Short-term outcomes of laparoscopic extended hepatectomy versus major hepatectomy: a single-center experience.

INTRODUCTION: Laparoscopic major hepatectomy (LMH) remains restricted to a few specialized centers and poses a challenge to surgeons performing laparoscopic resections. Laparoscopic extended resections are even more complex and rarely conducted. METHODS: From a single-institution database, we compared the short-term outcomes of patients who underwent major and extended laparoscopic resections, stratifying the entire retrospective cohort into four groups: right hepatectomy, left hepatectomy, right extended hepatectomy, and left extended hepatectomy. Patient demographics, tumor characteristics, operative variables, and especially postoperative outcomes were evaluated. RESULTS: 250 patients underwent major and extended laparoscopic liver resections, including 160 right, 31 right extended, 36 left, and 23 left extended laparoscopic hepatectomies. The most common indication for resection was colorectal liver metastases (64%). Laparoscopic extended hepatectomy (LEH) showed significantly longer operative time, more blood loss, need for Pringle maneuver, conversion to open surgery, higher rates of liver failure, postoperative ascites, and intra-abdominal hemorrhage, R1 margins and length of stay when compared with the LMH group. Mortality rates were similar between groups. Multivariate analysis revealed intraoperative blood transfusion (OR = 5.1[CI-95%: 1.15-6.79]; p = 0.02) as an independent predictor for major complications. CONCLUSIONS: LEH showed to be feasible, however with higher blood loss and significantly associated to major complications.

In vitro miltefosine and amphotericin B susceptibility of strains and clinical isolates of Leishmania species endemic in Brazil that cause tegumentary leishmaniasis.

Tegumentary leishmaniasis encompasses a spectrum of clinical manifestations caused by the parasitic protozoa of the genus Leishmania. In Brazil, there are at least seven Leishmania species that are endemic and responsible for this set of clinical manifestations of the disease. Current treatment is limited to a restricted number of drugs that in general have several drawbacks including parenteral use, toxicity, and severe side effects. Amphotericin B is considered a second-line drug for tegumentary leishmaniasis in Brazil, while miltefosine was recently approved for clinical use in the treatment of this disease. In this study, we investigated the in vitro susceptibility of Leishmania strains representative of the species endemic to Brazil, as well as a panel of thirteen clinical isolates of tegumentary leishmaniasis, to both amphotericin B and miltefosine. A moderate variation in the susceptibility to both drugs was found, where the EC50 values varied from 11.43 to 52.67 µM for miltefosine and from 12.89 to 62.36 nM for amphotericin B in promastigotes, while for the intracellular amastigotes, values ranged from 1.08 to 9.60 µM and from 1.69 to 22.71 nM for miltefosine and amphotericin B respectively. Furthermore, the clinical isolates and strains of the subgenus Viannia were evaluated for the presence of Leishmania RNA virus 1 (LRV1), as this is an important factor associated with disease severity and treatment outcome. These findings provide a preclinical dataset of the activity of these drugs against the causative species of tegumentary leishmaniasis in Brazil.

Repurposing of 5-nitrofuran-3,5-disubstituted isoxazoles: A thriving scaffold to antitrypanosomal agents.

Chagas disease (CD) is a neglected disease caused by the protozoan Trypanosoma cruzi. The two drugs used in the treatment schedules exhibit adverse effects and severe toxicity. Thus, searching for new antitrypanosomal agents is urgent to provide improved treatments to those affected by this disease. 5-Nitrofuran-isoxazole analogs were synthesized by cycloaddition reactions [3+2] between chloro-oximes and acetylenes in satisfactory yields. We analyzed the structure-activity relationship of the analogs based on Hammett's and Hansch's parameters. The 5-nitrofuran-isoxazole analogs exhibited relevant in vitro antitrypanosomal activity against the amastigote forms of T. cruzi. Analog 7s was the trending hit of the series, showing an IC50 value of 40 nM and a selectivity index of 132.50. A possible explanation for this result may be the presence of an electrophile near the isoxazole core. Moreover, the most active analogs proved to act as an in vitro substrate of type I nitroreductase rather than the cruzain, enzymes commonly investigated in molecular target studies of CD drug discovery. These findings suggest that 5-nitrofuran-isoxazole analogs are promising in the studies of agents for CD treatment.

1,4-Diaryl-1,2,3-triazole neolignan-celecoxib hybrids inhibit experimental arthritis induced by zymosan.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes cartilage damage. Anti-inflammatories are widely used in the management of RA, but they can have side effects such as gastrointestinal and/or cardiovascular disorders. Studies published by our group showed that the synthesis of hybrid triazole analogs neolignan-celecoxib containing the substituent groups sulfonamide (L15) or carboxylic acid (L18) exhibited anti-inflammatory activity in an acute model of inflammation, inhibited expression of P-selectin related to platelet activation and did not induce gastric ulcer, minimizing the related side effects. In continuation, the present study evaluated the anti-inflammatory effects of these analogs in an experimental model of arthritis and on the functions of one of the important cells in this process, macrophages. Mechanical hyperalgesia, joint edema, leukocyte recruitment to the joint and damage to cartilage in experimental arthritis and cytotoxicity, spread of disease, phagocytic activity and nitric oxide (NO) and hydrogen peroxide production by macrophages were evaluated. Pre-treatment with L15 and L18 reduced mechanical hyperalgesia, joint edema and the influx of leukocytes into the joint cavity after different periods of the stimulus. The histological evaluation of the joint showed that L15 and L18 reduced cartilage damage and there was no formation of rheumatoid pannus. Furthermore, L15 and L18 were non-cytotoxic. The analogs inhibited the spreading, the production of NO and hydrogen peroxide. L15 decreased the phagocytosis. Therefore, L15 and L18 may be potential therapeutic prototypes to treat chronic inflammatory diseases such as RA.

Anti-inflammatory, ulcerogenic and platelet activation evaluation of novel 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids.

This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors.

Isolation, typing, and drug susceptibility of Leishmania (Leishmania) infantum isolates from dogs of the municipality of Embu das Artes, an endemic region for canine leishmaniasis in Brazil.

The parasitic protozoa Leishmania (Leishmania) infantum is the etiological agent of human visceral leishmaniasis and canine leishmaniasis in South America, where Brazil is the most affected country. This zoonotic disease is transmitted by the bite of an infected phlebotomine sand fly and dogs constitute the main domestic reservoir of the parasite. In this study, we screened 2348 dogs of the municipality of Embu das Artes, Brazil, for antibodies against the parasite. Prevalence for canine leishmaniasis seropositivity was 2.81%, as assessed using a Dual-Path Platform rapid test for canine leishmaniasis. Twenty-five seropositive dogs were euthanized for parasite isolation and 14 isolates were successful obtained. Nucleotide sequencing of the internal transcribed spacer confirmed the isolates to be L. (L.) infantum, and very low sequence variability was observed among them. The in vitro susceptibility to miltefosine and paromomycin was assessed and moderate variation in paromomycin susceptibility was found among the isolates in the promastigote and intracellular amastigote stages. On the other hand, in vitro susceptibility to miltefosine of these isolates was homogenous, particularly in the amastigote stage (EC50 values from 0.69 to 2.07 µM). In addition, the miltefosine sensitivity locus was deleted in all the isolates, which does not corroborate the hypothesis that the absence of this locus is correlated with a low in vitro susceptibility. Our findings confirm that the municipality of Embu das Artes is endemic for canine leishmaniasis and that isolates from this region are susceptible to paromomycin and miltefosine, indicating the potential of these drugs to be clinically evaluated in the treatment of human visceral leishmaniasis in Brazil.

Design, synthesis, antileishmanial, and antifungal biological evaluation of novel 3,5-disubstituted isoxazole compounds based on 5-nitrofuran scaffolds.

Nineteen 3,5-disubstituted-isoxazole analogs were synthesized based on nitrofuran scaffolds, by a [3 + 2] cycloaddition reaction between terminal acetylenes and 5-nitrofuran chloro-oxime. The compounds were obtained in moderate to very good yields (45-91%). The antileishmanial activity was assayed against the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. Alkylchlorinated compounds 14p-r were active on both the promastigote and amastigote forms, with emphasis on compound 14p, which showed strong activity against the amastigote form (IC50 = 0.6 µM and selectivity index [SI] = 5.2). In the alkyl series, compound 14o stands out with an IC50 = 8.5 µM and SI = 8.0 on the amastigote form. In the aromatic series, the most active compounds were those containing electron-donor groups, such as trimethoxy isoxazole 14g (IC50 = 1.2 µM and SI = 20.2); compound 14h, with IC50 = 7.0 µM and SI = 6.1; and compound 14j containing the 4-SCH3 group, with IC50 = 5.7 µM and SI = 10.2. In addition, the antifungal activity of 19 nitrofuran isoxazoles was evaluated against five strains of Candida (C. albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata). Eleven isoxazole derivatives were active against C. parapsilosis, and compound 14o was found to be the most active (minimal inhibitory concentration [MIC] = 3.4 µM) for this strain. Compound 14p was active against all the strains tested, with an MIC = 17.5 µM for C. glabrata, lower than that of the fluconazole used as the reference drug.

Chemotherapy of leishmaniasis: present challenges.

Cutaneous and visceral leishmaniasis are amongst the most devastating infectious diseases of our time, affecting millions of people worldwide. The treatment of these serious diseases rely on a few chemotherapeutic agents, most of which are of parenteral use and induce severe side-effects. Furthermore, rates of treatment failure are high and have been linked to drug resistance in some areas. Here, we reviewed data on current chemotherapy practice in leishmaniasis. Drug resistance and mechanisms of resistance are described as well as the prospects for applying drug combinations for leishmaniasis chemotherapy. It is clear that efforts for discovering new drugs applicable to leishmaniasis chemotherapy are essential. The main aspects on the various steps of drug discovery in the field are discussed.

Efficacy of tamoxifen and miltefosine combined therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis.

OBJECTIVES: The objective of this study was to characterize in vitro interactions and evaluate the antileishmanial activity of tamoxifen and miltefosine combinations. METHODS: Interactions between drugs were evaluated in vitro against Leishmania amazonensis promastigotes and intracellular amastigotes by a modified isobologram method. Four different drug ratios were used to calculate the FIC index (FICI) and the mean sum of FICI. Treatment of L. amazonensis-infected BALB/c mice was initiated 4 weeks post-infection. Mice were treated with the half-maximal effective dose (ED50) or half the ED50 of tamoxifen and miltefosine orally for 15 days. Efficacy was evaluated by lesion growth and parasite burden measured through luciferase detection at the end of treatment and 30 days later. Characterization of growth curves and stepwise increase in drug concentrations in vitro were used to measure survival and resistance selection of parasite populations submitted to combination treatment. RESULTS: No in vitro interactions between tamoxifen and miltefosine were found. In infected mice, the combination of tamoxifen and miltefosine at doses corresponding to half the ED50 was more effective than monotherapy with either tamoxifen or miltefosine. When the ED50 was employed, the efficacy of the combination was equivalent to miltefosine monotherapy. In vitro, tamoxifen was able to retard or suppress the growth of parasites treated with miltefosine. CONCLUSIONS: In vitro and in vivo studies revealed no interaction between tamoxifen and miltefosine. Tamoxifen was able to hinder the emergence of miltefosine resistance.

Antileishmanial Activity and Structure-Activity Relationship of Triazolic Compounds Derived from the Neolignans Grandisin, Veraguensin, and Machilin G.

Sixteen 1,4-diaryl-1,2,3-triazole compounds 4-19 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania) amazonensis intracellular amastigotes. Triazole compounds 4-19 were synthetized via Click Chemistry strategy by 1,3-dipolar cycloaddition between terminal acetylenes and aryl azides containing methoxy and methylenedioxy groups as substituents. Our results suggest that most derivatives were active against intracellular amastigotes, with IC50 values ranging from 4.4 to 32.7 µM. The index of molecular hydrophobicity (ClogP) ranged from 2.8 to 3.4, reflecting a lipophilicity/hydrosolubility rate suitable for transport across membranes, which may have resulted in the potent antileishmanial activity observed. Regarding structure-activity relationship (SAR), compounds 14 and 19, containing a trimethoxy group, were the most active (IC50 values of 5.6 and 4.4 µM, respectively), with low cytotoxicity on mammalian cells (SI = 14.1 and 10.6). These compounds induced nitric oxide production by the host macrophage cells, which could be suggested as the mechanism involved in the intracellular killing of parasites. These results would be useful for the planning of new derivatives with higher antileishmanial activities.

Telomeric gene deletion and intrachromosomal amplification in antimony-resistant Leishmania.

Antimonials are still the mainstay of treatment against leishmaniasis but drug resistance is increasing. We carried out short read next-generation sequencing (NGS) and comparative genomic hybridization (CGH) of three independent Leishmania major antimony-resistant mutants. Copy number variations were consistently detected with both NGS and CGH. A major attribute of antimony resistance was a novel terminal deletion of variable length (67 kb to 204 kb) of the polyploid chromosome 31 in the three mutants. Terminal deletions in two mutants occurred at the level of inverted repeated sequences. The AQP1 gene coding for an aquaglyceroporin was part of the deleted region and its transfection into resistant mutants reverted resistance to SbIII. We also highlighted an intrachromosomal amplification of a subtelomeric locus on chromosome 34 in one mutant. This region encoded for ascorbate-dependent peroxidase (APX) and glucose-6-phosphate dehydrogenase (G6PDH). Overexpression of these genes in revertant backgrounds demonstrated resistance to SbIII and protection from reactive oxygen species (ROS). Generation of a G6PDH null mutant in one revertant exhibited SbIII sensitivity and a decreased protection of ROS. Our genomic analyses and functional validation highlighted novel genomic rearrangements, functionally important resistant loci and the implication of new genes in antimony resistance in Leishmania.

Administration of granulocyte colony-stimulating factor induces immunomodulation, recruitment of T regulatory cells, reduction of myocarditis and decrease of parasite load in a mouse model of chronic Chagas disease cardiomyopathy.

Chagas disease, caused by Trypanosoma cruzi infection, is a leading cause of heart failure in Latin American countries. In a previous study, we showed beneficial effects of granulocyte colony-stimulating factor (G-CSF) administration in the heart function of mice with chronic T. cruzi infection. Presently, we investigated the mechanisms by which this cytokine exerts its beneficial effects. Mice chronically infected with T. cruzi were treated with human recombinant G-CSF (3 courses of 200 µg/kg/d for 5 d). Inflammation and fibrosis were reduced in the hearts of G-CSF-treated mice, compared with the hearts of vehicle-treated mice, which correlated with decreased syndecan-4, intercellular adhesion molecule-1, and galectin-3 expressions. Marked reductions in interferon-γ and tumor necrosis factor-α and increased interleukin-10 and transforming growth factor-ß were found after G-CSF administration. Because the therapy did not induce a Th1 to Th2 immune response deviation, we investigated the role of regulatory T (Treg) cells. A significant increase in CD3(+)Foxp3(+) cells was observed in the hearts of G-CSF-treated mice. In addition, a reduction of parasitism was observed after G-CSF treatment. Our results indicate a role of Treg cells in the immunosuppression induced by G-CSF treatment and reinforces its potential therapeutic use for patients with Chagas disease.

Myopia Prevalence in Latin American Children and Adolescents: A Systematic Review and Meta-Analysis.

Although myopia is a growing global concern, comprehensive studies on its prevalence among Latin American (LATAM) children and adolescents are still lacking. Thus, we conducted a systematic review and meta-analysis to determine the prevalence of myopia in LATAM children and adolescents aged three to 20. The study conducted a thorough literature search from January 1, 1975, to February 28, 2023, identifying 24 studies on the prevalence of myopia in LATAM that met the inclusion criteria. Quality assessment and standardized data collection were performed. The meta-analysis used a random-effects model due to heterogeneity and calculated prevalence rates. Finally, the analysis of data from 24 eligible studies revealed a myopia prevalence of 8.61% (range 0.80-47.36%, 95% confidence interval (CI): 5.22-13.87%, p < 0.05) among 165,721 LATAM children and adolescents. No significant age-based associations or temporal trends were observed in this study. Studies with non-cycloplegic or objective assessment exhibited a numerically higher, although statistically non-significant, myopia prevalence (10.62%, 95% CI: 4.9-21.6%) compared to studies using cycloplegia (7.17%, 95% CI: 3.40-14.50%). In conclusion, myopia affects approximately one in 11 LATAM children and adolescents. Given the increasing exposure of LATAM youth to known myopia risk factors, such as extensive near-work, online learning, and limited outdoor activities, it is crucial to monitor myopia trends in this region. Further research is imperative to address and prevent myopia in LATAM.

Amphotericin B resistance in Leishmania amazonensis: In vitro and in vivo characterization of a Brazilian clinical isolate.

In Brazil, Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The state of Maranhão in the Northeast of Brazil is prevalent for these clinical forms of the disease and also has high rates of HIV infection. Here, we characterized the drug susceptibility of a L. amazonensis clinical isolate from a 46-year-old man with diffuse cutaneous leishmaniasis coinfected with HIV from this endemic area. This patient underwent several therapeutic regimens with meglumine antimoniate, liposomal amphotericin B, and pentamidine, without success. In vitro susceptibility assays against promastigotes and intracellular amastigotes demonstrated that this isolate had low susceptibility to amphotericin B, when compared with the reference strain of this species that is considered susceptible to antileishmanial drugs. Additionally, we investigated whether the low in vitro susceptibility would affect the in vivo response to amphotericin B treatment. The drug was effective in reducing the lesion size and parasite burden in mice infected with the reference strain, whereas those infected with the clinical isolate and a resistant line (generated experimentally by stepwise selection) were refractory to amphotericin B treatment. To evaluate whether the isolate was intrinsically resistant to amphotericin B in animals, infected mice were treated with other drugs that had not been used in the treatment of the patient (miltefosine, paromomycin, and a combination of both). Our findings demonstrated that all drug schemes were able to reduce lesion size and parasite burden in animals infected with the clinical isolate, confirming the amphotericin B-resistance phenotype. These findings indicate that the treatment failure observed in the patient may be associated with amphotericin B resistance, and demonstrate the potential emergence of amphotericin B-resistant L. amazonensis isolates in an area of Brazil endemic for cutaneous leishmaniasis.

Design and Synthesis of Novel 3-Nitro-1H-1,2,4-triazole-1,2,3-triazole-1,4-disubstituted Analogs as Promising Antitrypanosomatid Agents: Evaluation of In Vitro Activity against Chagas Disease and Leishmaniasis.

A series of 28 compounds, 3-nitro-1H-1,2,4-triazole, were synthesized by click-chemistry with diverse substitution patterns using medicinal chemistry approaches, such as bioisosterism, Craig-plot, and the Topliss set with excellent yields. Overall, the analogs demonstrated relevant in vitro antitrypanosomatid activity. Analog 15g (R1 = 4-OCF3-Ph, IC50 = 0.09 µM, SI = >555.5) exhibited an outstanding antichagasic activity (Trypanosoma cruzi, Tulahuen LacZ strain) 68-fold more active than benznidazole (BZN, IC50 = 6.15 µM, SI = >8.13) with relevant selectivity index, and suitable LipE = 5.31. 15g was considered an appropriate substrate for the type I nitro reductases (TcNTR I), contributing to a likely potential mechanism of action for antichagasic activity. Finally, 15g showed nonmutagenic potential against Salmonella typhimurium strains (TA98, TA100, and TA102). Therefore, 3-nitro-1H-1,2,4-triazole 15g is a promising antitrypanosomatid candidate for in vivo studies.

Three outbreak-causing Neisseria meningitidis serogroup C clones, Brazil(1.).

During 2003-2012, 8 clusters of meningococcal disease were identified in Rio de Janeiro State, Brazil, all caused by serogroup C Neisseria meningitidis. The isolates were assigned to 3 clonal complexes (cc): cc11, cc32, and cc103. These hyperinvasive disease lineages were associated with endemic disease, outbreaks, and high case-fatality rates.

Green Synthesis of Molecules for the Treatment of Neglected Diseases.

Neglected tropical diseases (NTDs) affect mainly poor and marginalized populations of tropical and subtropical areas in 150 countries. Many of the chemical processes involved in the synthesis of active pharmaceutical ingredients (APIs) are highly polluting and inefficient, both in terms of materials and energy-consuming. In this review, we present the green protocols developed in the last 10 years to access new small molecules with potential applications in the treatment of leishmania, tuberculosis, malaria, and Chagas disease. The use of alternative and efficient energy sources, like microwaves and ultrasound, as well as reactions using green solvents and solvent-free protocols, are discussed in this review.

In Vitro Drug Susceptibility of a Leishmania (Leishmania) infantum Isolate from a Visceral Leishmaniasis Pediatric Patient after Multiple Relapses.

The parasitic protozoan Leishmania (Leishmania) infantum is the etiological agent of human visceral leishmaniasis in South America, an infectious disease associated with malnutrition, anemia, and hepatosplenomegaly. In Brazil alone, around 2700 cases are reported each year. Treatment failure can occur as a result of drug, host, and/or parasite-related factors. Here, we isolated a Leishmania species from a pediatric patient with visceral leishmaniasis that did not respond to chemotherapy, experiencing a total of nine therapeutic relapses and undergoing a splenectomy. The parasite was confirmed as L. (L.) infantum after sequencing of the ribosomal DNA internal transcribed spacer, and the clinical isolate, in both promastigote and amastigote forms, was submitted to in vitro susceptibility assays with all the drugs currently used in the chemotherapy of leishmaniasis. The isolate was susceptible to meglumine antimoniate, amphotericin B, pentamidine, miltefosine, and paromomycin, similarly to another strain of this species that had previously been characterized. These findings indicate that the multiples relapses observed in this pediatric patient were not due to a decrease in the drug susceptibility of this isolate; therefore, immunophysiological aspects of the patient should be further investigated to understand the basis of treatment failure in this case.

Kinin B1 receptor controls maternal adiponectin levels and influences offspring weight gain.

Given the importance of the kinin B1 receptor in insulin and leptin hormonal regulation, which in turn is crucial in maternal adaptations to ensure nutrient supply to the fetus, we investigated the role of this receptor in maternal metabolism and fetoplacental development. Wild-type and kinin B1 receptor-deficient (B1KO) female mice were mated with male mice of the opposite genotype. Consequently, the entire litter was heterozygous for kinin B1 receptor, ensuring that there would be no influence of offspring genotype on the maternal phenotype. Maternal kinin B1 receptor blockade reduces adiponectin secretion by adipose tissue ex vivo, consistent with lower adiponectin levels in pregnant B1KO mice. Furthermore, fasting insulinemia also increased, which was associated with placental insulin resistance, reduced placental glycogen accumulation, and heavier offspring. Therefore, we propose the combination of chronic hyperinsulinemia and reduced adiponectin secretion in B1KO female mice create a maternal obesogenic environment that results in heavier pups.

In Vivo Antileishmanial Effect of 3,5-Diaryl-isoxazole Analogues Based on Veraguensin, Grandisin, and Machilin G: A Glance at a Preclinical Study.

New treatment approaches targeting cutaneous leishmaniasis (CL) are required since conventional drugs exhibit limitations due to their several adverse effects and toxicity. In this study, we aimed to evaluate the in vivo intralesional treatment efficacy of five isoxazole derivatives previously synthesized and effective in vitro against intracellular amastigote forms of Leishmania (L.) amazonensis. Among the tested analogues, 7 exhibited relevant in vivo therapeutic effects. The in silico predictions provided interesting information about the toxicity, suggesting the safety of analogue 7. Experiments performed with Salmonella typhimurium strains (TA98, TA100, and TA102) showed a non-mutagenicity profile of 7. The treatment of Leishmania-infected BALB/c mice with isoxazole 7 showed remarkably smaller CL lesions and decreased the parasitism (by 98.4%) compared to the control group. Hence, analogue 7 is a promising drug candidate and alternative treatment for CL caused by L. amazonensis.