Juan B. Rodriguez

Synthesis of cyclopropane-fused dideoxycarbocyclic nucleosides structurally related to neplanocin C

Abstract The syntheses of five novel carbocyclic dideoxynucleosides with a bicyclo[3.1.0]hexane skeleton was accomplished via a Mitsunobu-type coupling reaction with various heterocyclic bases. These compounds appear to prefer a typical nucleoside northern conformation.

New progresses in the enantioselective synthesis and biological properties of carbocyclic nucleosides.

The recent advances in the chemistry of carbocyclic nucleosides focused on different synthetic approaches that lead to optically pure products as well as a comprehensive overview of their biological properties are discussed. In the latter aspect, molecular recognition of enzymes of pharmacological importance such as: reverse transcriptase, adenosine deaminase, thymidine kinase, DNA cytosine-C5 methyl transferase, S-adenosylhomocysteine hydrolase, etc are considered. The role of conformation and puckering of the glycon moiety in modulating the biological activity and also the use of carbanucleosides as building blocks to prepare oligonucleotides are carefully illustrated.

Bisphosphonates derived from fatty acids are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase.

Studies on the mode of action of a series of bisphosphonates derived from fatty acids, which had previously proved to be potent inhibitors against Trypanosoma cruzi proliferation in in vitro assays, have been performed. Some of these drugs proved to be potent inhibitors against the intracellular form of the parasite, exhibiting IC(50) values at the low micromolar level. As bisphosphonates are FDA clinically approved for treatment of bone resorption disorders, their potential innocuousness makes them good candidates to control tropical diseases.

New antibacterials for the treatment of toxoplasmosis; a patent review

Introduction : Toxoplasma gondii is an opportunistic protozoan parasite responsible for toxoplasmosis. T. gondii is able to infect a wide range of hosts, particularly humans and warm-blooded animals. Toxoplasmosis can be considered as one of the most prevalent parasitic diseases affecting close to one billion people worldwide, but its current chemotherapy is still deficient and is only effective in the acute phase of the disease. Areas covered : This review covers different approaches to toxoplasmosis chemotherapy focused on the metabolic differences between the host and the parasite. Selective action on different targets such as the isoprenoid pathway, dihydrofolate reductase, T. gondii adenosine kinase, different antibacterials, T. gondii histone deacetylase and calcium-dependent protein kinases is discussed. Expert opinion : A new and safe chemotherapy is needed, as T. gondii causes serious morbidity and mortality in pregnant women and immunodeficient patients undergoing chemotherapy. A particular drawback of the available treatments is the lack of efficacy against the tissue cyst of the parasite. During this review a broad scope of several attractive targets for drug design have been presented. In this context, the isoprenoid pathway, dihydrofolate reductase, T. gondii histone deacetylase are promising molecular targets.

Mechanism of Action of 4-Phenoxyphenoxyethyl Thiocyanate (WC-9) against Trypanosoma cruzi, the Causative Agent of Chagas’ Disease

ABSTRACT We investigated the molecular basis of the activity of 4-phenoxyphenoxyethyl thiocyanate (WC-9) against Trypanosoma cruzi, the etiological agent of Chagas’ disease. We found that growth inhibition of T. cruzi epimastigotes induced by this compound was associated with a reduction in the content of the parasites endogenous sterols due to a specific blockade of their de novo synthesis at the level of squalene synthase.

Current status and progresses made in malaria chemotherapy.

Malaria is the most important parasitic disease worldwide, affecting more than 500 million people and causing close to 1 million deaths per annum. This serious fact is mainly attributable to the emergence of drug resistant strains of Plasmodium falciparum. The advances made in malaria chemotherapy based on unique aspects of the biochemistry and physiology of the responsible agents for this disease, parasites of Plasmodium genus, are covered in this review. Increasing resistance to conventional antimalarial drugs constitutes the main drawback for the persistence of this disease. In the present article, a comprehensive analysis of selected molecular targets is depicted in terms of their potential utility as chemotherapeutic agents. Our review focuses on different and important molecular targets for drug design that include proteases that hydrolyze hemoglobin, protein farnesyltransferase, heme detoxification pathway, polyamine pathways, dihydrofolate reductase, artemisinin-based combination therapies (ACTs), etc. Therefore, rational approaches to control malaria targeting metabolic pathways of malaria parasites which are essential for parasites survival are presented.

Bisphosphonates derived from fatty acids are potent growth inhibitors of Trypanosoma cruzi

We have investigated the effect of a series of bisphosphonates derived from fatty acids against Trypanosoma cruzi proliferation in in vitro assays. Some of these drugs proved to be potent inhibitors against the intracellular form of the parasite exhibiting IC50 values at the low micromolar level. As bisphosphonates are FDA clinically approved for treatment of bone resorption, their potential innocuousness makes them good candidates to control tropical diseases.

Design, synthesis and biological evaluation of sulfur-containing 1, 1-bisphosphonic acids as antiparasitic agents

As part of our efforts aimed at searching for new antiparasitic agents, 2-alkylmercaptoethyl-1,1-bisphosphonate derivatives were synthesized and evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and Toxoplasma gondii, the responsible agent for toxoplasmosis. Many of these sulfur-containing bisphosphonates were potent inhibitors against the intracellular form of T. cruzi, the clinically more relevant replicative form of this parasite, and tachyzoites of T. gondii targeting T. cruzi or T. gondii farnesyl diphosphate synthases (FPPSs), which constitute valid targets for the chemotherapy of these parasitic diseases. Interestingly, long chain length sulfur-containing bisphosphonates emerged as relevant antiparasitic agents. Taking compounds 37, 38, and 39 as representative members of this class of drugs, they exhibited ED(50) values of 15.8 μM, 12.8 μM, and 22.4 μM, respectively, against amastigotes of T. cruzi. These cellular activities matched the inhibition of the enzymatic activity of the target enzyme (TcFPPS) having IC(50) values of 6.4 μM, 1.7 μM, and 0.097 μM, respectively. In addition, these compounds were potent anti-Toxoplasma agents. They had ED(50) values of 2.6 μM, 1.2 μM, and 1.8 μM, respectively, against T. gondii tachyzoites, while they exhibited a very potent inhibitory action against the target enzyme (TgFPPS) showing IC(50) values of 0.024 μM, 0.025 μM, and 0.021 μM, respectively. Bisphosphonates bearing a sulfoxide unit at C-3 were also potent anti-Toxoplasma agents, particularly those bearing long aliphatic chains such as 43-45, which were also potent antiproliferative drugs against tachyzoites of T. gondii. These compounds inhibited the enzymatic activity of the target enzyme (TgFPPS) at the very low nanomolar range. These bisphosphonic acids have very good prospective not only as lead drugs but also as potential chemotherapeutic agents.

First Synthesis of (−)-Neplanocin C

Abstract (−)-Neplanocin C ( 4 ), a minor component of the neplanocin family of antibiotics and a lead drug for the design of several conformationally constrained nucleosides analogues, was enantioselectively synthesized starting from d -ribono-1,4-lactone via a convergent approach in twelve steps. The proton NMR spectrum of 4 was in agreement with the corresponding natural product. Calculated coupling constants obtained from ab initio molecular modeling studies and from previously published X-ray structure of neplanocin C also corresponded to the spectroscopic data.

1-(Fluoroalkylidene)-1,1-bisphosphonic Acids are Potent and Selective Inhibitors of the Enzymatic Activity of Toxoplasma gondii Farnesyl Pyrophosphate Synthase

α-Fluorinated-1,1-bisphosphonic acids derived from fatty acids were designed, synthesized and biologically evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and against Toxoplasma gondii, the agent responsible for toxoplasmosis, and also towards the target parasitic enzymes farnesyl pyrophosphate synthase of T. cruzi (TcFPPS) and T. gondii (TgFPPS). Interestingly, 1-fluorononylidene-1,1-bisphosphonic acid (compound 43) proved to be an extremely potent inhibitor of the enzymatic activity of TgFPPS at the low nanomolar range, exhibiting an IC(50) of 30 nM. This compound was two-fold more potent than risedronate (IC(50) = 74 nM) that was taken as a positive control. This enzymatic activity was associated with a strong cell growth inhibition against tachyzoites of T. gondii, with an IC(50) value of 2.7 μM.