuminates the stringent structural requirements and strict SAR for IMPDH II inhibition.

Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: impact on functional activity and selectivity for dopamine D2/D3 receptors.

The goal of the present study was to explore, in our previously developed hybrid template, the effect of introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replacement) on selectivity and affinity for the D3 versus D2 receptor. In addition, we wanted to explore the effect of derivatization of functional groups of the agonist binding moiety in compounds developed by us earlier from the hybrid template. Binding affinity (K(i)) of the new compounds was measured with tritiated spiperone as the radioligand and HEK-293 cells expressing either D2 or D3 receptors. Functional activity of selected compounds was assessed in the GTPγS binding assay. In the imidazole series, compound 10a exhibited the highest D3 affinity whereas the indole derivative 13 exhibited similar high D3 affinity. Functionalization of the amino group in agonist (+)-9d with different sulfonamides derivatives improved the D3 affinity significantly with (+)-14f exhibiting the highest affinity. However, functionalization of the hydroxyl and amino groups of 15 and (+)-9d, known agonist and partial agonist, to sulfonate ester and amide in general modulated the affinity. In both cases loss of agonist potency resulted from such derivatization.