Synthesis of bis-indole linked 1,3,4-oxadiazole 1–25 derivatives as inhibitors of Thymidine phosphorylase.
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Inhibition of Thymidine phosphorylase (TP) is continuously studied for the ...design and development of new drugs for the treatment of neoplastic diseases. As a part of our effort to identify TP inhibitors, we performed a structure-based virtual screening (SBVS) of our compound collection. Based on the insights gained from structures of virtual screening hits, a scaffold was designed using 1,3,4-oxadiazole as the basic structural feature and SAR studies were carried out for the optimization of this scaffold. Twenty-five novel bis-indole linked 1,3,4-oxadiazoles (7–31) were designed, synthesized and tested in vitro against E. coli TP (EcTP). Compound 7 emerged as potent TP inhibitor with an IC50 value of 3.50 ± 0.01 μM. Docking studies were carried out using GOLD software on thymidine phosphorylase from human (hTP) and E. coli (EcTP). Various hydrogen bonding, hydrophobic interactions, and π-π stacking were observed between designed molecules and the active site amino acid residues of the studied enzymes.
Ligands acting at multiple dopamine receptors hold potential as therapeutic agents for a number of neurodegenerative disorders. Specifically, compounds able to bind at D1R and D2R with high affinity ...could restore the effects of dopamine depletion and enhance motor activation on degenerated nigrostriatal dopaminergic systems. We have directed our research towards the synthesis and characterisation of heterocycle-peptide hybrids based on the indolo2,3-aquinolizidine core. This privileged structure is a water-soluble and synthetically accessible scaffold with affinity for diverse GPCRs. Herein we have prepared a solid-phase combinatorial library of 80 indoloquinolizidine-peptides to identify compounds with enhanced binding affinity at D2R, a receptor that is crucial to re-establish activity on dopamine-depleted degenerated GABAergic neurons. We applied computational tools and high-throughput screening assays to identify 9a{1,3,3} as a ligand for dopamine receptors with nanomolar affinity and agonist activity at D2R. Our results validate the application of indoloquinolizidine-peptide combinatorial libraries to fine-tune the pharmacological profiles of multiple ligands at D1 and D2 dopamine receptors.
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•Indolo2,3-aquinolizidines were used for the first time in solid-phase synthesis.•A positively charged C-terminus in indoloquinolizidine-peptides enhances their affinity at D2R.•Trans configuration of the indoloquinolizidine increases selectivity towards D2R.•9a{1,3,3} is a D1/D2 ligand with submicromolar affinity at D1R, and nanomolar affinity and agonist activity at D2R.
Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The ...inadequacy of available treatments calls for cost‐ and time‐effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high‐quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME‐tox profiling. Thus, an 18‐membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter‐screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10‐((1‐(3‐(1,1′‐biphenyl‐3‐yloxy)propyl)‐1H‐1,2,3‐triazol‐5‐yl)methyl)‐10H‐phenothiazine (7) and 10‐(3‐(1‐(3‐(1,1′‐biphenyl‐3‐yloxy)propyl)‐1H‐1,2,3‐triazol‐4‐yl)propyl)‐10H‐phenothiazine (12) showed respective IC50 values of 1.8 and 1.9 μg mL−1 against T. cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME‐tox profile. Thus, hit 7 might be progressed as an antichagasic lead.
An 18‐membered library, rapidly and efficiently assembled by combining three privileged structures by catalyst‐ and solvent‐free Huisgen cycloaddition, was screened in parasite/mammalian cell‐based and early ADME‐tox assays. Notably, compound 7 emerged as an antichagasic phenotypic hit, with a good ADME‐tox profile. The simple and versatile triazole‐based conjugation strategy of privileged scaffolds might produce high‐quality antiparasitic conjugates.
The 2(3H)-benzoxazolone heterocycle and its bioisosteric surrogates (such as 2(3H)-benzothiazolinone, benzoxazinone, etc.) have received considerable attention from the medicinal chemists owing to ...their capacity to mimic a phenol or a catechol moiety in a metabolically stable template. These heterocycles and pyrocatechol have indeed similar pKa's, electronic charge distribution, and chemical reactivity. Therapeutic applications of this template are very broad, and range from analgesic anti-inflammatory compounds (including PPAR-gamma antagonists) to antipsychotic and neuroprotective anticonvulsant compounds. High affinity ligands have been obtained also for dopaminergic (D2 and D4), serotoninergic (5-HT1A and 5-HT-2A), sigma-1 and sigma-2 receptors. Owing to the high number of positive hits encountered with this heterocycle and its congeners, 2(3H)-benzoxazolone template certainly deserves the title of "privileged scaffold" in medicinal chemistry.
Developing effective inhibitors against Mycobacterium tuberculosis (Mtb) is a challenging task, primarily due to the emergence of resistant strains. In this study, we have proposed and implemented an ...in silico guided polypharmacological approach, which is expected to be effective against resistant strains by simultaneously inhibiting several potential Mtb drug targets. A combination of pharmacophore and QSAR based virtual screening strategy taking three key targets such as InhA (enoyl-acyl-carrier-protein reductase), GlmU (N-acetyl-glucosamine-1-phosphate uridyltransferase) and DapB (dihydrodipicolinate reductase) have resulted in initial 784 hits from Asinex database of 435,000 compounds. These hits were further subjected to docking with 33 Mtb druggable targets. About 110 potential polypharmacological hits were taken by integrating the aforementioned screening protocols. Further screening was conducted by taking various parameters and properties such as cell permeability, drug-likeness, drug-induced phospholipidosisand structural alerts. A consensus analysis has yielded 59 potential hits that pass through all the filters and can be prioritized for effective drug-resistant tuberculosis. This study proposes about nine potential hits which are expected to be promising molecules, having not only drug-like properties, but also being effective against multiple Mtb targets.
Switching the motor off: Privileged chemical scaffolds were used as a starting point for the development of a specific chemical inhibitor 1 of myosin V, a key motor protein required for intracellular ...transport (see picture; ADP=adenosine diphosphate, ATP=adenosine triphosphate). The potency of 1, which does not compete directly with nucleotide binding, is comparable to that of other known motor‐protein inhibitors used as probes in chemical biology.
Tuberculosis remains a major threat to mankind, becoming more deadly due to COVID-19 pandemic. The worldwide scenario is daunted by additional factors such as drug resistance, non-adherence and ...complexity of the treatment. To overcome these obstacles, there is a constant need for novel drug development. However, drug development is an extensive process in itself requiring enormous financial investment and is time-consuming with a low success rate. A viable alternative to circumvent these complications is to explore ‘privileged scaffold/s’. Further logical approaches would be to study the privileged scaffold/s which materialize in the clinical pipeline of the disease. The present review summarizes clinically important privileged scaffolds explored in tuberculosis, namely, aryl quinolines, nitroheterocycles and oxazolidinones. Various developmental aspects have been reviewed along with the structural, pharmacological and physicochemical investigations as may be relevant. The understandings gained would thereby help in envisaging suitable structural modifications of these scaffolds for development of promising leads.
Gold complexes have emerged in the last few years as excellent catalysts in numerous homogeneous transformations involving the activation of carbon–carbon multiple bonds towards the attack of a large ...variety of nucleophiles. This article gives a brief overview of this enticing subject and identifies some of the most important aspects of homogeneous gold catalysis in organic synthesis focusing on the research done in our laboratory.
Hexadecahydro‐1H‐cyclopentaaphenanthrene framework (HHCPF) has been considered as one of the privileged scaffolds due to its versatile presence in many biologically essential molecules. In our quest ...to unravel the privileged nature of this framework, we undertook a systematic analysis of target binding and Absorption, Distribution, Metabolism, Elimination, Toxicity (ADMET)/physicochemical properties of 110 drugs containing HHCPF reported in DrugBank. Effect of number and positions of double bonds in the framework and substitutions at each carbon position on the target selectivity as well as drug like properties of these drugs were studied. Fifteen different scaffolds based on the numbers and positions of double bonds in the HHCPF were identified among these drugs. The optimum number of double bonds present in the HHCPF scaffolds was observed to be one to three, and one particular positional isomer is predominant among many scaffolds with same numbers of double bonds. Docking studies reveal the role of substituents at different positions to make specific interactions with their respective targets. Based on the docking interactions, we proposed structure based e‐Pharmacophore models for seven important targets of HHCPF drugs. Good correlations were observed between the substitutions carbon positions 3 and 17 of the scaffolds and ADMET properties of the HHCPF drugs. This work enables preliminary prediction of the target selectivity and ADMET properties of a new HHCPF molecule based on the scaffold, substituents and the pharmacophoric features.
We present a new class of inhibitors of pancreatic cholesterol esterase (CEase) based on ‘priviledged’ 5-benzylidenerhodanine and 5-benzylidene-2,4-thiazolidinedione structural scaffolds. The lead ...structures (5-benzylidenerhodanine 4a and 5-benzylidene-2,4-thiazolidinedione 4b) were identified in an in-house screening and these inhibited CEase with some selectivity over another serine hydrolase, acetylcholinesterase (AChE) (4a, CEase IC50=1.76μM vs AChE IC50=5.14μM and 4b, CEase IC50=5.89μM vs AChE IC50 >100μM). A small library of analogs (5a–10a) containing a core amino acid in place of the glycerol group of the lead structures, was prepared to explore other potential binding interaction with CEase. These analogs inhibited CEase with IC50 values ranging from 1.44 to 85μM, with the majority exhibiting some selectivity for CEase versus AChE. The most potent compound of the library (10a) had 17-fold selectivity over AChE. We also report molecular docking (with CEase) and detailed kinetic analysis on the amino acid analogs to further understand the associated structure–activity relationships.
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