Marcos C. de Souza

Synthesis and Antileishmanial Activity of New 1-Aryl-1H-Pyrazole-4- Carboximidamides Derivatives

Chemotherapy for leishmaniasis, diseases caused by protozoa of the genus Leishmania, remains inefficient in several treatments. So there is a need to search for new drugs. In this work, we have synthesized 1-aryl-1H-pyrazole-4-carboximidamides derivatives and evaluated antileishmanial activities in vitro, as well as cytotoxic effects. Structure-activity relationship (SAR) studies were carried out with all the compounds of the series. Compound 2 showed an activity profile that can be improved through medicinal chemistry strategies.

Porphyrin)Phosphoramidate Conjugates: Synthesis, Photostability and Singlet Oxygen Generation

meso-Tetrakis(pentafluorophenyl)porphyrin reacts with aminoalkylphosphoramidates to afford porphyrins substituted with one or four phosphoramidate groups in the 4-position of the meso-aryl groups. The new porphyrin derivatives show high photostability and some are better singlet oxygen generators than meso-tetrakis(1-methylpyridinium-4-yl)porphyrin, a well known good singlet oxygen producer.

From porphyrin benzylphosphoramidate conjugates to the catalytic hydrogenation of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin.

Summary Three new porphyrin aminoalkyl dibenzylphosphoramidates were synthesized by nucleophilic aromatic substitution of one p-fluorine atom of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TPPF 20) by primary aminoalkyl dibenzylphosphoramidates. The nucleophilic aromatic substitution was promoted by microwave irradiation in N-methyl-2-pyrrolidinone. Attempts to remove the benzyl groups of the phosphoramidate moiety by hydrogenolysis with 10% Pd/C led to the cleavage of the P–N bond and the reduction of the macrocycle to hydroporphyrin-type derivatives. The extent of the effect of the catalytic hydrogenation to TPPF 20 with 10% Pd/C was then studied with a variety of solvents. The results showed that ethanol/DMF is the solvent of choice to produce chlorin TPCF 20 and an ethanol/DMF/NEt3 mixture is more adequate to produce isobacteriochlorin (TPIF 20).

Principais métodos de síntese de amidinas

The amidine functional group is found in a wide range of natural products and is biologically active against several pathogens. In addition, amidines have long been regarded as useful intermediates in the synthesis of heterocyclic compounds. Consequently, a great number of methods have been developed for the preparation of amidines. Pinners method is the most commonly used. Conventional methods include: - the addition of metal amides or amines to nitriles, the addition of amines to imido esters and the condensation of amides with amines in the presence of halogenating reagents. In this report, the main methods for synthesis of amidines will be described.

ONE-POT SYNTHESIS OF N-ALKYL SUBSTITUTED PHOSPHORYL GUANIDINES

This article describes an attractive and one-pot synthesis of the title compound by phosphorylation of just prepared N-substituted guanidines from cyanamide and the desired amine. The method allows a variety of N-substituents to hang on the final phosphoryl guanidine as a function of the wider availability of commercial simple amines.

Selective Monophosphorylation of Aliphatic Diamines

This article describes an improved method to synthesize phosphoramidic acid aminoalkyl esters from diamines by the adaptation of industrial patents. Four mono-phosphorylated products having amino sites were obtained in good a yield. Such compounds have potential coordination properties with transition metals and also potential biological activity.

Synthesis and Anti-HSV-1 In Vitro Activity of New Phosphoramidates with 4-oxoquinoline and Phtalimidic Nuclei

Abstract: Aminoalkyl phosphoramidates were obtained by either direct phosphorylation of symmetric diamines or a three steps method analogue to Gabriel’s synthesis and coupled to a 4-oxoquinoline acyclonucleoside, in order to synthesize 4-oxoquinolone phosphoramidates. Two unpublished compounds demonstrated low cytotoxity in comparison to Acyclovir and good HSV-1 cytophatic effects on Acyclovir resistant strains. Keywords: Aminoalkyl phosphoramidates, 4-oxoquinoline acyclonucleoside, nucleotide analogues, Herpes Simplex Virus type 1 (HSV-1). 1. INTRODUCTION Herpes Simplex Virus type 1 (HSV-1) is a large, envel-oped DNA containing virus with a genome of approximately 152 kb. In humans infection usually begins on the skin or mucosal epithelium and subsequently spreads to the sensory ganglia whose nerve processes contact the primary site of infection. Once inside these neurons the virus can enter a dormant state characterized by the absence of lytic gene tran-scription [1]. Periodic reactivation of the dormant virus can lead to the development of infective and painful facial le-sions. Acyclovir (ACV) is used clinically as an anti-herpes drug. However, with increasing use of antiviral drugs there is an increased risk that resistant strains may develop. The her-pes viruses, for example, have been shown to acquire resis-tance to ACV in immunocompromised patients [2]. The de-velopment of new antivirals that have a wide range of effi-cacy against pre-existing and resistant strains, but that lack serious adverse effects, would clearly be advantageous. However, only a few compounds have reached prominence at the clinical level so far. A large number of compounds within the group of acyclic nucleosides demonstrate antiviral activity [3-7] and as such have prompted recent research in-terest due to their clinical potential. Most current anti-herpes drugs are inactive until phosphorylated by viral timidine kinase (TK) inside the target cell so that viruses lacking TK are at an advantage. Phosphorylated nucleoside analogues lack the ability to cross the plasma membrane due to the high anionic charge of the phosphate groups. This unsuitability for therapeutic use is compounded by the action of non-specific stearases in the cytoplasm which cleave and render them inactive [8-9]. To overcome these obstacles phosphonates have been developed

Synthesis of New Conjugates 1H-Pyrazolo[3,4-b]pyridine-phosphoramidate and Evaluation against Leishmania amazonensis

In this research three series of substituted 1H-pyrazolo[3,4-b]pyridine phosphoramidates were synthesized and characterized by infrared, H, C, and P nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry. The products were obtained in good yields (67-83%) under mild conditions by nucleophilic aromatic substitution reaction of aminoalkylphosphoramidates over 4-chloro-1H-pyrazolo[3,4-b]pyridines. These compounds were evaluated as antileishmanials against Leishmania amazonensis promastigotes in vitro. Among all, compounds of a series showed expressive antileishmanial activity. Two of them emerged as the most active, with IC50 values of 6.44 ± 1.49 and 12.25 ± 0.68 μM. The cytotoxicity of this series was assessed on murine cells and presented values similar to the reference drug pentamidine.

Synthesis, Crystal Structures, and in Silico Toxicity Prediction of Thienopyridine Phosphoramidates

Abstract New thieno[2,3-b]pyridine phosphoramidates compounds were synthesized and characterized by infrared; 1H, 13C, and 31P NMR spectroscopy; and high-resolution mass spectrometry. The products were obtained in good yields (64–82%) under mild conditions by nucleophilic aromatic substitution reaction of aminoalkylphosphoramidates over 4-chlorothieno[2,3-b]pyridine-5-carbonitrile. The crystal structures of two compounds were solved by x-ray diffraction and showed a network of intermolecular interactions involving phosphoramidate groups. Druglike properties and toxicity of the new compounds were studied with the help of the software Molinspiration, Osiris, and Toxtree, and were compared with the standard drugs amphotericin B, miltefosine, benznidazole, and nifurtimox. [Supplementary materials are available for this article. Go to the publishers online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT

NEW SYMMETRIC DIISOPROPYLPHOSPHORYL-S-ALKANEDI YLDIISOTHIOUREAS. INVESTIGATIONS ON THEIR SYNTHESIS

Abstract Symmetric dialkylphosphoryl-S-alkanediyldiisothiouas (RO)2P(O)NHC(=NH)S(CH2)n SC(=NH)NHP(O)(OR)2 (I, R = isopropyl; n = 2–5) have potential coordination sites involving O, P, N and S as donors atoms. For their synthesis, common two-phase reactions between the corresponding diisothiourea derivatives and diisopropyi phosphonate were unsuccessful. Herein we describe a new synthesis for such compounds using diisopropyl chlorophosphonate. Two new bis-phosphorylated alkanediyldiisothioureas with increasing carbon chain (I; n = 3, n = 5) were prepared by this method.