Publications by authors named "Babu L Tekwani"

159 Publications

Enantioselective Interactions of Anti-Infective 8-Aminoquinoline Therapeutics with Human Monoamine Oxidases A and B.

Pharmaceuticals (Basel) 2021 Apr 22;14(5). Epub 2021 Apr 22.

Division of Drug Discovery, Department of Infectious Diseases, Southern Research, Birmingham, AL 35205, USA.

8-Aminoquinolines (8-AQs) are an important class of anti-infective therapeutics. The monoamine oxidases (MAOs) play a key role in metabolism of 8-AQs. A major role for MAO-A in metabolism of primaquine (PQ), the prototypical 8-AQ antimalarial, has been demonstrated. These investigations were further extended to characterize the enantioselective interactions of PQ and NPC1161 (8-[(4-amino-1-methylbutyl) amino]-5-[3, 4-dichlorophenoxy]-6-methoxy-4-methylquinoline) with human MAO-A and -B. NPC1161B, the ()-(-) enantiomer with outstanding potential for malaria radical cure, treatment of visceral leishmaniasis and pneumocystis pneumonia infections is poised for clinical development. PQ showed moderate inhibition of human MAO-A and -B. Racemic PQ and ()-(-)-PQ both showed marginally greater (1.2- and 1.6-fold, respectively) inhibition of MAO-A as compared to MAO-B. However, ()-(+)-PQ showed a reverse selectivity with greater inhibition of MAO-B than MAO-A. Racemic NPC1161 was a strong inhibitor of MAOs with 3.7-fold selectivity against MAO-B compared to MAO-A. The ()-(+) enantiomer (NPC1161A) was a better inhibitor of MAO-A and -B compared to the ()-(-) enantiomer (NPC1161B), with more than 10-fold selectivity for inhibition of MAO-B over MAO-A. The enantioselective interaction of NPC1161 and strong binding of NPC1161A with MAO-B was further confirmed by enzyme-inhibitor binding and computational docking analyses. Differential interactions of PQ and NPC1161 enantiomers with human MAOs may contribute to the enantioselective pharmacodynamics and toxicity of anti-infective 8-AQs therapeutics.
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http://dx.doi.org/10.3390/ph14050398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146505PMC
April 2021

Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors.

J Med Chem 2021 04 9;64(8):4762-4786. Epub 2021 Apr 9.

Drug Discovery Division, Southern Research, 2000 Ninth Avenue South, Birmingham, Alabama 35205, United States.

A benzo[6]annulene, 4-(-butyl)--(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC = 1.45 μM and viral titer reduction (VTR) of 2.5 log at 10 μM with no observed cytotoxicity (CC = 169 μM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, and drug-like properties of resulted in a novel lead compound , which possessed excellent cellular antiviral activity (EC = 270 nM and VTR of 4.5 log at 10 μM) and improved liver microsomal stability. CHIKV resistance to an analog of , compound , tracked to a mutation in the nsP3 macrodomain. Further mechanism of action studies showed compounds working through inhibition of human dihydroorotate dehydrogenase in addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed in an CHIKV challenge mouse model for compound as viral replication was rescued from the pyrimidine salvage pathway.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02183DOI Listing
April 2021

Quantitative determination of primaquine-5,6-ortho-quinone and carboxyprimaquine-5,6-ortho-quinone in human erythrocytes by UHPLC-MS/MS.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jan 30;1163:122510. Epub 2020 Dec 30.

National Center for Natural Products Research, The University of Mississippi, University, MS 38677, USA. Electronic address:

The antimalarial drug primaquine (PQ) causes methemoglobinemia and hemolysis in individuals with a genetic deficiency of glucose 6-phosphate dehydrogenase. Reactive oxygen species (ROS) generated by redox cycling of the metabolite primaquine-5,6-orthoquinone (POQ) in erythrocytes has been attributed to be responsible for the toxicity of PQ. Carboxyprimaquine (CPQ), the major human plasma metabolite of PQ, can also form the analogous carboxyprimaquine-5,6-orthoquinone (CPOQ) metabolite, which can also generate ROS in erythrocytes by redox cycling, thus contributing to the hematotoxicity of this drug. In order to study these pathways and characterize such effects in vivo, methods are needed for characterization and quantification of POQ and CPOQ in human erythrocytes. The purpose of this work was to develop a validated method for the quantitative determination of CPOQ and POQ metabolites in human erythrocytes, suitable for clinical studies of PQ metabolism. Several liquid-liquid extraction methods using different organic solvents had been investigated. The solvent mixture of water-methanol-acetonitrile (9:9:5, v/v) was shown to yield the best results for the two analytes. Chromatographic analysis of POQ and CPOQ in human erythrocytes was achieved on a high strength silica (HSS) column and gradient elution (water and acetonitrile, both containing 0.1% formic acid) by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Quantitative estimation of POQ and CPOQ was executed by monitoring ion pairs of m/z 260.23 > 175.03 and m/z 275.19 > 175.04, respectively. The method, which was validated for precision, accuracy, selectivity, and linearity, was successfully applied for the quantitative determination of POQ and CPOQ, the key metabolites of PQ in human erythrocytes in PQ clinical study.
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http://dx.doi.org/10.1016/j.jchromb.2020.122510DOI Listing
January 2021

Antimalarials and Phytotoxins from Identified from a Seed of Diseased .

Molecules 2020 Dec 24;26(1). Epub 2020 Dec 24.

National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.

The metabolic pathways in the apicoplast organelle of parasites are similar to those in plastids in plant cells and are suitable targets for malaria drug discovery. Some phytotoxins released by plant pathogenic fungi have been known to target metabolic pathways of the plastid; thus, they may also serve as potential antimalarial drug leads. An EtOAc extract of the broth of the endophyte isolated from a seed collected from a plant with disease symptoms, showed in vitro antimalarial and phytotoxic activities. Bioactivity-guided fractionation of the extract afforded a mixture of two known isomeric phytotoxins, FRT-A and flavipucine (or their enantiomers, sapinopyridione and (-)-flavipucine), and two new unstable -lactam alkaloids dothilactaenes A and B. The isomeric mixture of phytotoxins displayed strong phytotoxicity against both a dicot and a monocot and moderate cytotoxicity against a panel of cell lines. Dothilactaene A showed no activity. Dothilactaene B was isolated from the active fraction, which showed moderate in vitro antiplasmodial activity with high selectivity index. In spite of this activity, its instability and various other biological activities shown by related compounds would preclude it from being a viable antimalarial lead.
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http://dx.doi.org/10.3390/molecules26010059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795089PMC
December 2020

Emergence and Reemergence of Human Coronaviruses: Spike Protein as the Potential Molecular Switch and Pharmaceutical Target.

Curr Pharm Des 2020 Dec 15. Epub 2020 Dec 15.

Department of Infectious Diseases, Division of Drug Discovery, Southern Research, Birmingham Alabama 35205. United States.

Background: Recent emergence of COVID-19 caused by a new human coronavirus (CoV) strain (SARS-CoV2), which originated from the China, poses future emergence of additional CoVs. In most of the cases of emergence of human CoVs bats, palm civets, raccoon dogs and camels have been identified as the sources of human infections and reservoir hosts. A review of comparative genomic and phenotypic characteristics of human CoV strains vis-à-vis their comparison with the corresponding animal isolates shall provide the clues regarding the potential genomic, phenotypic and molecular factors responsible for host-switching, which may lead to prospective emergence and reemergence of human CoV outbreaks in future.

Methods: The seven known human strains of CoV were analyzed for the host and viral factors responsible for human outbreaks. The molecular factors responsible for host-susceptibility, virulence and pathogenesis were reviewed to predict emergence and re-emergence of additional human CoV strains. CoV spike protein was evaluated as a potential viral receptor for host switching and the target for pharmaceutical design.

Results: Review of the factors associated with host-susceptibility, virulence and pathogenesis of seven known human CoV strains present significant possibilities for emergence of new CoV strain(s), leading to more human outbreaks. Continuous exposure of animals' handlers to the infected animals, environmental changes, improper sanitations, nondisposal of the solid waste and resumption of exotic animals markets provide favorable conditions for "host switching" and emergence of new and potentially more virulent human CoV strains. Mutations in target genes (like spike protein), which facilitate the viral entry into the host-cells, provide potential "molecular switch" for preferences of new hostreceptors, genetic diversity, genetic-recombination and high virulence. Additionally, the clinical and environmental factors, asymptomatic carriers, paucity of efficacious vaccines & therapeutics, inefficient disease management and infection control measures, lack of public awareness, and effective communication of information about more virulent human-adapted virus isolates are critical factors for emergence of new and virulent SARS-CoV strains with high mortality and varied incubation period in the near future. Small molecules binding with conserved druggable regions of the CoV spike proteins may be effective against multiple strains of CoVs.

Conclusions: High propensity of mutations and "molecular adaptations" in coronaviruses create the hot spots and high potential for "host switching" leading to emergence of more virulent strains human CoVs. The public/global health agencies, medical communities and research scientists should be prepared for emergence and reemergence of new human CoV strain(s) leading to potential disease outbreaks. The inhibitors binding with conserved druggable regions of spike proteins from multiple strains CoV may have utility as broad-spectrum antiviral drugs to combat future emergence of CoVs.
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http://dx.doi.org/10.2174/1381612826666201216113146DOI Listing
December 2020

Current investigations on clinical pharmacology and therapeutics of Glucose-6-phosphate dehydrogenase deficiency.

Pharmacol Ther 2021 06 14;222:107788. Epub 2020 Dec 14.

Department of Infectious Diseases, Division of Drug Discovery, Southern Research, 2000 9(th) Avenue South, Birmingham, AL 35205, United States of America. Electronic address:

Glucose-6-phospate dehydrogenase (G6PD) deficiency is estimated to affect more than 400 million people world-wide. This X-linked genetic deficiency puts stress on red blood cells (RBC), which may be further augmented under certain pathophysiological conditions and drug treatments. These conditions can cause hemolytic anemia and eventually lead to multi-organ failure and mortality. G6PD is involved in the rate-limiting step of the pentose phosphate pathway, which generates reduced nicotinamide adenine dinucleotide phosphate (NADPH). In RBCs, the NADPH/G6PD pathway is the only source for recycling reduced glutathione and provides protection from oxidative stress. Susceptibility of G6PD deficient populations to certain drug treatments and potential risks of hemolysis are important public health issues. A number of clinical trials are currently in progress investigating clinical factors associated with G6PD deficiency, validation of new diagnostic kits for G6PD deficiency, and evaluating drug safety, efficacy, and pathophysiology. More than 25 clinical studies in G6PD populations are currently in progress or have just been completed that have been examined for clinical pharmacology and potential therapeutic implications of G6PD deficiency. The information on clinical conditions, interventions, purpose, outcome, and status of these clinical trials has been studied. A critical review of ongoing clinical investigations on pharmacology and therapeutics of G6PD deficiency should be highly important for researchers, clinical pharmacologists, pharmaceutical companies, and global public health agencies. The information may be useful for developing strategies for treatment and control of hemolytic crisis and potential drug toxicities in G6PD deficient patients.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122012PMC
June 2021

Selective Interactions of -Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B.

Molecules 2020 Nov 17;25(22). Epub 2020 Nov 17.

Department of Infectious Diseases, Division of Drug Discovery, Southern Research, Birmingham, AL 35205, USA.

A set of structurally related -methylated flavonoid natural products isolated from (), ( and ), (), (), and () plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds , , and showed selective inhibition of MAO-A, while and showed selective inhibition of MAO-B. Compound showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds - and with MAO-A, and compounds and with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by and , while a partially-reversible mixed-type inhibition by . Similarly, enzyme inhibition-kinetics analysis with compounds , , and , suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the -methylated flavonoids ( and -) and chalcones ( and ) to MAO-A matched closely with the trend in the experimental ICs. Analysis of the binding free-energies suggested better interaction of and with MAO-B than with MAO-A. The natural -methylated flavonoid () with highly potent inhibition (IC 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.
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http://dx.doi.org/10.3390/molecules25225358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697615PMC
November 2020

Druggable targets of SARS-CoV-2 and treatment opportunities for COVID-19.

Bioorg Chem 2020 11 8;104:104269. Epub 2020 Sep 8.

Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Vidya Vihar, Pilani 333031, Rajasthan, India. Electronic address:

COVID-19 caused by the novel SARS-CoV-2 has been declared a pandemic by the WHO is causing havoc across the entire world. As of May end, about 6 million people have been affected, and 367 166 have died from COVID-19. Recent studies suggest that the SARS-CoV-2 genome shares about 80% similarity with the SARS-CoV-1 while their protein RNA dependent RNA polymerase (RdRp) shares 96% sequence similarity. Remdesivir, an RdRp inhibitor, exhibited potent activity against SARS-CoV-2 in vitro. 3-Chymotrypsin like protease (also known as M) and papain-like protease, have emerged as the potential therapeutic targets for drug discovery against coronaviruses owing to their crucial role in viral entry and host-cell invasion. Crystal structures of therapeutically important SARS-CoV-2 target proteins, namely, RdRp, M, endoribonuclease Nsp15/NendoU and receptor binding domain of CoV-2 spike protein has been resolved, which have facilitated the structure-based design and discovery of new inhibitors. Furthermore, studies have indicated that the spike proteins of SARS-CoV-2 use the Angiotensin Converting Enzyme-2 (ACE-2) receptor for its attachment similar to SARS-CoV-1, which is followed by priming of spike protein by Transmembrane protease serine 2 (TMPRSS2) which can be targeted by a proven inhibitor of TMPRSS2, camostat. The current treatment strategy includes repurposing of existing drugs that were found to be effective against other RNA viruses like SARS, MERS, and Ebola. This review presents a critical analysis of druggable targets of SARS CoV-2, new drug discovery, development, and treatment opportunities for COVID-19.
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http://dx.doi.org/10.1016/j.bioorg.2020.104269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476961PMC
November 2020

Salvia ceratophylla L. from South of Jordan: new insights on chemical composition and biological activities.

Nat Prod Bioprospect 2020 Oct 27;10(5):307-316. Epub 2020 Aug 27.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biocmedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany.

In Jordan, Salvia ceratophylla L. is traditionally used in the treatment of cancer, microbial infections, and urinary disorders. This study aimed: (1) to chemically characterize S. ceratophylla essential oil (EO) from South Jordan, by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS); and (2) to evaluate in vitro the cytotoxic, anti-inflammatory, and antiprotozoal activities of the EO, it's predominant components, and the hexane (A), ethyl acetate (B), methanol (C) and crude-methanol extracts (D). The analysis revealed that the EO has 71 compounds, with linalool (54.8%) as main constituent. Only the hexane extract (A) showed some cytotoxic activity against SK-MEL, KB, BT-549, SK-OV-3, LLC-PK1 and VERO cells lines with IC between 60 and > 100 µg/mL. The EO inhibited NO production (IC 90 µg/mL) and NF-κB activity (IC 38 µg/mL). The extracts A, B, and D inhibited NO production and NF- κB activity with IC between 32 and 150 µg/mL. Linalool considerably inhibited NO production (IC 18 µg/mL). The extracts tested did not exhibit antileishmanial activity. Regarding antitrypanosomal activity, the EO exhibited significant results with IC 2.65 µg/mL. In conclusion, Jordan S. ceratophylla EO represents a rich source of linalool and bears a promising therapeutic potential for further antitrypanosomal drug development.
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http://dx.doi.org/10.1007/s13659-020-00259-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520468PMC
October 2020

Expanding the scope of synthetic 1,2,4-trioxanes towards Trypanosoma cruzi and Leishmania donovani.

Bioorg Med Chem Lett 2020 10 11;30(20):127491. Epub 2020 Aug 11.

Instituto de Química Rosario (IQUIR-CONICET), Universidad Nacional de Rosario-CONICET, Suipacha 531, S2002LRK Rosario, Argentina; Departamento de Química Orgánica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina. Electronic address:

A series of synthetic 1,2,4-trioxanes related to artemisinin was tested against L. donovani and T. cruzi parasites. This screening identified some active compounds, with key common structural features. Interestingly, these selected trioxanes were efficient against both parasites, and achieved antiparasitic activities comparable or superior than those presented by the corresponding reference drugs, artemisinin and artesunate. This study represents the first example of synthetic trioxanes evaluated on T. cruzi and provides possible candidates for developing new drugs for the treatment of leishmaniasis and Chagas disease.
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http://dx.doi.org/10.1016/j.bmcl.2020.127491DOI Listing
October 2020

Hydroxychloroquine as Postexposure Prophylaxis for Covid-19.

Authors:
Babu L Tekwani

N Engl J Med 2020 09 15;383(11):1088-1089. Epub 2020 Jul 15.

Southern Research, Birmingham, AL

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http://dx.doi.org/10.1056/NEJMc2023617DOI Listing
September 2020

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation.

Front Pharmacol 2020 24;11:537. Epub 2020 Apr 24.

Division of Drug Discovery, Department of Infectious Diseases, Southern Research, Birmingham, AL, United States.

Histone deacetylases (HADC) are the enzymes that remove acetyl group from lysine residue of histones and non-histone proteins and regulate the process of transcription by binding to transcription factors and regulating fundamental cellular process such as cellular proliferation, differentiation and development. In neurodegenerative diseases, the histone acetylation homeostasis is greatly impaired, shifting towards a state of hypoacetylation. The histone hyperacetylation produced by direct inhibition of HDACs leads to neuroprotective actions. This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential of HDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases. The role of HDACs in neuronal cellular and disease models and their modulation with HDAC inhibitors are also discussed. Significance of these HDAC inhibitors has been reviewed on the process of neuronal differentiation, neurite outgrowth and neuroprotection regarding their potential therapeutic application for treatment of neurodegenerative diseases.
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http://dx.doi.org/10.3389/fphar.2020.00537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194116PMC
April 2020

Promising selective MAO-B inhibition by sesamin, a lignan from stems.

Saudi Pharm J 2020 Apr 13;28(4):409-413. Epub 2020 Feb 13.

National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, United States.

Monoamine oxidase inhibition is an important therapeutic approach for various neurodegenerative disorders. Reversible MAO inhibitors selectively targeting only one isoform possess substantial merit in terms of safety, efficacy, and side effect profile. This study aimed to isolate the secondary metabolites of stems and evaluate their recombinant human MAO inhibition, antimicrobial, and antiprotozoal activities. As a result, fourteen compounds were isolated and identified (nine of them were reported from for the first time). Compound (sesamin) exhibited potent selective MAO-B inhibition (IC value of  µM) which reported herein for the first time. Compound showed selective MAO-A inhibition activity, compound exhibited good trypanocidal activity, and compound displayed moderate antibacterial activity. The promising MAO-B inhibitory activity of sesamin provoked us to further explore the kinetic properties, the binding mode, and the underlying mechanism of MAO-B inhibition by this lignan. This detailed investigation substantiated a reversible binding and mixed MAO-B catalytic function inhibition via sesamin (K: 0.473 ± 0.076 μM). Selectivity and reversibility of sesamin on MAO-B provide exciting prerequisites for further in vivo investigation to confirm its therapeutic potentiality.
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http://dx.doi.org/10.1016/j.jsps.2020.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132610PMC
April 2020

Screening Marine Natural Products for New Drug Leads against Trypanosomatids and Malaria.

Mar Drugs 2020 Mar 31;18(4). Epub 2020 Mar 31.

Department of Biomedical Sciences, University of León, 24071 León, Spain.

Neglected Tropical Diseases (NTD) represent a serious threat to humans, especially for those living in poor or developing countries. Almost one-sixth of the world population is at risk of suffering from these diseases and many thousands die because of NTDs, to which we should add the sanitary, labor and social issues that hinder the economic development of these countries. Protozoan-borne diseases are responsible for more than one million deaths every year. Visceral leishmaniasis, Chagas disease or sleeping sickness are among the most lethal NTDs. Despite not being considered an NTD by the World Health Organization (WHO), malaria must be added to this sinister group. Malaria, caused by the apicomplexan parasite , is responsible for thousands of deaths each year. The treatment of this disease has been losing effectiveness year after year. Many of the medicines currently in use are obsolete due to their gradual loss of efficacy, their intrinsic toxicity and the emergence of drug resistance or a lack of adherence to treatment. Therefore, there is an urgent and global need for new drugs. Despite this, the scant interest shown by most of the stakeholders involved in the pharmaceutical industry makes our present therapeutic arsenal scarce, and until recently, the search for new drugs has not been seriously addressed. The sources of new drugs for these and other pathologies include natural products, synthetic molecules or repurposing drugs. The most frequent sources of natural products are microorganisms, e.g., bacteria, fungi, yeasts, algae and plants, which are able to synthesize many drugs that are currently in use (e.g. antimicrobials, antitumor, immunosuppressants, etc.). The marine environment is another well-established source of bioactive natural products, with recent applications against parasites, bacteria and other pathogens which affect humans and animals. Drug discovery techniques have rapidly advanced since the beginning of the millennium. The combination of novel techniques that include the genetic modification of pathogens, bioimaging and robotics has given rise to the standardization of High-Performance Screening platforms in the discovery of drugs. These advancements have accelerated the discovery of new chemical entities with antiparasitic effects. This review presents critical updates regarding the use of High-Throughput Screening (HTS) in the discovery of drugs for NTDs transmitted by protozoa, including malaria, and its application in the discovery of new drugs of marine origin.
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http://dx.doi.org/10.3390/md18040187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230869PMC
March 2020

NPC1161B, an 8-Aminoquinoline Analog, Is Metabolized in the Mosquito and Inhibits Oocyst Maturation.

Front Pharmacol 2019 25;10:1265. Epub 2019 Oct 25.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.

Malaria is a major global health threat, with nearly half the world's population at risk of infection. Given the recently described delayed clearance of parasites by artemisinin-combined therapies, new antimalarials are needed to facilitate the global effort toward elimination and eradication. NPC1161 is an 8-aminoquinoline that is derived from primaquine with an improved therapeutic profile compared to the parent compound. The ()-(-) enantiomer (NPC1161B) has a lower effective dose that results in decreased toxic side effects such as hemolysis compared to the ()-(+)-enantiomer, making it a promising compound for consideration for clinical development. We explored the effect of NPC1161B on oocyst and sporozoite development to evaluate its potential transmission-blocking activity viz. its ability to cure mosquitoes of an ongoing infection. When mosquitoes were fed NPC1161B 4 days after infection, we observed that total oocyst numbers were not affected by NPC1161B treatment. However, the sporozoite production capacity of the oocysts was impaired, and salivary gland sporozoite infections were completely blocked, rendering the mosquitoes non-infectious. Importantly, NPC1161B did not require prior liver metabolism for its efficacy as is required in mammalian systems, suggesting that an alternative metabolite is produced in the mosquito that is active against the parasite. We performed liquid chromatography-mass spectrometry (LC-MS)/MS analysis of methanol extracts from the midguts of mosquitoes fed on an NPC1161B (434.15 )-treated blood meal and identified a compound with a mass of 520.2 , likely a conjugate of NPC1161B or an oxidized metabolite. These findings establish NPC1161B, and potentially its metabolites, as transmission-blocking candidates for the treatment of .
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http://dx.doi.org/10.3389/fphar.2019.01265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823860PMC
October 2019

Design, synthesis and biological evaluation of 4-aminoquinoline-guanylthiourea derivatives as antimalarial agents.

Bioorg Chem 2019 10 2;91:103094. Epub 2019 Jul 2.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar 160062, Punjab, India. Electronic address:

Guanylthiourea (GTU) has been identified as an important antifolate antimalarial pharmacophore unit, whereas, 4-amino quinolones are already known for antimalarial activity. In the present work molecules carrying 4-aminoquinoline and GTU moiety have been designed using molecular docking analysis with PfDHFR enzyme and heme unit. The docking results indicated that the necessary interactions (Asp54 and Ile14) and docking score (-9.63 to -7.36 kcal/mmol) were comparable to WR99210 (-9.89 kcal/mol). From these results nine molecules were selected for synthesis. In vitro analysis of these synthesized compounds reveal that out of the nine molecules, eight show antimalarial activity in the range of 0.61-7.55 μM for PfD6 strain and 0.43-8.04 μM for PfW2 strain. Further, molecular dynamics simulations were performed on the most active molecule to establish comparative binding interactions of these compounds and reference ligand with Plasmodium falciparum dihydrofolate reductase (PfDHFR).
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http://dx.doi.org/10.1016/j.bioorg.2019.103094DOI Listing
October 2019

Hybridization of Fluoro-amodiaquine (FAQ) with Pyrimidines: Synthesis and Antimalarial Efficacy of FAQ-Pyrimidines.

ACS Med Chem Lett 2019 May 13;10(5):714-719. Epub 2019 Mar 13.

Department of Chemistry, University of Delhi, Delhi 110007, India.

To evade the possible toxicity associated with the formation of quinone-imine metabolite in amodiaquine (AQ), the -hydroxyl group was replaced with a -F atom, and the resulting 4'-fluoro-amodiaquine (FAQ) was hybridized with substituted pyrimidines. The synthesized FAQ-pyrimidines displayed better potency than chloroquine (CQ) against the resistant strain (Dd2), exhibiting up to 47.3-fold better activity (IC: 4.69 nM) than CQ (IC: 222 nM) and 2.8-fold better potency than artesunate (IC: 13.0 nM). Twelve compounds exhibited better antiplasmodial activity than CQ against the CQ-sensitive (NF54) strain. Two compounds were evaluated against a -mouse malaria model. Mechanistic heme-binding studies, computational docking studies against -DHFR and microsomal stability studies were performed for the representative molecules of the series to assess their antimalarial efficacy.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511959PMC
May 2019

Tetraazamacrocyclic derivatives and their metal complexes as antileishmanial leads.

Polyhedron 2019 May 23;163:42-53. Epub 2019 Feb 23.

Department of Pharmaceutical Sciences, College of Pharmacy, Southwestern Oklahoma State University. 100 Campus Drive, Weatherford, Ok 73096.

A total of 44 bis-aryl-monocyclic polyamines, monoaryl-monocyclic polyamines and their transition metal complexes were prepared, chemically characterized, and screened in vitro against the promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells. The IC and/or IC values showed that 10 compounds were similarly active at about 2-fold less potent than known drug pentamidine against promastigotes. The most potent compound had an IC of 2.82 μM (compared to 2.93 μM for pentamidine). Nine compounds were 1.1-13.6-fold more potent than pentamidine against axenic amastigotes, the most potent one being about 2-fold less potent than amphotericin B. Fourteen compounds were about 2-10 fold more potent than pentamidine, the most potent one is about 2-fold less potent than amphotericin B against intracellular amastigotes in THP1 cells. The 2 most promising compounds (FeCl and MnCl), with strong activity against both promastigotes and amastigotes and no observable toxicity against the THP1 cells are the Fe- and Mn- complexes of a dibenzyl cyclen derivative. Only 2 of the 44 compounds showed observable cytotoxicity against THP1 cells. Tetraazamacrocyclic monocyclic polyamines represent a new class of antileishmanial lead structures that warrant follow up studies.
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http://dx.doi.org/10.1016/j.poly.2019.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452907PMC
May 2019

Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from (Damiana).

Molecules 2019 Feb 23;24(4). Epub 2019 Feb 23.

National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA.

The investigation of the constituents that were isolated from (damiana) for their inhibitory activities against recombinant human monoamine oxidases (MAO-A and MAO-B) in vitro identified acacetin 7-methyl ether as a potent selective inhibitor of MAO-B (IC = 198 nM). Acacetin 7-methyl ether (also known as 5-hydroxy-4', 7-dimethoxyflavone) is a naturally occurring flavone that is present in many plants and vegetables. Acacetin 7-methyl ether was four-fold less potent as an inhibitor of MAO-B when compared to acacetin (IC = 50 nM). However, acacetin 7-methyl ether was >500-fold selective against MAO-B over MAO-A as compared to only two-fold selectivity shown by acacetin. Even though the IC for inhibition of MAO-B by acacetin 7-methyl ether was ~four-fold higher than that of the standard drug deprenyl (i.e., Selegiline or Zelapar, a selective MAO-B inhibitor), acacetin 7-methyl ether's selectivity for MAO-B over MAO-A inhibition was greater than that of deprenyl (>500- vs. 450-fold). The binding of acacetin 7-methyl ether to MAO-B was reversible and time-independent, as revealed by enzyme-inhibitor complex equilibrium dialysis assays. The investigation on the enzyme inhibition-kinetics analysis with varying concentrations of acacetin 7-methyl ether and the substrate (kynuramine) suggested a competitive mechanism of inhibition of MAO-B by acacetin 7-methyl ether with Ki value of 45 nM. The docking scores and binding-free energies of acacetin 7-methyl ether to the X-ray crystal structures of MAO-A and MAO-B confirmed the selectivity of binding of this molecule to MAO-B over MAO-A. In addition, molecular dynamics results also revealed that acacetin 7-methyl ether formed a stable and strong complex with MAO-B. The selective inhibition of MAO-B suggests further investigations on acacetin 7-methyl as a potential new drug lead for the treatment of neurodegenerative disorders, including Parkinson's disease.
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http://dx.doi.org/10.3390/molecules24040810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412401PMC
February 2019

Antiplasmodial and Cytotoxic Cytochalasins from an Endophytic Fungus, sp. UM10M, Isolated from a Diseased Leaf.

Molecules 2019 Feb 21;24(4). Epub 2019 Feb 21.

National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA.

Bioassay-guided fractionation of an EtOAc extract of the broth of the endophytic fungus sp. UM10M (Xylariaceae) isolated from a diseased leaf afforded three known cytochalasins, 19,20-epoxycytochalasins C () and D (), and 18-deoxy-19,20-epoxy-cytochalasin C (). All three compounds showed potent in vitro antiplasmodial activity and phytotoxicity with no cytotoxicity to Vero cells. These compounds exhibited moderate to weak cytotoxicity to some of the cell lines of a panel of solid tumor (SK-MEL, KB, BT-549, and SK-OV-3) and kidney epithelial cells (LLC-PK). Evaluation of in vivo antimalarial activity of 19,20-epoxycytochalasin C () in a mouse model at 100 mg/kg dose showed that this compound had weak suppressive antiplasmodial activity and was toxic to animals.
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http://dx.doi.org/10.3390/molecules24040777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413121PMC
February 2019

Formation primaquine-5,6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes.

Malar J 2019 Jan 30;18(1):30. Epub 2019 Jan 30.

The National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.

Background: The activity and haemolytic toxicity associated with primaquine has been linked to its reactive metabolites. The reactive metabolites are thought to be primarily formed through the action of cytochrome P-mediated pathways. Human erythrocytes generally are not considered a significant contributor to drug biotransformation. As erythrocytes are the target of primaquine toxicity, the ability of erythrocytes to mediate the formation of reactive oxidative primaquine metabolites in the absence of hepatic enzymes, was evaluated.

Methods: Primaquine and its enantiomers were incubated separately with human red blood cells and haemoglobin. Post-incubation analysis was performed with UPLC-MS/MS to identify products of biotransformation.

Results: The major metabolite detected was identified as primaquine-5,6-orthoquinone, reflecting the pathway yielding putative active and haematotoxic metabolites of primaquine, which was formed by oxidative demethylation of 5-hydroxyprimaquine. Incubation of primaquine with haemoglobin in a cell-free system yielded similar results. It appears that the observed biotransformation is due to non-enzymatic processes, perhaps due to reactive oxygen species (ROS) present in erythrocytes or in the haemoglobin incubates.

Conclusion: This study presents new evidence that primaquine-5,6-orthoquinone, the metabolite of primaquine reflecting the oxidative biotransformation pathway, is generated in erythrocytes, probably by non-enzymatic means, and may not require transport from the liver or other tissues.
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http://dx.doi.org/10.1186/s12936-019-2658-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352325PMC
January 2019

Evaluation of Triazole and Isoxazole Derivatives as Potential Anti-infective Agents.

Med Chem Res 2018 Apr 27;27(4):1269-1275. Epub 2018 Feb 27.

Department of BioMolecular Sciences, University of Mississippi, University, MS 38677, USA.

A series of isoxazole and triazole derivatives, with interesting bioactive scaffolds, were examined for their antibacterial, antifungal, and antiprotozoal activities. These compounds exhibited antitrypanosomal activity comparable to difluoromethylornithine (DMFO), a drug used in the treatment of human African trypanosomiasis. Isoxazole analogues , and , and triazole derivatives , , , , and showed the highest antitrypanosomal activity with IC values of 17.89, 1.82, 10.38, 10.26, 11.77, 9.29, 3.93, 2.11, and 0.93 μM, respectively. Compounds and showed the most potent activity against amastigotes with IC values of 18.28 and 10.54 μM, respectively. Compound showed the most potent activity against macrophage internalized amastigotes with an IC value of 8.32 μM. Conjugate triazoles displayed potential antimalarial activity against chloroquine-resistant W2 and chloroquine sensitive D6 strains (IC value range from 0.58 to 8.36 μM). Compound showed antibacterial activity against , MRSA and with IC values of 15.53, 14.22 and 47.45 μM, respectively. None of the compounds exhibited antifungal activity.
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http://dx.doi.org/10.1007/s00044-018-2146-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203334PMC
April 2018

Metabolism of primaquine in normal human volunteers: investigation of phase I and phase II metabolites from plasma and urine using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry.

Malar J 2018 Aug 13;17(1):294. Epub 2018 Aug 13.

National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.

Background: Primaquine (PQ), an 8-aminoquinoline, is the only drug approved by the United States Food and Drug Administration for radical cure and prevention of relapse in Plasmodium vivax infections. Knowledge of the metabolism of PQ is critical for understanding the therapeutic efficacy and hemolytic toxicity of this drug. Recent in vitro studies with primary human hepatocytes have been useful for developing the ultra high-performance liquid chromatography coupled with high-resolution mass spectrometric (UHPLC-QToF-MS) methods for simultaneous determination of PQ and its metabolites generated through phase I and phase II pathways for drug metabolism.

Methods: These methods were further optimized and applied for phenotyping PQ metabolites from plasma and urine from healthy human volunteers treated with single 45 mg dose of PQ. Identity of the metabolites was predicted by MetaboLynx using LC-MS/MS fragmentation patterns. Selected metabolites were confirmed with appropriate standards.

Results: Besides PQ and carboxy PQ (cPQ), the major plasma metabolite, thirty-four additional metabolites were identified in human plasma and urine. Based on these metabolites, PQ is viewed as metabolized in humans via three pathways. Pathway 1 involves direct glucuronide/glucose/carbamate/acetate conjugation of PQ. Pathway 2 involves hydroxylation (likely cytochrome P450-mediated) at different positions on the quinoline ring, with mono-, di-, or even tri-hydroxylations possible, and subsequent glucuronide conjugation of the hydroxylated metabolites. Pathway 3 involves the monoamine oxidase catalyzed oxidative deamination of PQ resulting in formation of PQ-aldehyde, PQ alcohol and cPQ, which are further metabolized through additional phase I hydroxylations and/or phase II glucuronide conjugations.

Conclusion: This approach and these findings augment our understanding and provide comprehensive view of pathways for PQ metabolism in humans. These will advance the clinical studies of PQ metabolism in different populations for different therapeutic regimens and an understanding of the role these play in PQ efficacy and safety outcomes, and their possible relation to metabolizing enzyme polymorphisms.
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http://dx.doi.org/10.1186/s12936-018-2433-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090659PMC
August 2018

Synthesis and Biological Evaluation of 8-Quinolinamines and Their Amino Acid Conjugates as Broad-Spectrum Anti-infectives.

ACS Omega 2018 Mar 14;3(3):3060-3075. Epub 2018 Mar 14.

Department of Medicinal Chemistry and Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.

In the search of therapeutic agents for emerging drug-resistant parasites, the synthesis of newer classes of 8-quinolinamines has emerged as a successful chemotherapeutic approach. We report synthesis of 8-quinolinamines bearing 5-alkoxy, 4-methyl, and 2--butyl groups in the quinoline framework and their amino acid conjugates as broad-spectrum anti-infectives. 8-Quinolinamines exhibited potent in vitro antimalarial activity [IC = 20-4760 ng/mL (drug-sensitive D6 strain) and IC = 22-4760 ng/mL (drug-resistant W2 strain)]. The most promising analogues have cured all animals at 25 mg/kg/day against drug-sensitive and at 50 mg/kg/day against multidrug-resistant infections in Swiss mice. The in vitro antileishmanial activities (IC = 0.84-5.0 μg/mL and IC = 1.95-7.0 μg/mL) comparable to standard drug pentamidine were exhibited by several of the synthesized 8-quinolinamines. At the same time, very promising antifungal activities (-IC = 4.93-19.38 μg/mL; -IC = 3.96-19.22 μg/mL; -IC = 2.89-18.95 μg/mL; -IC = 0.67-18.64 μg/mL; and -IC = 6.0-19.32 μg/mL) and antibacterial activities (-IC = 1.33-18.9 μg/mL; methicillin-resistant -IC = 1.38-15.34 μg/mL; and -IC = 3.12-20 μg/mL) were also observed. None of the 8-quinolinamines exhibited cytotoxicity and therefore are a promising structural class of compounds as antiparasitic and antimicrobials.
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http://dx.doi.org/10.1021/acsomega.7b02047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045484PMC
March 2018

Interactions of endocannabinoid virodhamine and related analogs with human monoamine oxidase-A and -B.

Biochem Pharmacol 2018 09 26;155:82-91. Epub 2018 Jun 26.

Department of BioMolecular Sciences and National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, United States; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, United States. Electronic address:

The endocannabinoid system plays an important role in the pathophysiology of various neurological disorders, such as anxiety, depression, neurodegenerative diseases, and schizophrenia; however, little information is available on the coupling of the endocannabinoid system with the monoaminergic systems in the brain. In the present study, we tested four endocannabinoids and two anandamide analogs for inhibition of recombinant human MAO-A and -B (monoamine oxidase). Virodhamine inhibited both MAO-A and -B (IC values of 38.70 and 0.71 μM, respectively) with ∼55-fold greater inhibition of MAO-B. Two other endocannabinoids (noladin ether and anandamide) also showed good inhibition of MAO-B with IC values of 18.18 and 39.98 μM, respectively. Virodhamine was further evaluated for kinetic characteristics and mechanism of inhibition of human MAO-B. Virodhamine inhibited MAO-B (K value of 0.258 ± 0.037 μM) through a mixed mechanism/irreversible binding and showed a time-dependent irreversible mechanism. Treatment of Neuroscreen-1 (NS-1) cells with virodhamine produced significant inhibition of MAO activity. This observation confirms potential uptake of virodhamine by neuronal cells. A molecular modeling study of virodhamine with MAO-B and its cofactor flavin adenine dinucleotide (FAD) predicted virodhamine's terminal -NH group to be positioned near the N5 position of FAD, but for docking to MAO-A, virodhamine's terminal -NH group was far away (∼6.52 Å) from the N5 position of FAD, and encountered bad contacts with nearby water molecules. This difference could explain virodhamine's higher potency and preference for MAO-B. The binding free energies for the computationally-predicted poses also showed that virodhamine was selective for MAO-B. These findings suggest potential therapeutic applications of virodhamine for the treatment of neurological disorders.
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http://dx.doi.org/10.1016/j.bcp.2018.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298601PMC
September 2018

Sequential Elution of Essential Oil Constituents during Steam Distillation of Hops (Humulus lupulus L.) and Influence on Oil Yield and Antimicrobial Activity.

J Oleo Sci 2018 Jul 7;67(7):871-883. Epub 2018 Jun 7.

National Center for Natural Products Research & Department of Pharmacology, School of Pharmacy, University of Mississippi.

The profile and bioactivity of hops (Humulus lupulus L.) essential oil, a complex natural product extracted from cones via steam distillation, depends on genetic and environmental factors, and may also depend on extraction process. We hypothesized that compound mixtures eluted sequentially and captured at different timeframes during the steam distillation process of whole hop cones would have differential chemical and bioactivity profiles. The essential oil was collected sequentially at 8 distillation time (DT) intervals: 0-2, 2-5, 5-10, 10-30, 30-60, 60-120, 120-180, and 180-240 min. The control was a 4-h non-interrupted distillation. Nonlinear regression models described the DT and essential oil compounds relationship. Fractions yielded 0.035 to 0.313% essential oil, while control yielded 1.47%. The oil eluted during the first hour was 83.2%, 9.6% during the second hour, and only 7.2% during the second half of the distillation. Essential oil (EO) fractions had different chemical profile. Monoterpenes were eluted early, while sequiterpenes were eluted late. Myrcene and linalool were the highest in 0-2 min fraction, β-caryophyllene, β-copaene, β-farnesene, and α-humulene were highest in fractions from middle of distillation, whereas α- bergamotene, γ-muurolene, β- and α-selinene, γ- and δ-cadinene, caryophyllene oxide, humulne epoxide II, τ-cadinol, and 6-pentadecen-2-one were highest in 120-180 or 180-240 min fractions. The Gram-negative Escherichia coli was strongly inhibited by essential oil fractions from 2-5 min and 10-30 min, followed by oil fraction from 0-2 min. The strongest inhibition activity against Gram-negative Yersinia enterocolitica, and Gram-positive Clostridium perfringens, Enterococcus faecalis, and Staphylococcus aureus subs. aureus was observed with the control essential oil. This is the first study to describe significant activity of hops essential oils against Trypanosoma brucei, a parasitic protozoan that causes African trypanosomiasis (sleeping sickness in humans and nagana in other animals). Hops essential oil fractions or whole oil may be used as antimicrobial agents or for the development of new drugs.
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http://dx.doi.org/10.5650/jos.ess17216DOI Listing
July 2018

Isoform selectivity of harmine-conjugated 1,2,3-triazoles against human monoamine oxidase.

Future Med Chem 2018 06 23;10(12):1435-1448. Epub 2018 May 23.

National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, MS 38677, USA.

Aim: There is little information available on the monoamine oxidase isoform selectivity of N-alkyl harmine analogs, which exhibit a myriad of activities including MAO-A, DYRK1A and cytotoxicity to several select cancer cell lines.

Results: Compounds 3e and 4c exhibited an IC of 0.83 ± 0.03 and 0.43 ± 0.002 μM against MAO-A and an IC of 0.26 ± 0.04 and 0.36 ± 0.001 μM against MAO-B, respectively. Molecular docking studies revealed π-π interactions between the synthesized molecules and aromatic amino acid residues. Conclusion & future perspective: The current study delineates the structural requirements for MAO-A selectivity and such information may be helpful in designing selective analogs for kinase, DYRK1A and harmine-based cytotoxics without apparent MAO enzyme inhibition.
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http://dx.doi.org/10.4155/fmc-2018-0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021913PMC
June 2018

Isolation and Biological Evaluation of Prenylated Flavonoids from .

Evid Based Complement Alternat Med 2018 14;2018:1370368. Epub 2018 Jan 14.

National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA.

Phytochemical analysis of the ethanolic extract of fruits yielded four new compounds (-) along with eleven known compounds (-). The crude extract exhibited significant activity towards cannabinoid receptors (CB1: 103.4% displacement; CB2: 68.8% displacement) and possibly allosteric interaction with and opioid receptors (-49.7 and -53.8% displacement, resp.). Compound was found to be possibly allosteric for and opioid receptors (-88.4 and -27.2% displacement, resp.) and showed moderate activity (60.5% displacement) towards CB1 receptor. Compound exhibited moderate activity towards cannabinoid receptors CB1 and CB2 (47.9 and 42.3% displacement, resp.). The known compounds (-) exhibited prominent activity towards cannabinoid receptors: pomiferin () (IC of 2.110 and 1.318 M for CB1 and CB2, resp.), auriculasin () (IC of 8.923 M for CB1), warangalone () (IC of 1.670 and 4.438 M for CB1 and CB2, resp.), and osajin () (IC of 3.859 and 7.646 M for CB1 and CB2, resp.). The isolated compounds were also tested for inhibition of human monoamine oxidase-A and monoamine oxidase-B enzymes activities, where all the tested compounds showed fewer inhibitory effects on MAO-A compared to MAO-B activities: auriculasin () (IC of 1.91 and 45.98 M for MAO-B and MAO-A, resp.).
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http://dx.doi.org/10.1155/2018/1370368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820588PMC
January 2018

Inhibition of human monoamine oxidase A and B by flavonoids isolated from two Algerian medicinal plants.

Phytomedicine 2018 Feb 27;40:27-36. Epub 2017 Dec 27.

Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, United States.

Background: Monoamine oxidases (MAOs) are outer mitochondrial membrane flavoenzymes. They catalyze the oxidative deamination of a variety of neurotransmitters. MAO-A and MAO-B may be considered as targets for inhibitors to treat neurodegenerative diseases and depression and for managing symptoms associated with Parkinson's and Alzheimer's diseases.

Purpose: The objective was to evaluate the inhibitory effect of Hypericum afrum and Cytisus villosus against MAO-A and B and to isolate the compounds responsible for the MAO-inhibitory activity.

Methods: The inhibitory effect of extracts and purified constituents of H. afrum and C. villosus were investigated in vitro using recombinant human MAO-A and B, and through bioassay-guided fractionation of ethyl acetate fractions of areal parts of the two plants collected in northeastern Algeria. In addition, computational protein-ligand docking and molecular dynamics simulations were carried out to explain the MAO binding at the molecular level.

Results: The ethyl acetate (EtOAc) fractions of H. afrum and C. villosus showed the highest MAO inhibition activity against MAO A and B with IC values of 3.37 µg/ml and 13.50 µg/ml as well as 5.62 and 1.87 µg/ml, respectively. Bioassay-guided fractionation of the EtOAc fractions resulted in the purification and identification of the known flavonoids quercetin, myricetin, genistein and chrysin as the principal MAO-inhibitory constituents. Their structures were established by extensive 1 and 2D NMR studies and mass spectrometry. Quercetin, myricetin and chrysin showed potent inhibitory activity towards MAO-A with IC values of 1.52, 9.93 and 0.25 µM, respectively, while genistein more efficiently inhibited MAO-B (IC value: 0.65 µM). The kinetics of the inhibition and the study of dialysis dissociation of the complex of quercetin and myricetin and the isoenzyme MAO-A showed competitive and mixed inhibition, respectively. Both compounds showed reversible binding. Molecular docking experiments and molecular dynamics simulations allowed to estimate the binding poses and to identify the most important residues involved in the selective recognition of molecules in the MAOs enzymatic clefts.

Conclusion: Quercetin and myricetin isolated from H. afrum together with genistein and chrysin isolated from C. villosus have been identified as potent MAO-A and -B inhibitors. H. afrum and C. villosus have properties indicative of potential neuroprotective ability and may be new candidates for selective MAO-A and B inhibitors.
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http://dx.doi.org/10.1016/j.phymed.2017.12.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947877PMC
February 2018

Design, Synthesis and Biological Evaluation of 7-arylbenzo[c]acridine-5,6- diones as Potential Anti-Leishmanial and anti-trypanosomal Agents.

Med Chem 2018 ;14(6):563-572

Department of Natural Products, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar (Mohali) 160062, Punjab, India.

Background: Leishmaniasis is endemic in 98 countries and is closely associated with poverty. On the basis of current evidence, it may be safely suggested that over time Leishmania spp. have evolved coexistence in different macrophage types and developed adaptations in order to ensure their intracellular survival. Considering new drugs, the need of the hour the present study deals with the synthesis of novel compounds of biological importance based on naturally occurring scaffolds.

Objective: Synthesis, anti-leishmanial and anti-trypanosomal activities of a series of thirty three (eighteen newly synthesized and fifteen previously reported) 7-arylbenzo[c]acridine-5,6-diones.

Method: A series of thirty-three 7-arylbenzo[c]acridine-5,6-diones was designed and synthesized. The anti-leishmanial and anti-trypanosomal activities of the newly synthesized compounds were done.

Results: Seven compounds (14, 17, 19, 26, 27, 38 and 39) were found to exhibit excellent antiparasitic activities. Compound 14 was identified as the most potent compound against L. donovani promastigotes while compound 27 showed most significant inhibition activity against amastigotes. Compounds 14 and 27 showed remarkable inhibitory activity with IC50 values of 0.38 and 0.53 µM, respectively, when tested in human macrophage cell line (THP) infected with L. donovani amastigotes. Against trypanomastigotes, six compounds (15, 17, 19, 25, 26 and 43) demonstrated remarkable inhibition.

Conclusion: Compound 19 was found to be the best anti-trypanosomal agent and showed 300-fold superior inhibitory activity to that of the standard drug DFMO. Significant anti-leishmanial and anti-trypanosomal activities combined with the non-cytotoxic profile presents 7-arylbenzo[c]acridine- 5,6-diones as new candidates with therapeutic potential in the treatment of parasitic diseases.
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http://dx.doi.org/10.2174/1573406414666180226163222DOI Listing
September 2018
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