Impact of COVID-19 Pandemic on the Trends of Infection in a Tertiary Hospital of Madrid, Spain.

More than one million sexually transmitted infections (STIs) occur every day, and is responsible for more than 156 million cases each year worldwide. Nevertheless, epidemiological studies of this parasite in Europe are scarce. The aim of this study was to evaluate the impact that the COVID-19 pandemic may have had in the diagnosis and epidemiology of trichomoniasis.

5-Nitroindazole-based compounds: further studies for activity optimization as anti-Trypanosoma cruzi agents.

In this study, a new series of eleven 5-nitroindazole derivatives (10-20) and a related 6-nitroquinazoline (21) was synthesized and tested in vitro against different forms of the kinetoplastid parasite Trypanosoma cruzi, etiological agent of Chagas disease. Among these compounds, derivatives 11-14 and 17 showed trypanocidal profiles on epimastigotes (IC = 1.00-8.

Thio- and selenosemicarbazones as antiprotozoal agents against and .

Herein, we report the preparation of a panel of Schiff bases analogues as antiprotozoal agents by modification of the stereoelectronic effects of the substituents on N-1 and N-4 and the nature of the chalcogen atom (S, Se). These compounds were evaluated towards and . Thiosemicarbazide showed the best trypanocidal profile (epimastigotes), similar to benznidazole (BZ): IC ()=28.

Promising hit compounds against resistant trichomoniasis: Synthesis and antiparasitic activity of 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles.

A series of 11 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles (2-12) has been prepared starting from 1-benzyl-5-nitroindazol-3-ol 13, and evaluated against sensitive and resistant isolates of the sexually transmitted protozoan Trichomonas vaginalis. Compounds 2, 3, 6, 9, 10 and 11 showed trichomonacidal profiles with IC < 20 µM against the metronidazole-sensitive isolate. Moreover, all these compounds submitted to cytotoxicity assays against mammalian cells exhibited low non-specific cytotoxic effects, except compounds 3 and 9 which displayed moderate cytotoxicity (CC = 74.

Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Y strain (DTU TcII): and studies.

In previous studies, we have identified several families of 5-nitroindazole derivatives as promising antichagasic prototypes. Among them, 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one, (hydrochloride) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one (compounds 16 and 24, respectively) have recently shown outstanding activity in vitro over the drug-sensitive Trypanosoma cruzi CL strain (DTU TcVI). Here, we explored the activity of these derivatives against the moderately drug-resistant Y strain (DTU TcII), in vitro and in vivo.

Trichomoniasis in a tertiary hospital of Madrid, Spain (2013-2017): prevalence and pregnancy rate, coinfections, metronidazole resistance, and endosymbiosis.

Trichomoniasis is the most prevalent curable sexually transmitted infection (STI) worldwide and a risk factor for the acquisition of other STIs and adverse pregnancy outcomes. The objectives of this study were to determine the prevalence of T. vaginalis and related coinfections in women attending a third-level hospital of Madrid (Spain).

Experimental models in Chagas disease: a review of the methodologies applied for screening compounds against Trypanosoma cruzi.

One of the main problems of Chagas disease (CD), the parasitic infection caused by Trypanosoma cruzi, is the lack of a completely satisfactory treatment, which is currently based on two old nitroheterocyclic drugs (i.e., nifurtimox and benznidazole) that show important limitations for treating patients.

Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2-Benzyl-5-nitroindazole-Derived Amines.

Three different series of new 5-nitroindazole derivatives-1-(ω-aminoalkyl)-2-benzylindazolin-3-ones (series A; ten compounds), 3-(ω-aminoalkoxy)-2-benzylindazoles (series B; four compounds) and 3-alkylamino-2-benzylindazoles (series C; five compounds)-have been synthesized and evaluated against the protozoan parasites Trypanosoma cruzi, Leishmania amazonensis, and Trichomonas vaginalis: etiological agents of Chagas disease, cutaneous leishmaniasis, and trichomoniasis, respectively. Many indazoles of series A, B, and C were efficient against T. cruzi.

Drug repositioning for novel antitrichomonas from known antiprotozoan drugs using hierarchical screening.

Aim: Metronidazole is the most widely used drug in trichomoniasis therapy. However, the emergence of metronidazole-resistant Trichomonas vaginalis isolates calls for the search for new drugs to counter the pathogenicity of these parasites.

Results: Classification models for predicting the antitrichomonas activity of molecules were built.

Novel Imidazo[4,5-c][1,2,6]thiadiazine 2,2-dioxides as antiproliferative trypanosoma cruzi drugs: Computational screening from neural network, synthesis and in vivo biological properties.

A new family of imidazo[4,5-c][1,2,6]thiadiazine 2,2-dioxide with antiproliferative Trypanosoma cruzi properties was identified from a neural network model published by our group. The synthesis and evaluation of this new class of trypanocidal agents are described. These compounds inhibit the growth of Trypanosoma cruzi, comparable with benznidazole or nifurtimox.

Biological approaches to characterize the mode of action of two 5-nitroindazolinone prototypes on Trypanosoma cruzi bloodstream trypomastigotes.

The phenotypic activity of two 5-nitroindazolinones, i.e. 2-benzyl-1-propyl (22) and 2-benzyl-1-butyl (24) derivatives, previously proposed as anti-Trypanosoma cruzi prototypes, was presently assayed on bloodstream trypomastigotes (BT) of the moderately drug-resistant Y strain.

Antichagasic and trichomonacidal activity of 1-substituted 2-benzyl-5-nitroindazolin-3-ones and 3-alkoxy-2-benzyl-5-nitro-2H-indazoles.

Two series of new 5-nitroindazole derivatives, 1-substituted 2-benzylindazolin-3-ones (6-29, series A) and 3-alkoxy-2-benzyl-2H-indazoles (30-37, series B), containing differently functionalized chains at position 1 and 3, respectively, have been synthesized starting from 2-benzyl-5-nitroindazolin-3-one 5, and evaluated against the protozoan parasites Trypanosoma cruzi and Trichomonas vaginalis, etiological agents of Chagas disease and trichomonosis, respectively. Many indazolinones of series A were efficient against different morphological forms of T. cruzi CL Brener strain (compounds 6, 7, 9, 10 and 19-21: IC50 = 1.

In vitro trichomonacidal activity and preliminary in silico chemometric studies of 5-nitroindazolin-3-one and 3-alkoxy-5-nitroindazole derivatives.

A selection of 1,2-disubstituted 5-nitroindazolin-3-ones (1-19) and 3-alkoxy-5-nitroindazoles substituted at positions 1 (20-24) or 2 (25-39) from our in-house compound library were screened in vitro against the most common curable sexually transmitted pathogen, Trichomonas vaginalis. A total of 41% of the studied molecules (16/39) achieved a significant activity of more than 85% growth inhibition at the highest concentration assayed (100 µg mL(-1)). Among these compounds, 3-alkoxy-5-nitroindazole derivatives 23, 24, 25 and 27 inhibited parasite growth by more than 50% at 10 µg mL(-1).

Bond-based bilinear indices for computational discovery of novel trypanosomicidal drug-like compounds through virtual screening.

Two-dimensional bond-based bilinear indices and linear discriminant analysis are used in this report to perform a quantitative structure-activity relationship study to identify new trypanosomicidal compounds. A data set of 440 organic chemicals, 143 with antitrypanosomal activity and 297 having other clinical uses, is used to develop the theoretical models. Two discriminant models, computed using bond-based bilinear indices, are developed and both show accuracies higher than 86% for training and test sets.

Synthesis and in vitro and in vivo biological evaluation of substituted nitroquinoxalin-2-ones and 2,3-diones as novel trichomonacidal agents.

Two series of ten novel 7-nitroquinoxalin-2-ones and ten 6-nitroquinoxaline-2,3-diones with diverse substituents at positions 1 and 4 were synthesized and evaluated against the sexually transmitted parasite Trichomonas vaginalis. Furthermore, diverse molecular and drug-likeness properties were analyzed to predict the oral bioavailability following the Lipinski's "rule of five". 7-Nitroquinoxalin-2-one derivatives displayed moderate to high in vitro activity while the efficiency of most nitroquinoxaline-2,3-diones was rather low; both kinds of compounds did not show cytotoxic effects in mammalian cells.

Novel solid dispersions of benznidazole: preparation, dissolution profile and biological evaluation as alternative antichagasic drug delivery system.

Solid dispersions (SD) of benznidazole (BNZ) in sodium deoxycholate (NaDC) or low-substituted hydroxypropylcellulose (L-HPC) were developed by freeze-drying process to improve the solubility of this low water-soluble drug and consequently, its trypanocidal activity. Although the dissolution studies showed a progressive decrease in the release rate of BNZ when formulated in the presence of NaDC, the increase in the surfactant concentration resulted in a better trypanocidal profile on epimastigotes, as well as in an enhancement of the unspecific cytotoxicity. However, such an effect was not so evident on amastigotes and in vivo (blood-trypomastigotes), where high concentrations of surfactant (BNZ:NaDC ≥ 1:6) experimented a loss of activity, correlating this fact with the minor cession of BNZ these formulations accomplished in acidic locations (i.

A sequential procedure for rapid and accurate identification of putative trichomonacidal agents.

In the current report, a sequential step-wise methodology based on in silico, in vitro and in vivo experimental procedures for the prompt detection of potential trichomonacidal drugs is proposed. A combinatorial of 12 QSAR (Quantitative Structure-Activity Relationship) models based on Linear Discrimination Analysis (LDA) are suggested for the rational identification of new trichomonacidal drugs from virtual screening of in house chemical libraries and drug databases. Subsequently, compounds selected as potential anti-trichomonas are screened in vitro against Trichomonas vaginalis.

Development of novel benznidazole formulations: physicochemical characterization and in vivo evaluation on parasitemia reduction in Chagas disease.

This work aims to develop novel benznidazole (BZN) solid dispersions (SD) to improve its solubility and bioavailability properties. Low-substituted hydroxypropylcellulose (L-HPC) and sodium deoxycholate (NaDC) were evaluated as carriers. BZN solid dispersions containing different ratios of carrier were prepared by a freeze-drying process and characterized by SEM, powder X-ray diffraction (XRD), differential scanning calorimetry (DSC) and dissolution studies.

Antiprotozoan lead discovery by aligning dry and wet screening: prediction, synthesis, and biological assay of novel quinoxalinones.

Protozoan parasites have been one of the most significant public health problems for centuries and several human infections caused by them have massive global impact. Most of the current drugs used to treat these illnesses have been used for decades and have many limitations such as the emergence of drug resistance, severe side-effects, low-to-medium drug efficacy, administration routes, cost, etc. These drugs have been largely neglected as models for drug development because they are majorly used in countries with limited resources and as a consequence with scarce marketing possibilities.

In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents.

In this study, a series of 22 pre-synthesized 7-chloro-4-amino(oxy)quinoline derivatives was assayed in vitro as potential antichagasic agents. A primary screening against Trypanosoma cruzi epimastigotes and a non-specific cytotoxicity assay on murine fibroblasts were simultaneously performed, resulting quinolines 3, 7 and 12 with great selectivity (SI) on the extracellular parasite (SI7, SI3, SI12 and SIBZ >9.44).

Further insights into biological evaluation of new anti-Trypanosoma cruzi 5-nitroindazoles.

Twelve molecules from a series of 35 new 5-nitroindazole derivatives, selected from a successful primary screening on Trypanosoma cruzi epimastigotes, have been evaluated against intracellular amastigotes according to the previous results of their trypanocidal activity and unspecific cytotoxicity. 2-Benzyl-1-propyl (22), 2-benzyl-1-isopropyl (23), and 2-benzyl-1-butyl (24) 5-nitroindazolin-3-ones have inhibited the growth of amastigotes similarly to the reference drugs benznidazole and nifurtimox, inducing complete growth inhibition at concentrations lower than 8 μM (IC₅₀ < 5 μM) and accomplishing great selectivity indexes on the intracellular form of the parasite (SI > 30). Further in vivo assays were developed only for two of the most active molecules (22 and 24), reaching significant reductions in parasitemia levels (52 % and 77%, respectively) after their oral administration to infected mice.

Determination of internal transcribed spacer regions (ITS) in Trichomonas vaginalis isolates and differentiation among Trichomonas species.

The nucleotide sequence of the 5.8S rRNA gene and the flanked internal transcribed spacer (ITS) regions of six Trichomonas vaginalis isolates with different metronidazole sensitivity and geographic origin were genotyped. A multiple sequence alignment was performed with different sequences of other isolates available at the GenBank/EMBL/DDBJ databases, which revealed 5 different sequence patterns.

Selective activity of 2,4-diaryl-1,2,3,4-tetrahydroquinolines on Trypanosoma cruzi epimastigotes and amastigotes expressing β-galactosidase.

The growth inhibitory effect on Trypanosoma cruzi epimastigotes and the unspecific cytotoxicity over NCTC-929 fibroblasts of two series of previously synthesized 2,4-diaryl-1,2,3,4-tetrahydroquinolines (THQ), have been studied in vitro and compared with those of benznidazole (BZ). Derivatives AR39, AR40, AR41, AR91 and DM15 achieved outstanding selectivity indexes (SI) on the extracellular form (SITHQ>SIBZ>9.44) and thus, were tested in a more specific in vitro assay against amastigotes, showing less effectiveness than the reference drug (SIBZ>320) but also accomplishing great selectivity on the intracellular stage (SITHQ>25).

Synthesis, biological evaluation and chemometric analysis of indazole derivatives. 1,2-Disubstituted 5-nitroindazolinones, new prototypes of antichagasic drug.

Chagas disease chemotherapy, currently based on only two drugs, nifurtimox and benznidazole, is far from satisfactory and therefore the development of new antichagasic compounds remains an important goal. On the basis of antichagasic properties previously described for some 1,2-disubstituted 5-nitroindazolin-3-ones (21, 33) and in order to initiate the optimization of activity of this kind of compounds, we have prepared a series of related analogs (22-32, 34-38, 58 and 59) and tested in vitro these products against epimastigote forms of Trypanosoma cruzi. 2-Benzyl-1-propyl (22), 2-benzyl-1-isopropyl (23) and 2-benzyl-1-butyl (24) derivatives have shown high trypanocidal activity and low unspecific toxicity.

Identification in silico and in vitro of novel trypanosomicidal drug-like compounds.

Atom-based bilinear indices and linear discriminant analysis are used to discover novel trypanosomicidal compounds. The obtained linear discriminant analysis-based quantitative structure-activity relationship models, using non-stochastic and stochastic indices, provide accuracies of 89.02% (85.