New Pentamidine Analogues in Medicinal Chemistry

Abstract

Sixty years after its introduction, 1,5-bis(4-amidinophenoxy)pentane (Pentamidine) is still one of the most used drugs for the treatment of the first stage of Human African trypanosomiasis and other neglected diseases such as malaria and leishmaniasis. These protozoan infections are prevalent in the poorest world areas such as sub-saharian and developing countries, however the increasing immigration from these countries to the richest part of the world and the overlap of HIV with parasitic infections result in a growing number of cases in developed nations. A great effort has been made to develop new generations of diamidines for the treatment of these infections transmitted by insects. This review summarises the synthesis and evaluation of pentamidine analogues reported in the last years in the effort to find new drugs with better pharmaceutical activity, higher lipophilicity and lower citotoxycicty.

Recent Developments in Drug Discovery for Leishmaniasis and Human African Trypanosomiasis

“…The diamidine pharmacophore has been researched extensively and its role in medicinal chemistry has been previously reviewed. 176 …”

Screening and Identification of Inhibitors of Trypanosoma brucei Cathepsin L with Antitrypanosomal Activity

“…The most active (against the cysteine protease) out of the substructure analogues was compound 1 , its IC 50 value against rhodesain was 0.89 μ m , IC 50 against T. brucei was 5.80 μ m , and it displayed low toxicity to Hep G2 cells at 20 μ m . Compound 1 is structurally interesting in the sense that it mimics the bidentate structural feature of the clinically used antitrypanosomal drug, pentamidine, and the simplicity of its structure makes it a good candidate for both structure‐ and phenotype‐based lead discovery and optimization . In addition, if the free amine groups in the compound are converted to nitro groups, its antitrypanosomal activity may be enhanced, as nitro group seems to be an important structural motif in many potent antitrypanosomal agents .…”

Comparative in vitro transportation of pentamidine across the blood-brain barrier using polycaprolactone nanoparticles and phosphatidylcholine liposomes

“…The major problems and challenges in treatment of HAT are the level of toxicities exhibited by the drugs [1,10]. Pentamidine isethionate (see chemical structure in Figure 1) is an aromatic dicationic diamidine molecule [11,12] which is a white crystalline powder soluble in water and glycerine and insoluble in acetone, ether and chloroform. It is chemically designated as 4, 4 0 diamidino-dephenoxypentane di (b hydroxyethanesulfonate) [13].…”

“…It is administered daily by deep intramuscular administration at a dose of 4 mg/kg for 7-10 days [8,12,14]. Patients treated with pentamidine are reported to experience undesirable side effects including abdominal pain, diarrhoea, nausea, vomiting [15] cardiac arrhythmias, very high or low blood sugar, pancreas, kidney and liver problems [11,16]. Furthermore, pentamidine treatment is complicated by the mode of drug administration which requires hospitalization of a patient for more than 7 days and therefore, creates significant logistical and societal problems in the remote rural areas of Africa, where HAT is endemic.…”

“…This makes it difficult to implement with consistency because of poor health facilities and few healthcare personnel [5,12,16,17]. Pentamidine is not well absorbed through gastrointestinal tract (GIT) which leads to poor oral bioavailability and has a very slow rate of diffusion across the biological membranes and thus, making the concentrations not sufficient enough to affect the trypanosomes which advance to the central nervous system (CNS) [11].…”