CysLT receptor-mediated NOX2 activation is required for IL-8 production in HMC-1 cells induced by Trichomonas vaginalis-derived secretory products.

Trichomoniasis is caused by a sexually transmitted flagellate protozoan parasite Trichomonas vaginalis. T. vaginalis-derived secretory products (TvSP) contain lipid mediators such as leukotriene B4 (LTB4) and various cysteinyl leukotrienes (CysLTs) which included LTC4, LTD4, and LTE4. However, the signaling mechanisms by which T. vaginalis-induced CysLTs stimulate interleukin (IL)-8 production in human mast cells remain unclear. In this study, we investigated these mechanisms in human mast cells (HMC-1). Stimulation with TvSP resulted in increased intracellular reactive oxygen species (ROS) generation and NADPH oxidase 2 (NOX2) activation compared to unstimulated cells. Pre-treatment with NOX2 inhibitors such as diphenyleneiodonium chloride (DPI) or apocynin significantly reduced ROS production in TvSP-stimulated HMC-1 cells. Additionally, TvSP stimulation increased NOX2 protein expression and the translocation of p47phox from the cytosol to the membrane. Pretreatment of HMC-1 cells with PI3K or PKC inhibitors reduced TvSP-induced p47phox translocation and ROS generation. Furthermore, NOX2 inhibitors or NOX2 siRNA prevented CREB phosphorylation and IL-8 gene expression or protein secretion induced by TvSP. Pretreatment with a CysLTR antagonist significantly inhibited TvSP-induced ROS production, CREB phosphorylation, and IL-8 production. These results indicate that CysLT-mediated activation of NOX2 plays a crucial role in ROS-dependent IL-8 production in human mast cells stimulated by T. vaginalis-secreted CysLTs. These findings enhance our understanding of the inflammatory response in trichomoniasis and may inform the development of targeted therapies to mitigate this response.

Antiparasitic activity of chalcones analogue against Trichomonas vaginalis: biochemical, molecular and in silico aspects.

Trichomonas vaginalis is the etiologic agent of trichomoniasis, a worldwide distributed sexually transmitted infection (STI) that affects the genitourinary tract. Even though this disease already has a treatment in the prescription of drugs of the 5-nitroimidazole class, described low treatments adhesion, adverse side effects and cases of resistant isolates demonstrate the need for new formulations. With this in mind, chalcones emerge as a potential alternative to be tested, being compounds widely distributed in nature, easy to chemically synthesize and presenting several biological activities already reported. In this experiment, we evaluated the antiparasitic activity of 10 chalcone at a concentration of 100 µM against ATCC 30236 T. vaginalis isolates, considering negative (live trophozoites), positive (Metronidazole 100 µM) and vehicle (DMSO 0.6%) controls. Compounds 3a, 3c, 3 g and 3i showed promising results, with MICs set at 70 µM, 80 µM, 90 µM and 90 µM, respectively (p < 0,05). Cytotoxicity assays were performed on VERO and HMVII cell lines and revealed low inhibition rates at concentrations bellow 20 µM. To elucidate a possible mechanism of action for these molecules, the DPPH, ABTS and FRAP assays were performed, in which none of the four compounds presented antioxidant activity. Assays to verify ROS and lipid peroxidation in the parasite membrane were performed. None of the tested compounds identified ROS accumulation after incubation with trophozoites. 3 g molecule promoted an increase in MDA production after incubation. Results presented in this paper demonstrate the promising trichomonicidal profile, although further tests are still needed to optimize their performance and better elucidate the mechanisms of action involved.

Investigation of the Antitrichomonal Activity of Cinnamaldehyde, Carvacrol and Thymol and Synergy with Metronidazole.

Objective: Trichomonas vaginalis is a sexually transmitted protozoan parasite that usually causes infections in women. Metronidazole is used as the first choice in the treatment of this parasitic disease, but there is a need for new drugs since 1980's with increasing numbers of reported resistance. In this study, it was aimed to determine the antitrichomonal activity of the major components of Cinnamomum zeylanicum (cinnamon) and Thymus vulgaris (thyme) essential oils, cinnamaldehyde, carvacrol and thymol against metronidazole resistant and susceptible T. vaginalis strains, and to determine their interaction with metronidazole by checkerboard method. Methods: Cinnamaldehyde, carvacrol, thymol and metronidazole were obtained commercially. Two clinical isolates and one metronidazole resistant T. vaginalis reference strain were used in the study. MIC50 and MLC values of essential oil components and metronidazole were determined by broth microdilution method. The combinations of essential oil components with metronidazole were determined by the checkerboard method. Results: According to in vitro activity tests, cinnamaldehyde was determined to be most effective essential oil component. Clinical isolates were susceptible to metronidazole. In combination study, metronidazole showed synergy with cinnamaldehyde and carvacrol, and partial synergy with thymol. Conclusion: It was determined that cinnamaldehyde, carvacrol and thymol, which are known to have high antimicrobial activity, also have strong activity against T. vaginalis isolates and show a synergistic interaction with metronidazole. The use of metronidazole at lower doses in the synergistic interaction may contribute to the literature in terms of reducing drug side effects, creating a versatile antimicrobial target, and reducing the rate of resistance development.

Bacterial vaginosis (BV) and Trichomonas vaginalis (TV) co-infection, and bacterial antibiogram profile of pregnant women studied in Lagos, Nigeria.

AIM: This study was undertaken to determine the prevalence of Bacterial Vaginosis (BV), Trichomonas Vaginalis (TV) co-infection, and the antibacterial sensitivity profile of bacterial isolates. METHODS: The study was a cross-sectional study of 232 pregnant women on a routine antenatal visit between April 2019 and Sept. 2020, at Amukoko clinic in Lagos, Nigeria. The gynaecologist conducted the clinical examination on each patient looking for vaginal discharge and its consistency/homogeneity, colour and odour. Two High Vaginal Swab (HVS) samples were taken from every patient and a semi-structured questionnaire was used to gather the socio-demographic, practices/attitudes, and clinical information of each participant. One sample was employed for wet preparation to identify the TV and BV diagnosis using Amsel's criteria and Whiff's test. The second sample was used for bacterial culture and antibiogram was conducted using the disc diffusion technique. The Clinical Laboratory Standard Institutes' (CLSI) interpretative criteria were used to categorise the results. RESULTS: The mean age of the clients was 28.11 ± 7.08 years of age. The majority (88%) were aged 15-35 years. Only 81 (34.9%) had microbial organisms isolated or seen from their specimens and 19 (8.2%) of such were classified as having BV (Bacteriods or Gardnerella isolated). Of the 81 infected, 33 (40.8%) had only bacterial infection, 36 (44.4%) had TV alone and 12 (14.8%) had bacteria co-infected with TV. From the clinical records, the population that was classified as having UTI or vaginitis was only 46 (20.7%) The study observed age (15-35 years) related association between vaginosis/ TV co-infection (X2 = 7.9; P = 0.005). Participants with symptoms of vaginitis or UTI (mainly E. coli & pseudomonas spp. isolated), BV/co-infection with TV significantly associated with female traders (X2 = 8.5; P = 0.003) and were more associated with those from polygamous relationships (X2 = 18.79, P = 0.0001). Women in their 3rd and 2nd. trimester were more significantly associated with vaginal infection (X2 = 9.47, P = 0.002; X2 = 4.79, P = 0.029) respectively. The Pseudomonas showed susceptibility to ciprofloxacin (CIP) and cefuroxime (CXM). While, E. coli isolates were susceptible to cefepime, ciprofloxacin, and imipenem. CONCLUSION: There is a relatively low prevalence of BV and flagellate co-infection in the community studied. RECOMMENDATION: We recommend screening of antenatal women with underlying symptoms for BV and flagellates co-infection to avoid its progression to vaginitis.

Imidazole Carbamates as a Promising Alternative for Treating Trichomoniasis: In Vitro Effects on the Growth and Gene Expression of Trichomonas vaginalis.

Metronidazole (MTZ) is the most common drug used against Trichomonas vaginalis (T. vaginalis) infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in T. vaginalis to MTZ. Therefore, research into new therapeutic options against T. vaginalis infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC50 value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC50 values in the nanomolar range and AGR-2 being the most potent (IC50 400 nM). To gain insight into molecular events related to AGR-induced cell death in T. vaginalis, we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (CK, PFK, TPI, and ENOL) and genes involved in metabolism (G6PD, TKT, TALDO, NADHOX, ACT, and TUB), suggesting that disturbing these key metabolic genes alters the survival of the T. vaginalis parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against T. vaginalis.

Dequalinium chloride vaginal tablets for recalcitrant Trichomonas vaginalis: A case report.

Treatment options for recalcitrant Trichomonas vaginalis (TV), when very high dose systemic 5-nitroimidazole plus intravaginal therapy for over 14 days has failed, are very limited. They have poor efficacy, unpleasant side effects, and are difficult and expensive to acquire. We report successful treatment with 24 weeks of daily dequalinium chloride vaginal tablets. Dequalinium is licensed in Europe where it is readily available and cheap. It offers a safe and pragmatic alternative for recalcitrant TV.

Effect of Trichomonacide 6-Nitro-1H-benzimidazole Derivative Compounds on Expression Level of Metabolic Genes in Trichomonas vaginalis.

The parasite Trichomonas vaginalis is the etiologic agent of trichomoniasis, the most common non-viral sexually transmitted disease worldwide. This infection often remains asymptomatic and is related to several health complications. The traditional treatment for trichomoniasis is the use of drugs of the 5-nitroimidazole family, such as metronidazole; however, scientific reports indicate an increasing number of drug-resistant strains. Benzimidazole derivatives could offer an alternative in the search for new anti-trichomonas drugs. In this sense, two attractive candidates are the compounds O2N-BZM7 and O2N-BZM9 (1H-benzimidazole derivatives), since, through in vitro tests, they have shown a higher trichomonacide activity. In this study, we determined the effect on the expression level of metabolic genes in T. vaginalis. The results show that genes involved in redox balance (NADHOX, G6PD::6PGL) are overexpressed, as well as the gene that participates in the first reaction of glycolysis (CK); on the other hand, structural genes such as ACT and TUB are decreased in expression in trophozoites treated with the compound O2N-BZM9, which would probably affect its morphology, motility and virulence. These results align with the trichomonacidal activity of the compounds, with benzimidazole O2N-BZM9 being the most potent, with an IC50 value of 4.8 µM. These results are promising for potential future therapeutic applications.

Antibacterial and anti-trichomunas characteristics of local landraces of Lawsonia inermis L.

BACKGROUND: Henna (Lawsonia inermis) with anti-bacterial properties has been widely used in traditional medicine especially Persian medicine. Henna oil is suggested for diseases of infectious origin, such as cervical ulcers. Group B Streptococcus agalactiae, Pseudomonas aeruginosa and, Trichomonas vaginalis are involved in the infection of women especially cervicitis. Henna grows in dry and tropical regions. The main important landraces of henna landraces are cultivated in Kerman, Sistan and Baluchestan, Hormozgan, and Bushehr provinces in Iran. Proper use of antimicrobial agents, use of new antimicrobial strategies, and alternative methods, such as herbal methods may help reduce drug resistance in the future. This study's objective was to investigate the anti-Trichomonas vaginalis activity of three different henna landraces and antimicrobial effects against group B Streptococcus agalactiae and, Pseudomonas aeruginosa. METHODS: Total phenol content was measured by Folin ciocaltu method. Antibacterial effect of landraces of Henna against P. aeruginosa and S. agalactiae were assayed by well diffusion method and minimal inhibitory concentration assessments were done using the broth micro-dilution technique. Anti-Trichomonas effect of Henna landraces were assayed by Hemocytometery method. RESULTS: Total phenol content of Shahdad, Rudbar-e-Jonub, and Qaleh Ganj was 206.51, 201.96, and 254.85 µg/ml, respectively. Shahdad, Rudbar-e-Jonub, and Qaleh Ganj had MIC against GBS at 15, 15 and, 4 µg/ml. The growth inhibition diameter of the most effective henna (Shahdad landrace) at a concentration of 20 µg/ml on P. aeruginosa was 2.46 ± 0.15 cm and in the MIC method at a concentration of 5 µg/ml of Shahdad landrace, P. aeruginosa did not grow. IC50 of shahdad Henna after 24 h, 48 h, and 72 h was 7.54, 4.83 and 20.54 µg/ml, respectively. IC50 of Rudbar-e-Jonub extract was 5.76, 3.79 and 5.77 µg/ml in different days. IC50 of Qaleh Ganj extract was 6.09, 4.08 and 5.74 µg/ml in different days. CONCLUSIONS: The amount of total phenol in Qaleh Ganj was higher than the other varieties. In the well diffusion method, Qaleh Ganj was more effective against group B Streptococcus (Gram-positive bacterium) than the other two landraces, and Shahdad landrace was more effective against P. aeruginosa (Gram-negative bacterium) than other. In the MIC method, the same result was obtained as in the well diffusion method, but at a lower concentration.

Thio- and selenosemicarbazones as antiprotozoal agents against Trypanosoma cruzi and Trichomonas vaginalis.

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 Trypanosoma cruzi and Trichomonas vaginalis. Thiosemicarbazide 31 showed the best trypanocidal profile (epimastigotes), similar to benznidazole (BZ): IC50 (31)=28.72 µM (CL-B5 strain) and 33.65 µM (Y strain), IC50 (BZ)=25.31 µM (CL-B5) and 22.73 µM (Y); it lacked toxicity over mammalian cells (CC50 > 256 µM). Thiosemicarbazones 49, 51 and 63 showed remarkable trichomonacidal effects (IC50 =16.39, 14.84 and 14.89 µM) and no unspecific cytotoxicity towards Vero cells (CC50 ≥ 275 µM). Selenoisosters 74 and 75 presented a slightly enhanced activity (IC50=11.10 and 11.02 µM, respectively). Hydrogenosome membrane potential and structural changes were analysed to get more insight into the trichomonacidal mechanism.

Single gene targeted nanopore sequencing enables simultaneous identification and antimicrobial resistance detection of sexually transmitted infections.

OBJECTIVES: To develop a simple DNA sequencing test for simultaneous identification and antimicrobial resistance (AMR) detection of multiple sexually transmitted infections (STIs). METHODS: Real-time PCR (qPCR) was initially performed to identify Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Mycoplasma genitalium (MG) and Trichomonas vaginalis (TV) infections among a total of 200 vulvo-vaginal swab samples from female sex workers in Ecuador. qPCR positive samples plus qPCR negative controls for these STIs were subjected to single gene targeted PCR MinION-nanopore sequencing using the smartphone operated MinIT. RESULTS: Among 200 vulvo-vaginal swab samples 43 were qPCR positive for at least one of the STIs. Single gene targeted nanopore sequencing generally yielded higher pathogen specific read counts in qPCR positive samples than qPCR negative controls. Of the 26 CT, NG or MG infections identified by qPCR, 25 were clearly distinguishable from qPCR negative controls by read count. Discrimination of TV qPCR positives from qPCR negative controls was poorer as many had low pathogen loads (qPCR cycle threshold >35) which produced few specific reads. Real-time AMR profiling revealed that 3/3 NG samples identified had gyrA mutations associated with fluoroquinolone resistance, 2/10 of TV had mutations related to metronidazole resistance, while none of the MG samples possessed 23S rRNA gene mutations contributing to macrolide resistance. CONCLUSIONS: Single gene targeted nanopore sequencing for diagnosing and simultaneously identifying key antimicrobial resistance markers for four common genital STIs shows promise. Further work to optimise accuracy, reduce costs and improve speed may allow sustainable approaches for managing STIs and emerging AMR in resource poor and laboratory limited settings.

Lactate dehydrogenase and malate dehydrogenase: Potential antiparasitic targets for drug development studies.

Parasitic diseases remain a major public health concern for humans, claiming millions of lives annually. Although different treatments are required for these diseases, drug usage is limited due to the development of resistance and toxicity, which necessitate alternative therapies. It has been shown in the literature that parasitic lactate dehydrogenases (LDH) and malate dehydrogenases (MDH) have unique pharmacological selective and specificity properties compared to other isoforms, thus highlighting them as viable therapeutic targets involved in aerobic and anaerobic glycolytic pathways. LDH and MDH are important therapeutic targets for invasive parasites because they play a critical role in the progression and development of parasitic diseases. Any strategy to impede these enzymes would be fatal to the parasites, paving the way to develop and discover novel antiparasitic agents. This review aims to highlight the importance of parasitic LDH and MDH as therapeutic drug targets in selected obligate apicoplast parasites. To the best of our knowledge, this review presents the first comprehensive review of LDH and MDH as potential antiparasitic targets for drug development studies.

Antibacterial and anti-Trichomonas Vaginalis effects of Rosa Damascena mill petal oil (a persian medicine product), aqueous and hydroalcoholic extracts.

BACKGROUND: Oils in traditional medicine are important products and used routinely for therapeutic purposes. Rose oil (Rosa damascene Mill), a product of Persian medicine, is advised for the treatment of Infectious diseases related to the female genitourinary tract. In the present study, R. damascena petal oil, aqueous, and hydroalcoholic extracts were evaluated for their in vitro antibacterial and anti-Trichomonas vaginalis effects. METHODS: Anti-trichomonas activity evaluation of extracts and oil were assayed by the Homocytometery method. Their antibacterial effects against Escherichia coli, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and clinically isolated Group B Streptococcus were assayed by broth microdilution in 96-well plates. RESULTS: The MIC of hydroalcoholic and aqueous extracts ranged from 25-50 and 25-100 mg/ml, respectively. Rose oil at all administered doses failed to show any antibacterial activity. CONCLUSION: All extracts and oil concentrations showed some degree of growth inhibition activity on T. vaginalis; however, hydroalcoholic extract was more efficient.

Pharmacological activities of Asclepias curassavica L. (Apocynaceae) aerial parts.

ETHNOPHARMACOLOGICAL RELEVANCE: Asclepias curassavica L. (Apocynaceae) is a perennial shrub used in the folk treatment of parasitism, pain, and inflammation. AIM OF THE STUDY: This work assessed the antiparasitic, anti-inflammatory, antinociceptive, and sedative effects of an ethanol extract from the aerial parts of Asclepias curassavica (ACE). MATERIALS AND METHODS: The antiparasitic activity against Trichomonas vaginalis was evaluated using the trypan blue exclusion test. The in vitro anti-inflammatory actions of ACE (1-200 µg/ml) were analyzed using LPS-stimulated primary murine macrophages. The in vivo pharmacological activity of ACE (50-200 mg/kg p.o.) was evaluated using animal models of inflammation (TPA-induced ear edema test and carrageenan-induced paw edema test) and nociception (acetic acid-induced writhing test, formalin-induced licking test, and hot plate test). RESULTS: ACE showed poor antiparasitic effects against Trichomonas vaginalis (IC50 = 302 µg/ml). ACE increased the production of IL-10 in both in vitro assays (EC50 = 3.2 pg/ml) and in vivo assays (ED50 = 111 mg/kg). ACE showed good antinociceptive actions (ED50 = 158 mg/kg in phase 1 and ED50 = 83 mg/kg in phase 2) in the formalin test. Pre-treatment with naloxone blocked the antinociceptive response induced by ACE. In addition, ACE did not induce sedative effects or motor coordination deficits in mice. CONCLUSION: Findings showed that the anti-inflammatory activity of ACE is associated with increasing levels of IL-10 in both in vitro and in vivo assays, whereas the antinociceptive effect is associated with the participation of the opioidergic system, without inducing sedation or motor coordination impairment.

Modulation of peptidases by 2,4-diamine-quinazoline derivative induces cell death in the amitochondriate parasite Trichomonas vaginalis.

Trichomonas vaginalis is an amitochondriate protozoan and the agent of human trichomoniasis, the most prevalent non-viral sexually transmitted infection (STI) in the world. In this study we showed that 2,4-diamine-quinazoline derivative compound (PH100) kills T. vaginalis. PH100 showed activity against fresh clinical and American Type Culture Collection (ATCC) T. vaginalis isolates with no cytotoxicity against cells (HMVI, 3T3-C1 and VERO) and erythrocytes. In addition, PH100 showed synergistic action with metronidazole, indicating that these compounds act by different mechanisms. When investigating the mechanism of action of PH100 to ATCC 30236, apoptosis-like characteristics were observed, such as phosphatidylserine exposure, membrane alterations, and modulation of gene expression and activity of peptidases related to apoptosis. The apoptosis-like cell death features were not observed for the fresh clinical isolate treated with PH100 revealing distinct profiles. Our data revealed the heterogeneity among T. vaginalis isolates and contribute with the understanding of mechanisms of cell death in pathogenic eukaryotic organisms without mitochondria.

Gold(I) Phosphine Derivatives with Improved Selectivity as Topically Active Drug Leads to Overcome 5-Nitroheterocyclic Drug Resistance in Trichomonas vaginalis.

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure-activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1-C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.

Distribution of genotypes in relation to metronidazole susceptibility patterns in Trichomonas vaginalis isolated from South African pregnant women.

Reports on metronidazole resistance of Trichomonas vaginalis strains have been on the increase. This study investigated the in vitro metronidazole resistance patterns in T. vaginalis isolates obtained from South African pregnant women and the genotypes of these isolates. This study included 362 pregnant women recruited from a hospital in Durban, South Africa. The women provided self-collected vaginal swabs for the detection of T. vaginalis by culture in Diamonds media. Cultured isolates were then subjected to anaerobic susceptibility assays to metronidazole. For the genotyping assays, the actin gene was digested by HindII, MseI, and RsaI. The banding patterns obtained after digestion was used to determine the genotypes. A total of 21/362 (5.8%) pregnant women tested positive for T. vaginalis infection. Of the 21 T. vaginalis isolates tested for metronidazole susceptibility, 9.5% (2/21) had a minimum inhibitory concentration (MIC) of 4 µg/ml (resistant), 38.1% (8/21) had a MIC of 2 µg/ml (intermediate), and 52.4% (11/21) had a MIC ≤ 1 µg/ml (susceptible). The dominant genotype that was identified across the isolates was genotype G. There was no correlation between genotype harboured and metronidazole susceptibility patterns. In this study, resistance to metronidazole was observed in clinical isolates of T. vaginalis. This study did not find a correlation between genotype harboured and metronidazole susceptibility patterns. Despite the lack of association, our study provides data on an area of research that is currently lacking in our setting.

Bioactive half-sandwich Rh and Ir bipyridyl complexes containing artemisinin.

Reaction of dihydroartemisinin (DHA) with 4-methyl-4'-carboxy-2,2'-bipyridine yielded the new ester derivative L1. Six novel organometallic half-sandwich chlorido Rh(III) and Ir(III) complexes (1-6) containing pentamethylcyclopentadienyl, (Cp*), tetramethylphenylcyclopentadienyl (Cpxph), or tetramethylbiphenylcyclopentadienyl (Cpxbiph), and N,N-chelated bipyridyl group of L1, have been synthesized and characterized. The complexes were screened for inhibitory activity against the Plasmodium falciparum 3D7 (sensitive), Dd2 (multi-drug resistant) and NF54 late stage gametocytes (LSGNF54), the parasite strain Trichomonas vaginalis G3, as well as A2780 (human ovarian carcinoma), A549 (human alveolar adenocarcinoma), HCT116 (human colorectal carcinoma), MCF7 (human breast cancer) and PC3 (human prostate cancer) cancer cell lines. They show nanomolar antiplasmodial activity, outperforming chloroquine and artemisinin. Their activities were also comparable to dihydroartemisinin. As anticancer agents, several of the complexes showed high inhibitory effects, with Ir(III) complex 3, containing the tetramethylbiphenylcyclopentadienyl ligand, having similar IC50 values (concentration for 50% of maximum inhibition of cell growth) as the clinical drug cisplatin (1.06-9.23 µM versus 0.24-7.2 µM, respectively). Overall, the iridium complexes (1-3) are more potent compared to the rhodium derivatives (4-6), and complex 3 emerges as the most promising candidate for future studies.

Synthesis, Antiprotozoal Activity, and Cheminformatic Analysis of 2-Phenyl-2H-Indazole Derivatives.

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2H-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan's cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against E. histolytica, G. intestinalis, and T. vaginalis had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR.

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 IC50 < 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 (CC50 = 74.7 and 59.1 µM, respectively). Those compounds with trichomonacidal effect were also evaluated against a metronidazole-resistant culture. Special mention deserve compounds 6 and 10, which displayed better IC50 values (1.3 and 0.5 µM respectively) than that of the reference drug (IC50 MTZ = 3.0 µM). The high activity of these compounds against the resistant isolate reinforces the absence of cross-resistance with the reference drug. The remarkable trichomonacidal results against resistant T. vaginalis isolates suggest the interest of 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles to be considered as good prototypes to continue in the development of new drugs with enhanced trichomonacidal activity, aiming to increase the non-existent drugs to face clinical resistance efficiently for those patients in whom therapy with 5-nitroimidazoles is contraindicated.

Successful treatment of trichomoniasis with tinidazole following desensitization in a patient allergic to metronidazole.

Metronidazole desensitization is recommended in patients with trichomoniasis and history of an allergic reaction to metronidazole due to presumed cross reactivity with tinidazole and lack of reliably safe and effective alternative therapies. We report our experiences in a patient with persistent trichomoniasis who failed to complete metronidazole desensitization due to a burning sensation over her whole body and pruritus but was later successfully desensitized to tinidazole without experiencing any adverse effects.