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European Journal of Medicinal Chemistry Aug 2021The development of new molecules for the treatment of leishmaniasis is, a neglected parasitic disease, is urgent as current anti-leishmanial therapeutics are hampered by...
The development of new molecules for the treatment of leishmaniasis is, a neglected parasitic disease, is urgent as current anti-leishmanial therapeutics are hampered by drug toxicity and resistance. The pyrrolo[1,2-b]isoquinoline core was selected as starting point, and palladium-catalyzed Heck-initiated cascade reactions were developed for the synthesis of a series of C-10 substituted derivatives. Their in vitro leishmanicidal activity against visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis was evaluated. The best activity was found, in general, for the 10-arylmethyl substituted pyrroloisoquinolines. In particular, 2ad (IC = 3.30 μM, SI > 77.01) and 2bb (IC = 3.93 μM, SI > 58.77) were approximately 10-fold more potent and selective than the drug of reference (miltefosine), against L. amazonensis on in vitro promastigote assays, while 2ae was the more active compound in the in vitro amastigote assays (IC = 33.59 μM, SI > 8.93). Notably, almost all compounds showed low cytotoxicity, CC > 100 μg/mL in J774 cells, highest tested dose. In addition, we have developed the first Perturbation Theory Machine Learning (PTML) algorithm able to predict simultaneously multiple biological activity parameters (IC, K, etc.) vs. any Leishmania species and target protein, with high values of specificity (>98%) and sensitivity (>90%) in both training and validation series. Therefore, this model may be useful to reduce time and assay costs (material and human resources) in the drug discovery process.
Topics: Algorithms; Antiprotozoal Agents; Dose-Response Relationship, Drug; Isoquinolines; Leishmania; Leishmaniasis; Molecular Structure; Palladium; Parasitic Sensitivity Tests; Structure-Activity Relationship
PubMed: 33901901
DOI: 10.1016/j.ejmech.2021.113458 -
British Journal of Anaesthesia 1986
Review
Topics: Animals; Atracurium; Dogs; Half-Life; Hemodynamics; Histamine Release; Humans; Isoquinolines; Neuromuscular Blocking Agents
PubMed: 2423104
DOI: 10.1093/bja/58.suppl_1.2s -
Bioorganic & Medicinal Chemistry Dec 2021The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human...
The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10-20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.
Topics: ADP Ribose Transferases; Crystallography, X-Ray; Dose-Response Relationship, Drug; Humans; Isoquinolines; Models, Molecular; Molecular Structure; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins; Structure-Activity Relationship; Thiophenes
PubMed: 34801828
DOI: 10.1016/j.bmc.2021.116511 -
British Journal of Clinical Pharmacology 19771. Nomifensine is a new antidepressant of novel chemical structure (a tetrahydroisoquinoline) with a pharmacological and therapeutic profile which differentiates it from...
1. Nomifensine is a new antidepressant of novel chemical structure (a tetrahydroisoquinoline) with a pharmacological and therapeutic profile which differentiates it from any existing group of psychotropic agents. 2. The basic animal pharmacological profile is similar to that of the tricyclic antidepressants, imipramine and desmethylimipramine, but with a comparative lack of peripheral anticholinergic and cardiotoxic effects. 3. The pattern of effects on monoamine neurotransmitters is unique amongst antidepressants in that nomifensine is a potent dopamine agonist, has a powerful inhibitory effect on noradrenaline uptake and a weaker inhibitory effect on serotonin uptake. These pharmacological differences are reflected in the behavioural activity of the drug. 4. Clinically nomifensine has been shown to be an effective non-sedative antidepressant; its relative lack of anticholinergic and other somatic side-effects (particularly on the cardiovascular system) have been confirmed in patients.
Topics: Animals; Chemical Phenomena; Chemistry; Humans; Isoquinolines; Nomifensine
PubMed: 911653
DOI: 10.1111/j.1365-2125.1977.tb05760.x -
Molecules (Basel, Switzerland) Jun 2022An important strategy for treating neurodegenerative disorders is to maintain the levels of acetylcholine in the synaptic cleft by blocking the cholinesterases....
An important strategy for treating neurodegenerative disorders is to maintain the levels of acetylcholine in the synaptic cleft by blocking the cholinesterases. Searching for new effective compounds with inhibited acetylcholinesterase and butyrylcholinesterase activity is one of the most significant challenges of the modern scientific research. The aim of this study was the optimization of the condition for cholinesterase activity determination by high-performance liquid chromatography coupled with diode array detector (HPLC-DAD) in terms of concentrations of enzymatic reaction mixture components, temperature of incubation, and incubation time. In vitro investigation of acetylcholinesterase and butyrylcholinesterase activity inhibition by some isoquinoline alkaloids and extracts obtained from the aerial part and roots of collected in May, July, and September. Acetylcholinesterase and butyrylcholinesterase activity inhibition of the extracts obtained from the plant had not been tested previously. The application of the HPLC method allowed eliminating absorption of interfering components, for example, alkaloids such as sanguinarine and berberine. The HPLC method was successfully applied for the evaluation of the acetylcholinesterase inhibitory activity in samples such as plant extracts, especially those containing colored components adsorbing at the same wavelength as the adsorption wavelength of 5-thio-2-nitro-benzoic acid, which is the product of the reaction between thiocholine (product of the hydrolysis of acetyl/butyrylthiocholine reaction) with Ellman's reagent. Moreover, liquid chromatography coupled with a triple quadrupole mass spectrometer (LC-QqQ-ESI-MS/MS) analysis allowed evaluating the identification of relevant bioactive compounds in the obtained plant extracts. The investigated alkaloids, especially sanguinarine and chelerythrine, and all the extracts, especially the extract obtained from the aerial part collected in May, exhibited very high cholinesterase activity inhibition. HPLC-DAD was also applied for the kinetics study of the most active alkaloids sanguinarine and chelerythrine. Our investigations demonstrated that these plant extracts can be recommended for further in vivo experiments to confirm their cholinesterase inhibition activity.
Topics: Acetylcholinesterase; Alkaloids; Antineoplastic Agents; Butyrylcholinesterase; Cholinesterase Inhibitors; Isoquinolines; Papaveraceae; Plant Extracts; Tandem Mass Spectrometry
PubMed: 35684539
DOI: 10.3390/molecules27113606 -
Proceedings of the Japan Academy.... 2013Plants produce a variety of secondary metabolites that possess strong physiological activities. Unfortunately, however, their production can suffer from a variety of... (Review)
Review
Plants produce a variety of secondary metabolites that possess strong physiological activities. Unfortunately, however, their production can suffer from a variety of serious problems, including low levels of productivity and heterogeneous quality, as well as difficulty in raw material supply. In contrast, microorganisms can be used to produce their primary and some of their secondary metabolites in a controlled environment, thus assuring high levels of efficiency and uniform quality. In an attempt to overcome the problems associated with secondary metabolite production in plants, we developed a microbial platform for the production of plant isoquinoline alkaloids involving the unification of the microbial and plant metabolic pathways into a single system. The potential applications of this system have also been discussed.
Topics: Alkaloids; Bacteria; Biosynthetic Pathways; Isoquinolines; Metabolic Engineering; Plants
PubMed: 23666088
DOI: 10.2183/pjab.89.165 -
Clinical Cardiology Jun 1990Major clinical trials are reviewed comparing the efficacy and safety of quinapril hydrochloride, a new nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, with... (Clinical Trial)
Clinical Trial Review
Major clinical trials are reviewed comparing the efficacy and safety of quinapril hydrochloride, a new nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, with that of placebo, captopril, and enalapril in the treatment of mild to moderate essential hypertension. A randomized, double-blind 12-week study of 270 patients compared the efficacy of placebo with once or twice daily doses of quinapril (20, 40, 80 mg/day, with forced titration). Quinapril effectively lowered both diastolic blood pressure (DBP) and systolic blood pressure. Mean reductions in DBP of up to 13 mmHg from baseline were obtained. At full dosage, more than 65% of patients achieved a clinically significant reduction in DBP. Quinapril was similarly effective whether the total daily dose was given once or twice daily. In a multicenter, double-blind study involving more than 400 patients, the efficacy of quinapril (10-40 mg/day, given once or twice daily) was found to be similar to captopril (25 mg bid to 50 mg tid). Hydrochlorothiazide (HCTZ) safely provided additive effects when given to nonresponders in both treatment groups. In a 28-week double-blind study of 258 patients comparing the efficacy of quinapril or enalapril at doses of 10, 20, and 40 mg/day (with optional titration), quinapril was found to be of similar efficacy as enalapril. The large majority of patients on either regimen were controlled with monotherapy. HCTZ again safely provided additive effects. Quinapril was well tolerated in all trials, with the incidence of adverse events and withdrawals tending to be lower with quinapril than with enalapril or captopril.
Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Clinical Trials as Topic; Enalapril; Humans; Hypertension; Isoquinolines; Quinapril; Tetrahydroisoquinolines
PubMed: 2189617
DOI: 10.1002/clc.4960131405 -
International Journal of Molecular... Sep 2022(Thunb.) Druce is a traditional medicinal plant containing a variety of alkaloids, which are important active ingredients. Brassinolide (BR) is a plant hormone that...
(Thunb.) Druce is a traditional medicinal plant containing a variety of alkaloids, which are important active ingredients. Brassinolide (BR) is a plant hormone that regulates plant response to environmental stress and promotes the accumulation of secondary metabolites in plants. However, the regulatory mechanism of BR-induced alkaloid accumulation in is not clear. In this study, we investigated the effects of BR and BR biosynthesis inhibitor (propiconazole, Pcz) treatments on alkaloid biosynthesis in the bulbil of . The results showed that total alkaloid content and bulbil yield was enhanced by 90.87% and 29.67% under BR treatment, respectively, compared to the control. We identified 818 (476 up-regulated and 342 down-regulated) and 697 (389 up-regulated and 308 down-regulated) DEGs in the BR-treated and Pcz-treated groups, respectively. Through this annotated data and the Kyoto encyclopedia of genes and genomes (KEGG), the expression patterns of unigenes involved in the ephedrine alkaloid, tropane, piperidine, pyridine alkaloid, indole alkaloid, and isoquinoline alkaloid biosynthesis were observed under BR and Pcz treatments. We identified 11, 8, 2, and 13 unigenes in the ephedrine alkaloid, tropane, piperidine, and pyridine alkaloid, indole alkaloid, and isoquinoline alkaloid biosynthesis, respectively. The expression levels of these unigenes were increased by BR treatment and were decreased by Pcz treatment, compared to the control. The results provided molecular insight into the study of the molecular mechanism of BR-promoted alkaloid biosynthesis.
Topics: Alkaloids; Brassinosteroids; Ephedrine; Gene Expression Profiling; Isoquinolines; Pinellia; Piperidines; Plant Growth Regulators; Pyridines; Steroids, Heterocyclic; Transcriptome; Tropanes
PubMed: 36142812
DOI: 10.3390/ijms231810898 -
Marine Drugs Jan 2022Puniceusines A-N (-), 14 new isoquinoline alkaloids, were isolated from the extracts of a deep-sea-derived fungus, SCSIO z021. Their structures were elucidated by...
Puniceusines A-N (-), 14 new isoquinoline alkaloids, were isolated from the extracts of a deep-sea-derived fungus, SCSIO z021. Their structures were elucidated by spectroscopic analyses. The absolute configuration of was determined by ECD calculations, and the structures of and were further confirmed by a single-crystal X-ray diffraction analysis. Compounds - and - unprecedentedly contained an isoquinolinyl, a polysubstituted benzyl or a pyronyl at position C-7 of isoquinoline nucleus. Compounds and showed selective inhibitory activity against protein tyrosine phosphatase CD45 with IC values of 8.4 and 5.6 µM, respectively, also had a moderate cytotoxicity towards human lung adenocarcinoma cell line H1975 with an IC value of 11.0 µM, and , which contained an active center, -C=N, exhibited antibacterial activity. An analysis of the relationship between the structures, enzyme inhibitory activity and cytotoxicity of - revealed that the substituents at C-7 of the isoquinoline nucleus could greatly affect their bioactivity.
Topics: Alkaloids; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Aquatic Organisms; Aspergillus; Cell Line, Tumor; Humans; Inhibitory Concentration 50; Isoquinolines; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Protein Tyrosine Phosphatases
PubMed: 35049933
DOI: 10.3390/md20010078 -
Advances in Therapy Apr 2017This article informs the reader of the current information available on a novel therapeutic agent and new class of drug for the treatment of anemia. The data show... (Review)
Review
This article informs the reader of the current information available on a novel therapeutic agent and new class of drug for the treatment of anemia. The data show promising results for alternative erythropoietin-stimulating agents and offers a time line of when Phase III data will be available. The information on this new drug and new drug class will change how nephrologists approach treating anemia within their patients.
Topics: Anemia; Glycine; Hematinics; Humans; Isoquinolines; Renal Insufficiency, Chronic
PubMed: 28290095
DOI: 10.1007/s12325-017-0508-9