Publications by authors named "Francisco Franco-Montalban"

7 Publications

  • Page 1 of 1

Synthesis, bioevaluation and docking studies of new imidamide derivatives as nitric oxide synthase inhibitors.

Bioorg Med Chem 2021 Aug 28;44:116294. Epub 2021 Jun 28.

Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Spain. Electronic address:

In search of new Nitric Oxide Synthase (NOS) inhibitor agents, two isosteric series of derivatives with an imidamide scaffold (one of them with a hydroxyl group and the other with a carbonyl one) were synthesized and evaluated on inducible (iNOS) and neuronal (nNOS) isoforms. These compounds have been designed by combining a kynurenamine framework with an amidine moiety in order to improve selectivity for the inducible isoform. In general, the in vitro inhibitory assays exhibited better inhibition values on the iNOS isoform, being the N-(3-(2-amino-5-methoxyphenyl)-3-hydroxypropyl)-4-(trifluoromethyl)benzimidamide 4i the most active inhibitor with the highest iNOS selectivity, without inhibiting eNOS. Docking studies on the two most active compounds suggest a different binding mode on both isozymes, supporting the experimentally observed selectivity towards the inducible isoform. Physicochemical in silico studies suggest that these compounds possess good drug-likeness properties.
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http://dx.doi.org/10.1016/j.bmc.2021.116294DOI Listing
August 2021

-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity.

J Med Chem 2020 06 26;63(11):5734-5751. Epub 2020 May 26.

Departamento de Quı́mica Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja, 18071 Granada, Spain.

() causes visceral, cutaneous, and mucosal leishmaniasis in humans and canine leishmaniasis in dogs. Herein, we describe that -alkyl hydroxamate derivatives displayed potent and selective activity against the amastigote stage of while no activity was observed against promastigotes. Compound showed potent activity against . Moreover, the combination of compound supported on gold nanoparticles and meglumine antimoniate was also effective and improved the activity of these compounds compared to that of the individual treatment. Docking studies showed that compound did not reach highly conserved pocket C and established interactions with the semiconserved residues V44, A45, R242, and E243 in pocket A of LiSIR2rp1. The surface space determined by these four amino acids is not conserved in human sirtuins. Compound represents a new class of selective ligands with antileishmanial activity.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02016DOI Listing
June 2020

Synthesis and Characterization of a Click-Assembled 18-Atom Macrocycle That Displays Selective AXL Kinase Inhibitory Activity.

ACS Omega 2019 Dec 3;4(25):21620-21626. Epub 2019 Dec 3.

Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, U.K.

A novel macrocyclic construct consisting of a pyrazolopyrimidine scaffold concatenated to a benzene ring through two triazoles has been developed to investigate uncharted chemical space with bioactive potential. The 18-atom macrocycle was assembled via a double copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction between 1,3-bis(azidomethyl)benzene and a bis-propargylated pyrazolo[3,4-]pyrimidine core. The resulting macrocycle was functionalized further into a multicyclic analog that displays selective inhibitory activity against the receptor tyrosine kinase AXL.
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http://dx.doi.org/10.1021/acsomega.9b03525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921642PMC
December 2019

NMR studies of pyrimidinic nucleosides derived from 2,3-dideoxy-d-ribose with inhibitory activity on LINE-1 mobility.

Magn Reson Chem 2020 01 13;58(1):118-125. Epub 2019 Nov 13.

Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, Granada, Spain.

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http://dx.doi.org/10.1002/mrc.4942DOI Listing
January 2020

Synthesis and Characterization of Specific Reverse Transcriptase Inhibitors for Mammalian LINE-1 Retrotransposons.

Cell Chem Biol 2019 08 30;26(8):1095-1109.e14. Epub 2019 May 30.

GENYO. Centro de Genómica e Investigación Oncológica: Pfizer-Universidad de Granada-Junta de Andalucía, Avenida de la Ilustración 114, PTS Granada, 18016 Granada, Spain; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. Electronic address:

Retrotransposons are a type of transposable element (TE) that have amplified to astonishing numbers in mammalian genomes, comprising more than a third of the human and mouse genomes. Long interspersed element class 1 (LINE-1 or L1) retrotransposons are abundant and currently active retroelements in the human and mouse genomes. Similarly, long terminal repeat (LTR)-containing retrotransposons are abundant in both genomes, although only active in mice. LTR- and LINE-1-retroelements use different mechanisms for retrotransposition, although both involve the reverse transcription of an intermediate retroelement-derived RNA. Retrotransposon activity continues to effect the germline and somatic genomes, generating interindividual variability over evolution and potentially influencing cancer and brain physiology, respectively. However, relatively little is known about the functional consequences of retrotransposition. In this study, we have synthesized and characterized reverse transcriptase inhibitors specific for mammalian LINE-1 retrotransposons, which might help deciphering the functional impact of retrotransposition in vivo.
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http://dx.doi.org/10.1016/j.chembiol.2019.04.010DOI Listing
August 2019

A nanodelivered Vorinostat derivative is a promising oral compound for the treatment of visceral leishmaniasis.

Pharmacol Res 2019 01 29;139:375-383. Epub 2018 Nov 29.

Departamento de Parasitología, Universidad de Granada, Campus de Cartuja sn, 18011, Granada, Spain. Electronic address:

There is currently no satisfactory treatment for visceral leishmaniasis; the disease is thus in desperate need of novel drugs. The ideal candidate should be effective, safe, affordable, and administered via the oral route. Histone deacetylases (HDACs) are involved in silencing critical regulatory pathways, including pro-apoptotic programs, and represent potential therapeutic targets for pharmacological interventions. O-alkyl hydroxamates have traditionally been considered to exert no effect on mammal HDACs. The aim of this study was to evaluate the effect of MDG, a SAHA derivative of the O-alkyl hydroxamate family with no activity on human histone deacetylase enzymes, on the visceral leishmaniasis causative agents and in a murine model of the disease. The effects of vorinostat, tubacin and valproic acid (well-known mammal HDAC inhibitors) on the parasite were also evaluated. MDG was found to be highly active against Leishmania infantum and L. donovani intracellular amastigotes in vitro but not against the promastigote stage. In contrast, vorinostat, tubacin and valproic acid showed no activity against the parasite. Assays investigating hERG and Cav1.2 channels in vitro found no evidence of MDG-driven cardiotoxicity. MDG showed neither hepatotoxicity nor mutagenicity, nor did it exert activity on cytochrome P450 enzymes. MDG was adsorbed onto gold nanoparticles for the in vivo experiments, performed on infected Balb/c mice. MDG was effective at reducing the parasite load in major target tissues (bone marrow, spleen and liver) in more than 70% at 25 mg/kg through both the oral and intraperitoneal route, proving more active than the reference compounds (meglumine antimoniate, MA) without showing toxicity. In addition, the combination of MDG and MA was very effective.
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http://dx.doi.org/10.1016/j.phrs.2018.11.039DOI Listing
January 2019

Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1.

J Med Chem 2018 08 6;61(16):7144-7167. Epub 2018 Aug 6.

Departamento de Química Farmacéutica y Orgánica , Universidad de Granada , Campus de Cartuja s/n , 18071 Granada , Spain.

Primary hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease related to glyoxylate metabolism and characterized by accumulation of calcium oxalate crystals. Current therapies involve hepatic and/or renal transplantation, procedures that have significant morbidity and mortality and require long-term immunosuppression. Thus, a pharmacological treatment is urgently needed. We introduce here an unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range, which means a potential use in the treatment of PH1. Though correlation of this phenotypic activity with glycolate oxidase (GO) inhibition is still to be verified, most of the salicylic acids described here are GO inhibitors with IC values down to 3 μM. Binding mode of salicylic acids inside GO has been studied using in silico methods, and preliminary structure-activity relationships have been established. The drug-like structure and ease of synthesis of our compounds make them promising hits for structural optimization.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00399DOI Listing
August 2018
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