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Acta Poloniae Pharmaceutica 2012The amino analogues of pentamidine with a polymethylene (n = 3 - 6) chain and their chlorambucil derivatives were synthesized. The obtained compounds revealed cytotoxic...
The amino analogues of pentamidine with a polymethylene (n = 3 - 6) chain and their chlorambucil derivatives were synthesized. The obtained compounds revealed cytotoxic effect on MCF-7 human breast cancer cell line (IC50 = 22 - 95 +/- 2 pM), mainly by the induction of apoptosis. The topoisomerase I/II inhibition assay and the ethidium displacement assay with the use of pBR322 plasmid DNA were used to the study of mechanism by which the obtained compounds could act. All the compounds are able to bind with DNA and interfere in vitro with the activity of topoisomerase (I and II). The determination of association constants with the use of calf thymus DNA, T4 coliphage DNA, poly(dA-dT)2 and poly(dG-dC)2 showed that the tested compounds bind within minor groove of B-DNA, but not selectively. The alkylating activity of chlorambucil derivatives determined in vitro using a Preussmann test was similar to the activity of chlorambucil. The influence of all the compounds on the amidolytic activity of plasmin and trypsin was also examined. The plasmin activity was inhibited by pentamidine, chlorambucil and aromatic bis-amines (IC50 = 0.1 - 8 mM), whereas the trypsin activity was influenced only by pentamidine.
Topics: Antifibrinolytic Agents; Antineoplastic Agents, Alkylating; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Chlorambucil; DNA; Dose-Response Relationship, Drug; Female; Humans; Inhibitory Concentration 50; Molecular Structure; Pentamidine; Structure-Activity Relationship; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Trypsin Inhibitors
PubMed: 22574508
DOI: No ID Found -
Drug Delivery Dec 2023Topical drug delivery is preferable route over systemic delivery in case of (CL). Among the available agents, amphotericin B (AmB) and pentamidine (PTM) showed...
Topical drug delivery is preferable route over systemic delivery in case of (CL). Among the available agents, amphotericin B (AmB) and pentamidine (PTM) showed promising result against CL. However, monotherapy is associated with incidences of reoccurrence and resistance. Combination therapy is therefore recommended. Thin film hydration method was employed for amphotericin B-pentamidine loaded niosomes (AmB-PTM-NIO) preparation followed by their incorporation into chitosan gel. The optimization of AmB-PTM-NIO was done via Box Behnken Design method and in vitro and ex vivo analysis was performed. The optimized formulation indicated 226 nm particle size (PS) with spherical morphology, 0.173 polydispersity index (PDI), -36 mV zeta potential (ZP) and with entrapment efficiency (EE) of 91% (AmB) and 79% (PTM), respectively. The amphotericin B-pentamidine loaded niosomal gel (AmB-PTM-NIO-Gel) showed desirable characteristics including physicochemical properties, pH (5.1 ± 0.15), viscosity (31870 ± 25 cP), and gel spreadability (280 ± 26.46%). In vitro release of the AmB and PTM from AmB-PTM-NIO and AmB-PTM-NIO-Gel showed more prolonged release behavior as compared to their respective drug solution. Higher skin penetration, greater percentage inhibition and lower IC50 against the promastigotes shows that AmB-PTM-NIO has better antileishmanial activity. The obtained findings suggested that the developed AmB-PTM-NIO-Gel has excellent capability of permeation via skin layers, sustained release profile and augmented anti-leishmanial outcome of the incorporated drugs.
Topics: Humans; Pentamidine; Amphotericin B; Leishmaniasis, Cutaneous; Combined Modality Therapy; Skin
PubMed: 36722301
DOI: 10.1080/10717544.2023.2173335 -
Parasitology Sep 2021Aquaglyceroporins (AQPs) are membrane proteins that function in osmoregulation and the uptake of low molecular weight solutes, in particular glycerol and urea. The AQP...
Aquaglyceroporins (AQPs) are membrane proteins that function in osmoregulation and the uptake of low molecular weight solutes, in particular glycerol and urea. The AQP family is highly conserved, with two major subfamilies having arisen very early in prokaryote evolution and retained by eukaryotes. A complex evolutionary history indicates multiple lineage-specific expansions, losses and not uncommonly a complete loss. Consequently, the AQP family is highly evolvable and has been associated with significant events in life on Earth. In the African trypanosomes, a role for the AQP2 paralogue, in sensitivity to two chemotherapeutic agents, pentamidine and melarsoprol, is well established, albeit with the mechanisms for cell entry and resistance unclear until very recently. Here, we discuss AQP evolution, structure and mechanisms by which AQPs impact drug sensitivity, suggesting that AQP2 stability is highly sensitive to mutation while serving as the major uptake pathway for pentamidine.
Topics: Aquaglyceroporins; Drug Resistance; Protozoan Proteins; Trypanocidal Agents; Trypanosoma
PubMed: 33602349
DOI: 10.1017/S0031182021000354 -
Antimicrobial Agents and Chemotherapy Nov 2016Leishmaniasis is a disease caused by pathogenic Leishmania parasites; current treatments are toxic and expensive, and drug resistance has emerged. While pentamidine, a...
Leishmaniasis is a disease caused by pathogenic Leishmania parasites; current treatments are toxic and expensive, and drug resistance has emerged. While pentamidine, a diamidine-type compound, is one of the treatments, its antileishmanial mechanism of action has not been investigated in depth. Here we tested several diamidines, including pentamidine and its analog DB75, against Leishmania donovani and elucidated their antileishmanial mechanisms. We identified three promising new antileishmanial diamidine compounds with 50% effective concentrations (ECs) of 3.2, 3.4, and 4.5 μM, while pentamidine and DB75 exhibited ECs of 1.46 and 20 μM, respectively. The most potent antileishmanial inhibitor, compound 1, showed strong DNA binding properties, with a shift in the melting temperature (ΔT) of 24.2°C, whereas pentamidine had a ΔT value of 2.1°C, and DB75 had a ΔT value of 7.7°C. Additionally, DB75 localized in L. donovani kinetoplast DNA (kDNA) and mitochondria but not in nuclear DNA (nDNA). For 2 new diamidines, strong localization signals were observed in kDNA at 1 μM, and at higher concentrations, the signals also appeared in nuclei. All tested diamidines showed selective and dose-dependent inhibition of kDNA, but not nDNA, replication, likely by inhibiting L. donovani topoisomerase IB. Overall, these results suggest that diamidine antileishmanial compounds exert activity by accumulating toward and blocking replication of parasite kDNA.
Topics: Amidines; Benzamidines; DNA Replication; DNA Topoisomerases, Type II; DNA, Kinetoplast; DNA, Mitochondrial; DNA-Binding Proteins; Drug Evaluation, Preclinical; Fluorescence; Leishmania donovani; Molecular Targeted Therapy; Pentamidine; Protozoan Proteins; Topoisomerase II Inhibitors; Trypanocidal Agents
PubMed: 27600039
DOI: 10.1128/AAC.01129-16 -
International Journal of Molecular... Jan 2023This in vivo study in mice addresses the relationship between the biodiversity of the microbiota and the levels of S100B, a protein present in enteroglial cells, but...
This in vivo study in mice addresses the relationship between the biodiversity of the microbiota and the levels of S100B, a protein present in enteroglial cells, but also in foods such as milk. A positive significant correlation was observed between S100B levels and Shannon values, which was reduced after treatment with Pentamidine, an inhibitor of S100B function, indicating that the correlation was influenced by the modulation of S100B activity. Using the bootstrap average method based on the distribution of the S100B concentration, three groups were identified, exhibiting a significant difference between the microbial profiles. Operational taxonomic units, when analyzed by SIMPER analysis, showed that genera regarded to be eubiotic were mainly concentrated in the intermediate group, while genera potentially harboring pathobionts often appeared to be more concentrated in groups where the S100B amounts were very low or high. Finally, in a pilot experiment, S100B was administered orally, and the microbial profiles appeared to be modified accordingly. These data may open novel perspectives involving the possibility of S100B-mediated regulation in the intestinal microbiota.
Topics: Mice; Animals; Gastrointestinal Microbiome; Pentamidine; Microbiota; Biodiversity; RNA, Ribosomal, 16S; S100 Calcium Binding Protein beta Subunit
PubMed: 36768570
DOI: 10.3390/ijms24032248 -
Journal of Pharmaceutical Sciences Mar 2020Initially developed as a synthetic analogue of insulin, pentamidine (PTM) is an antimicrobial drug that has recently shown in vitro and in vivo anticancer activity....
Initially developed as a synthetic analogue of insulin, pentamidine (PTM) is an antimicrobial drug that has recently shown in vitro and in vivo anticancer activity. Nevertheless, systemic administration of PTM causes severe side effects, especially nephrotoxicity. Here we propose the association of PTM to different biocompatible nanosystems in order to compare the physicochemical characteristics of the loaded nanocarriers and their influence on the drug cytotoxicity toward cancer cells. In particular, PTM (as free base or with different counterions) was encapsulated into liposomes and poly(lactide-co-glycolide) (PLGA) nanoparticles and all the formulations have been deeply characterized concerning mean diameter, polydispersity index, zeta potential, stability, morphology, PTM loading, and drug release profile. The anticancer activity was evaluated on a human ovarian cancer cell line over 72 h. Results showed that PTM is efficiently loaded into liposomes with a transmembrane citrate or sulfate gradient; concerning PLGA nanoparticles, important association occurred, thanks to ionic interactions between the drug and the polymer. The in vitro studies confirmed the anticancer activity of PTM, which was gradually released with different profiles depending on the drug form and the nanocarrier structure.
Topics: Drug Carriers; Drug Delivery Systems; Humans; Lipids; Nanoparticles; Particle Size; Pentamidine; Polymers
PubMed: 31751563
DOI: 10.1016/j.xphs.2019.11.011 -
Frontiers in Cellular and Infection... 2018Enterobacteriaceae cause different types of community- and hospital-acquired infections. Moreover, the spread of multidrug-resistant Enterobacteriaceae is a public...
Activity of Pentamidine Alone and in Combination With Aminoglycosides, Tigecycline, Rifampicin, and Doripenem Against Clinical Strains of Carbapenemase-Producing and/or Colistin-Resistant Enterobacteriaceae.
Enterobacteriaceae cause different types of community- and hospital-acquired infections. Moreover, the spread of multidrug-resistant Enterobacteriaceae is a public health problem and the World Health Organization pointed them among the pathogens in which the search of new antibiotics is critical. The objective of this study was to analyze the activity of pentamidine alone and in combination with gentamicin, tobramycin, amikacin, tigecycline, rifampicin, or doripenem against eight clinical strains of carbapenemase-producing and/or colistin-resistant Enterobacteriaceae: five carbapenemase-producing , one carbapenemase-producing , and two colistin-resistant . MIC and MBC were determined following standard protocols. MIC results were interpreted for all the antibiotics according to the EUCAST breakpoints but for rifampicin in which the French FSM breakpoint was used. Bactericidal and synergistic activity of pentamidine alone and in combination with antibiotics at concentrations of 1xMIC was measured by time-kill curves. For one selected strain, OXA-48/CTX-M-15 time-kill curves were performed also at 1/2xMIC of pentamidine. All studies were performed in triplicate. Pentamidine MIC range was 200-800 μg/mL. The 50, 12.5, 62.5, 87.5, and 62.5% of the strains were susceptible to gentamicin, tobramycin, amikacin, tigecycline, and doripenem, respectively. Only the two strains were susceptible to rifampicin. Pentamidine alone at 1xMIC showed bactericidal activity against all strains, except for the 32 strain. The bactericidal activity of pentamidine alone was also observed in combination. The combinations of pentamidine were synergistic against 32 with amikacin and tobramycin at 24 h and with tigecycline at 8 h. Pentamidine plus rifampicin was the combination that showed synergistic activity against more strains (five out of eight). Pentamidine plus doripenem did not show synergy against any strain. At 1/2xMIC, pentamidine was synergistic with all the studied combinations against the K. pneumoniae OXA-48/CTX-M-15 strain. In summary, pentamidine alone and in combination shows activity against carbapenemase-producing and/or colistin-resistant Enterobacteriaceae. Pentamidine appears to be a promising option to treat infections caused by these pathogens.
Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Colistin; Drug Resistance, Bacterial; Drug Synergism; Enterobacteriaceae Infections; Humans; Microbial Sensitivity Tests; Microbial Viability; Pentamidine
PubMed: 30406040
DOI: 10.3389/fcimb.2018.00363 -
Cell Proliferation Jan 2020We investigated the anti-cancer activity of pentamidine, an anti-protozoal cationic aromatic diamidine drug, in prostate cancer cells and aimed to provide valuable...
OBJECTIVES
We investigated the anti-cancer activity of pentamidine, an anti-protozoal cationic aromatic diamidine drug, in prostate cancer cells and aimed to provide valuable insights for improving the efficacy of prostate cancer treatment.
MATERIALS AND METHODS
Prostate cancer cell lines and epithelial RWPE-1 cells were used in the study. Cell viability, wound-healing, transwell and apoptosis assays were examined to evaluate the influences of pentamidine in vitro. RNA-seq and qPCR were performed to analyse changes in gene transcription levels upon pentamidine treatment. Mitochondrial changes were assessed by measuring mitochondrial DNA content, morphology, membrane potential, cellular glucose uptake, ATP production and ROS generation. Nude mouse xenograft models were used to test anti-tumour effects of pentamidine in vivo.
RESULTS
Pentamidine exerted profound inhibitory effects on proliferation, colony formation, migration and invasion of prostate cancer cells. In addition, the drug suppressed growth of xenograft tumours without exhibiting any obvious toxicity in nude mice. Mechanistically, pentamidine caused mitochondrial DNA content reduction and induced mitochondrial morphological changes, mitochondrial membrane potential dissipation, ATP level reduction, ROS production elevation and apoptosis in prostate cancer cells.
CONCLUSIONS
Pentamidine can efficiently suppress prostate cancer progression and may serve as a novel mitochondria-targeted therapeutic agent for prostate cancer.
Topics: Animals; Cell Proliferation; DNA, Mitochondrial; DNA, Neoplasm; Humans; Male; Membrane Potential, Mitochondrial; Mice; Mice, Nude; Mitochondria; PC-3 Cells; Pentamidine; Prostatic Neoplasms; Xenograft Model Antitumor Assays
PubMed: 31721355
DOI: 10.1111/cpr.12718 -
Parasitology Jul 2013Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease,... (Review)
Review
Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.
Topics: Amidines; Animals; Antiprotozoal Agents; Humans; Intracellular Space; Microscopy, Electron, Transmission; Parasites; Pentamidine; Protozoan Infections; Ultrasonography
PubMed: 23561006
DOI: 10.1017/S0031182013000292 -
BMJ (Clinical Research Ed.) Jan 1990
Review
Topics: Acquired Immunodeficiency Syndrome; Aerosols; Humans; Pentamidine; Pneumonia, Pneumocystis
PubMed: 2106927
DOI: 10.1136/bmj.300.6719.211