Multi-faceted dysregulated immune response for COVID-19 infection explaining clinical heterogeneity.

Clinical heterogeneity and varied prognosis are well noted for SARS-CoV-2 infection. Altered immune response is a major feature for the adverse prognosis however focus on altered immune response has been primarily limited to hyper-inflammatory responses like Cytokine storm. A deeper understanding of viral pathobiology and the interplay of innate and adaptive immune cells against SARS-CoV-2 infection is essential to optimize intervention strategy and future preparedness for SARS-CoV-2 or its related viral diseases. To uncover the immunological signatures driving the progression of SARS-CoV-2 infection, we performed an extensive immunophenotype on blood samples from 79 hospitalized patients with mild/moderate to severe infections as well as from healthy controls and recovered donors to understand the interplay between innate and adaptive responses impacting severity and prognosis. We observed multifarious immune dysregulation, varied across patients of the clinical spectrum. We observed 4 major dysregulations of immune phenotypes 1) depletion of M1φ (impaired antiviral response as APC), 2) immune suppression/exhaustion via activation of repressor like CD4+/CD8+PD1, TIM3, LAG3 3) inappropriate differentiation of lymphocyte (extreme elevated proportion of CD4 naive, memory B and T cells along with reduction of inflammatory activator like TLR2/4/TIGIT) and 4) cytokine storm. Our results show the identification of biomarkers to differentiate the different trajectories for SARS-CoV-2 infection.

Microwave produced 8-methyl-1,2,4,8-tetraazaspiro[4.5]dec-2-en-3-amine derivatives: their in vitro and in silico analysis.

Compound 1 is formed by a microwave-assisted multicomponent reaction of 1-methylpiperidin-4-one, 2-amino-4-methoxy-6-methyl-1,3,5-triazine, and thiosemicarbazide, followed by the synthesis of Schiff base 2a-l with a variety of aldehydes. A comparison was made between the conventional and microwave methods, and the microwave approach was shown to be considerably superior to the classical method since it takes less time and produces higher yields. Several spectral investigations, including 1H NMR, 13C NMR, Mass, and IR spectroscopy, are used to characterize the complete series. In vitro antibacterial testing suggests that compounds 2c, 2f, and 2g are promising antibacterial agents, although compounds 2d, 2e, and 2l are effective antimycobacterial agents when compared to the conventional medicine Rifampicin. The docking score from docking studies is considerable, which validates the results of the biological examination. Molecular docking was performed on Escherichia coli DNA gyrase. According to the in silico ADME analysis, each drug molecule is ideal for use in terms of drug solubility, hydrogen bonding, and cell permeability.

Association of Pyuria with Uropathogens in Young Children.

OBJECTIVE: To examine the association between uropathogens and pyuria in children <24 months of age. STUDY DESIGN: A retrospective study of children <24 months of age evaluated in the emergency department for suspected urinary tract infection (UTI) with paired urinalysis and urine culture during a 6-year period. Bagged urine specimens or urine culture growing mixed/multiple urogenital organisms were excluded. Analysis was limited to children with positive urine culture as defined by the American Academy of Pediatrics clinical practice guideline culture thresholds. RESULTS: Of 30 462 children, 1916 had microscopic urinalysis and positive urine culture. Urine was obtained by transurethral in-and-out catheterization in 98.3% of cases. Pyuria (≥5 white blood cells per high-powered field) and positive leukocyte esterase (small or more) on the urine dipstick were present in 1690 (88.2%) and 1692 (88.3%) of the children respectively. Children with non-Escherichia coli species were less likely to exhibit microscopic pyuria than children with E coli (OR 0.24, 95% CI 0.17-0.34) with more pronounced effect on Enterococcus and Klebsiella (OR 0.08, 95% CI 0.03-0.18 and OR 0.18, 95% CI 0.11-0.27 respectively). Similarly, positive leukocyte esterase was less frequently seen in non-E coli uropathogens compared with E coli. CONCLUSIONS: Pyuria and leukocyte esterase are not sensitive markers to identify non-E coli UTI in young children. More sensitive screening biomarkers are needed to identify UTI with these uropathogens.

Smooth Muscle Tumors of the Visceral Adnexal and Uterine Ligaments and Adnexal Connective Tissue: A Clinicopathologic Study of 67 Cases.

The endopelvic fascia is a biomechanical network of supportive tissue that suspends and secures the female reproductive organs to the pelvic sidewall. Several visceral adnexal and uterine ligaments are part of this framework, and we have observed that smooth muscle tumors (SMTs) arising from these structures morphologically resemble gynecologic smooth muscle neoplasms. To determine whether gynecologic smooth muscle tumor criteria for malignancy are valid in these tumors, we evaluated the morphologic features of 67 tumors from 67 patients and correlated our findings with patient outcome. Using current uterine SMT WHO definitions, 57 tumors (85%) were classified as leiomyoma, 2 (3%) as smooth muscle tumor of uncertain malignant potential (STUMP), and 8 (12%) as leiomyosarcoma. Clinical follow-up was available for 88% of patients (range: 1-296 mo, mean: 174 mo, median: 79 mo). Only 1 case of leiomyosarcoma had metastasis at time of presentation, but 6 of 8 (75%) patients eventually died of disease. The other 2 cases of leiomyosarcoma that have not recurred are 11 and 16 mo from initial diagnosis. No cases of STUMP or leiomyoma recurred. On the basis of morphologic features and patient outcome, we believe these tumors distribute into similar categories of leiomyoma, STUMP and leiomyosarcoma, paralleling the biologic potential of uterine SMTs as well as SMTs of other gynecologic sites. We propose use of uterine WHO SMT criteria to classify spindled SMTs that arise in the visceral adnexal and uterine ligaments and adnexal connective tissue.

Artificial Intelligence Applied to Gastrointestinal Diagnostics: A Review.

Artificial intelligence (AI), a discipline encompassed by data science, has seen recent rapid growth in its application to healthcare and beyond, and is now an integral part of daily life. Uses of AI in gastroenterology include the automated detection of disease and differentiation of pathology subtypes and disease severity. Although a majority of AI research in gastroenterology focuses on adult applications, there are a number of pediatric pathologies that could benefit from more research. As new and improved diagnostic tools become available and more information is retrieved from them, AI could provide physicians a method to distill enormous amounts of data into enhanced decision-making and cost saving for children with digestive disorders. This review provides a broad overview of AI and examples of its possible applications in pediatric gastroenterology.

Genes associated with bowel metastases in ovarian cancer.

OBJECTIVE: This study is designed to identify genes and pathways that could promote metastasis to the bowel in high-grade serous ovarian cancer (OC) and evaluate their associations with clinical outcomes. METHODS: We performed RNA sequencing of OC primary tumors (PTs) and their corresponding bowel metastases (n = 21 discovery set; n = 18 replication set). Differentially expressed genes (DEGs) were those expressed at least 2-fold higher in bowel metastases (BMets) than PTs in at least 30% of patients (P < .05) with no increased expression in paired benign bowel tissue and were validated with quantitative reverse transcription PCR. Using an independent OC cohort (n = 333), associations between DEGs in PTs and surgical and clinical outcomes were performed. Immunohistochemistry and mouse xenograft studies were performed to confirm the role of LRRC15 in promoting metastasis. RESULTS: Among 27 DEGs in the discovery set, 21 were confirmed in the replication set: SFRP2, Col11A1, LRRC15, ADAM12, ADAMTS12, MFAP5, LUM, PLPP4, FAP, POSTN, GRP, MMP11, MMP13, C1QTNF3, EPYC, DIO2, KCNA1, NETO1, NTM, MYH13, and PVALB. Higher expression of more than half of the genes in the PT was associated with an increased requirement for bowel resection at primary surgery and an inability to achieve complete cytoreduction. Increased expression of LRRC15 in BMets was confirmed by immunohistochemistry and knockdown of LRRC15 significantly inhibited tumor progression in mice. CONCLUSIONS: We identified 21 genes that are overexpressed in bowel metastases among patients with OC. Our findings will help select potential molecular targets for the prevention and treatment of malignant bowel obstruction in OC.

Follicular thyroid carcinoma metastasis to the facial skeleton: a systematic review.

BACKGROUND: Follicular thyroid carcinoma (FTC) metastasis to the facial skeleton is exceedingly rare. A case of FTC metastasizing to the mandible is presented and a systematic review of the literature describing thyroid metastasis to the facial skeleton is performed. CASE PRESENTATION: A 73-year-old female presented with metastatic FTC to the mandible and underwent total thyroidectomy, segmental mandibulectomy, bone impacted fibular free flap reconstruction, and adjuvant radioactive iodine treatment. The PubMed database was searched for literature describing thyroid cancer with facial skeleton metastasis using the key words "thyroid," "cancer," "carcinoma," "metastasis," and "malignancy" with "oral cavity," "maxilla," "mandible," "sinus," "paranasal," and "orbit." Reports that only involved the soft tissues were excluded. Systematic review revealed 59 cases of well-differentiated thyroid cancer with facial skeleton metastasis: 35 mandibular metastases (21 = FTC), 6 maxilla metastases (2 = FTC), 9 orbital metastases (4 = FTC), and 11 paranasal sinus metastases (7 = FTC). Treatment included surgery, RAI, external beam radiotherapy (XRT), or a combination of these modalities. The one, two, and five-year survival rates were 100%, 79%, and 16%, respectively. CONCLUSION: Facial skeleton metastasis of FTC is a rare clinical challenge. Optimal treatment appears to include total thyroidectomy and resection of involved structures with or without adjuvant treatment.

Endometrial Thickness as Measured by Transvaginal Ultrasound and the Corresponding Histopathologic Diagnosis in Women With Postmenopausal Bleeding.

Endometrial thickness as measured by transvaginal ultrasound (TVUS) is being increasingly used as a first-line method to evaluate patients with vaginal bleeding. Our study aims to examine correlation between the histopathologic diagnosis and the results of TVUS and find a threshold that could reliably exclude carcinoma. We included women, age 55 years and above, who presented with postmenopausal bleeding and had a TVUS within 30 days of their endometrial biopsy. Total of 304 patients met our criteria and were divided into 4 groups. Patients in group A (n=198) had benign/atrophic endometrium, group B (n=44) had polyps, group C (n=30) had hyperplasia, and group D (n=32) had carcinoma. The endometrial thickness obtained by TVUS was compared with the histopathologic finding of the endometrial biopsy. The mean endometrial thickness was 7.5, 12.1, 14.8, and 16.9 mm for groups A to D, respectively. Statistical analysis showed that very low endometrial thickness (3 to 4 mm) would be ideal to use as a threshold to maximize sensitivity. Three of 32 patients in group D had an endometrial thickness ≤4 mm. At a threshold of 4 mm, the sensitivity is 90.6% and increases to 96.9% when decreasing the threshold to 3 mm. However, other parameters such as test accuracy, specificity, and positive predictive values are very low at these thresholds. Sensitivity can be maximized to 96.9% using a threshold of 3 mm. However, this would call into question the cost-effectiveness of this method. Postmenopausal bleeding remains the most reliable indicator of endometrial pathology.

Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer.

BACKGROUND: Modifications of FOLFIRINOX are widely used despite the absence of prospective data validating efficacy in metastatic disease (metastatic pancreatic cancer (MPC)) or locally advanced pancreatic cancer (LAPC). We conducted a multicentre phase II study of modified FOLFIRINOX in advanced pancreatic cancer to assess the impact of dose attenuation in MPC and efficacy in LAPC. METHODS: Patients with untreated MPC or LAPC received modified FOLFIRINOX (irinotecan and bolus 5-fluorouracil reduced by 25%). Adverse events (AEs) were compared with full-dose FOLFIRINOX. Response rate (RR), median progression-free survival (PFS) and median overall survival (OS) were determined. RESULTS: In total, 31 and 44 patients with LAPC and MPC were enrolled, respectively. In MPC, efficacy of modified FOLFIRINOX was comparable with FOLFIRINOX with RR 35.1%, OS 10.2 months (95% CI 7.65-14.32) and PFS 6.1 months (95% CI 5.19-8.31). In LAPC, efficacy was notable with RR 17.2%, resection rate 41.9%, PFS 17.8 months (95% CI 11.0-23.9) and OS 26.6 months (95% CI 16.7, NA). Neutropenia (P<0.0001), vomiting (P<0.001) and fatigue (P=0.01) were significantly decreased. [(18)F]-Fluorodeoxyglucose positron emission tomography imaging response did not correlate with PFS or OS. CONCLUSIONS: In this first prospective study of modified FOLFIRINOX in MPC and LAPC, we observed decreased AEs compared with historical control patients. In MPC, the efficacy appears comparable with FOLFIRINOX. In LAPC, PFS and OS were prolonged and support the continued use of FOLFIRINOX in this setting.

Academic portfolio in the digital era: organizing and maintaining a portfolio using reference managers.

The academic portfolio has become an integral part of the promotions process. Creating and maintaining an academic portfolio in paper-based or web-based formats can be a cumbersome and time-consuming task. In this article, we describe an alternative way to efficiently organize an academic portfolio using a reference manager software, and discuss some of the afforded advantages. The reference manager software Papers (Mekentosj, Amsterdam, The Netherlands) was used to create an academic portfolio. The article outlines the key steps in creating and maintaining a digital academic portfolio. Using reference manager software (Papers), we created an academic portfolio that allows the user to digitally organize clinical, teaching, and research accomplishments in an indexed library enabling efficient updating, rapid retrieval, and easy sharing. To our knowledge, this is the first digital portfolio of its kind.

Intramedullary Kirschner Wire Fixation for Metatarsal Fractures: A Comprehensive Review of Treatment Outcomes.

Metatarsal fractures pose significant challenges in orthopedic practice, necessitating effective treatment methods to ensure optimal patient outcomes. This comprehensive review focuses on intramedullary Kirschner wire fixation as a promising intervention for metatarsal fractures. Beginning with an overview of metatarsal fractures and the imperative for effective treatments, the review delves into intramedullary fixation's definition, historical background, advantages, and disadvantages. Indications for its use in metatarsal fractures are discussed, providing a foundation for understanding its application. The surgical technique section outlines critical aspects, including patient selection criteria and preoperative planning. Before presenting a detailed step-by-step procedure for intramedullary Kirschner wire fixation, anesthesia considerations are explored. Emphasizing precision, fluoroscopic guidance, and meticulous postoperative care, this section provides insights for surgeons and healthcare practitioners. Considerations for rehabilitation follow, addressing postoperative care, expected recovery timelines, and physical therapy recommendations. Early mobilization, weight-bearing guidelines, and a structured rehabilitation program play pivotal roles in recovery. In the conclusion, key findings are summarized, highlighting the efficacy of intramedullary Kirschner wire fixation, its advantages, and recommendations for clinical practice. Additionally, areas for future research are identified, guiding further exploration and refinement of this surgical approach. This review is valuable for clinicians, researchers, and healthcare practitioners involved in metatarsal fracture management, contributing to the evolution of treatment strategies and improving patient care.

Exploring implications of Medicaid participation and wait times for colorectal screening on early detection efforts in Connecticut--a secret-shopper survey.

BACKGROUND: Routine colorectal screening, decreases in incidence, and advances in treatment have lowered colorectal cancer mortality rates over the past three decades. Nevertheless, it remains the second most common cause of cancer death amongst men and women combined in U.S. Most cases of colon cancer are diagnosed at a late stage leading to poor survival outcomes for patients. After extensive research of publically available data, it would appear that the state of Connecticut does not have available state-wide data on patient wait times for routine colonoscopy screening. Furthermore, there are no publicly available, or Connecticut-specific, reports on Medicaid participation rates for colorectal screening amongst gastroenterologists (GI) in Connecticut. In 2012, the American Cancer Society report on Colorectal Cancer Screening Rates confirmed barriers to health-care access and disparities in health outcomes and survival rates for colon cancer patients based on race, ethnicity, and low socioeconomic status. Given this information, one could conjecture that low Medicaid participation rates among GIs could potentially have a more severe impact on health-care access and outcomes for underserved populations. At present, funding and human resources are being employed across the state of Connecticut to address bottlenecks in colorectal cancer screening. More specifically, patient navigation and outreach programs are emerging and expanding to address the gaps in services for hard-to-reach populations and the medically underserved. Low Medicaid participation rates and increased wait times for colonoscopy screening may impair the efficacy of colorectal cancer patient navigation and outreach efforts and potentially funding for future interventions. In this study, we report the results of our secret-shopper telephone survey comprising of 93 group and independent gastroenterologist (GI) practices in different counties of Connecticut. METHODS: Reviewing online resources and yellow pages, researchers compiled a county-specific list of GI practices throughout Connecticut and conducted a secret-shopper survey by telephone. A standard script and set of questions was formulated and used for each telephone call to GI practices. Data was analyzed in context of statistics available to the public at large from the U.S. Census Bureau. RESULTS: Overall, 46% of all 93 practices and 62% of individual GIs from all 93 practices state-wide reported Medicaid participation. About 35% of surveyed practices were independent practices; 41% of these reported Medicaid participation. About 65% of surveyed practices were group practices; 49% of these reported Medicaid participation. Approximately, 85% of all practices are in Fairfield, Hartford, orNew Haven counties. Of all three counties, New Haven reported the highest Medicaid participation rate by practices; 62% of all practices in New Haven reported participation. Fairfield reported the lowest Medicaid participation rate by practices; 29% of all practices in Fairfield reported participation. When Medicaid participation rates were calculated for total number of gastroenterologists from all practices in a given county (as opposed to participation rates by number of practices), Medicaid participation rates were 80% and 44% for New Haven and Fairfield, respectively. Of all practices in Hartford, only 50% reported Medicaid participation, whereas 67% of the total number of gastroenterologists (as opposed to practices) reported Medicaid participation. According to a recent national survey, 47% of gastroenterologists reported stopping accepting new Medicaid patients. Overall minimum and maximum wait times were reported to be the highest for Hartford, but wait times were long even for smaller counties, reflecting a possible imbalance in supply and demand or inefficiency in allocating the available resources. CONCLUSIONS: Only a limited number of gastroenterology practices in Connecticut accept Medicaid patients, notably in selected counties, but in all counties, and this may add to access barriers. It is yet unclear whether these disparities are significant enough to create a supply-demand imbalance and thus, have a significantly negative impact on health outcomes for the underserved. Nevertheless, with the high unemployment rates and impending implementation of mandated state-wide health-care reform as outlined in the Affordable Care Act, the Medicaid population in the state of Connecticut will increase, increasing future demand for services. In addition, based on the survey findings, longer wait times for colonoscopy screening are reported for the many of GI practices in Connecticut for Medicaid-insured as well as non-Medicaid patients. Longer wait times may have an impact on patient compliance, especially for the underserved populations that are hard to reach and ensure follow-up, contributing to potential delayed diagnosis. A Medicaid-associated disparity in this area will serve to exacerbate the problem for the underserved compared to those relatively well served. Those currently not seeking screening are at even higher risk of contributing to the higher mortality rate, and we need to find out how best to ensure that we can more uniformly apply screening and have the capacity to do so.

Thiazolidinediones: Recent Development in Analytical Methodologies.

The instrumental analytical methods that have been developed and utilized for the determination of thiazolidinedione in bulk medications, formulations and biological fluids have been reviewed after an in-depth analysis of the literature published in a variety of analytical and pharmaceutical chemistry-related journals. The approaches covered by this research, which covers the years 2001-2022, include complex methods for analysis, chromatographic techniques and spectrometric analytical procedures. The mobile phase, flow rate, sample matrix, wavelength and other factors identified in the literature were just a few of the parameters used to evaluate thiazolidinediones. The present review focuses on the published analytical techniques for thiazolidinedione analysis that have been previously identified in the literature. The specified outcomes followed extensive learning, and the most recent advances in analytical methods for the identification of pioglitazone, pioglitazone HCl, rosiglitazone, rosiglitazone maleate and lobeglitazone were reviewed. Additionally, this article briefly discusses features of analytical discovery on thiazolidinediones, which will enable readers to access all discoveries in one place with precise outcomes.

Motor-Augmented Wrist-Driven Orthosis: Flexible Grasp Assistance for People with Spinal Cord Injury.

This paper presents the design of a motor-augmented wrist-driven orthosis (MWDO) for improved grasp articulation for people with C6-C7 spinal cord injuries. Based on the traditional passive, wrist-driven orthotic (WDO) mechanism, the MWDO allows for both body-powered and motorized actuation of the grasping output thus enabling more flexible and dexterous operation. Here, the associated control scheme enables active decoupling of wrist and finger articulation, which can be useful during certain phases of manipulation tasks. An additional modification to the traditional WDO is the integration of a magnetic latch at the Distal Interphalangeal (DIP) joint allowing for improved pinching. These abilities are demonstrated with common activities of daily living (ADL).

Corded and hyalinized mesonephric-like adenocarcinoma of the uterine corpus: report of a case mimicking endometrioid carcinoma.

Mesonephric-like adenocarcinoma is a recently described adenocarcinoma of the uterine body and ovary with overlapping features of mesonephric adenocarcinoma and endometrioid carcinoma. It is thought to be a mullerian adenocarcinoma that has differentiated along mesonephric lines. A 71-year-old woman had a 3-cm endometrial mass that invaded the myometrium without gross or microscopic evidence of cervical involvement. The tumor had a variety of architectural patterns and produced prominent stromal hyalinization containing embedded cords and trabeculae of tumor cells. No squamous or mucinous differentiation or associated mesonephric remnants or hyperplasia was identified. The tumor was positive for TTF1 and GATA3, very focally and weakly positive for estrogen receptor and negative for progesterone receptor and nuclear expression of ß-catenin. An unusual inverse pattern of TTF1 and GATA3 immunoreactivity was observed. DNA analysis by digital droplet polymerase chain reaction and quantitative polymerase chain reaction identified an activating KRAS (G12A) mutation. The tumor was interpreted as corded and hyalinized mesonephric-like adenocarcinoma that mimicked corded and hyalinized endometrioid carcinoma.

Synthesis, In silico Molecular Docking and Pharmacokinetic Studies, In vitro Antimycobacterial and Antimicrobial Studies of New Imidozolones Clubbed with Thiazolidinedione.

BACKGROUND: A series of (E)-5-(4-((Z)-4-substitutedbenzylidene-2-thienylmethylene-5-oxo- 2-phenyl-4,5-dihydro-1H-imidazol-1-yl) benzylidene)thiazolidine-2,4-diones were synthesized and evaluated for antimycobacterial and antimicrobial activity. All these ligands were docked against protein (InhA) Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, (PDB ID: 4COD). OBJECTIVE: In this report, we have designed and synthesized azole scaffolds with good antitubercular activities as there is a real need to develop new candidates with less toxicity and more efficiency toward pathogen. The obtained antimycobacterial activity data have been validated in the terms of ligand-protein interaction and were also analyzed for ADME properties to determine their potential to build up as good oral drug candidates. METHODS: All the synthesized compounds have been established by elemental analysis, IR, 1H NMR, 13C NMR and Mass spectral data. In vitro antimycobacterial activity was carried out against (M. tuberculosis) H37Rv strain using Lowenstein-Jensen medium and antimicrobial activity against two gram-positive bacteria (S. aureus, S. pyogenes), two gram-negative bacteria (E. coli, P. aeruginosa) and three fungal species (C. albicans, A. niger, A. clavatus) using the broth microdilution method. In silico molecular docking studies were carried out using Glide (grid-based ligand docking) program incorporated in the Schrödinger molecular modeling package by Maestro 11.0 and ADME properties of synthesized compounds was performed using DruLito software. RESULTS: Compounds 3a, 3b, 3d, 3g, 3i and 3n exhibited promising antimicrobial activity whereas compound 3n showed very good antimycobacterial activity along with Gilde docking score (-8.864) and with the one violation in Lipinski's rule of five. CONCLUSION: The wet lab result for compound 3n along with Glide XP docking score and the calculated ADME parameters give the best choice for the preparation of new derivatives in order to improve antitubercular activity in future with more improved potency.

Synthesis, biological evaluation and molecular dynamics studies of 1,2,4-triazole clubbed Mannich bases.

The present work highlightsthe synthesis of a newer biologically active Mannich bases contributing 4-((4-fluorobenzylidene)amino)-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol and various heterocyclic amines via N-Mannich reaction by the conventional method as well as microwave heating approach as a part of an environmentally benign synthetic protocol. All the synthesized compounds were characterized by spectral analysis and were screened for in vitro antimicrobial, antitubercular and antiprotozoal activity. The compound 4k was found to be most active respectively against S. aureus (MIC 12.5 µM) and C. albicans (MIC 100 µM). The derivative 4 g displayed potency against L.mexicana and T. cruzi with IC50 value 1.01 and 3.33 µM better than reference drug Miltefosina and Nifurtimox. The compound 4b displayed excellent potency against M. tuberculosis (MIC 6.25 µM) in the primary screening. The computational studies revealed for that Mannich derivative (4b) showed a high affinity toward the active site of enzyme which provides a strong platform for new structure-based design efforts. The Lipinski's parameters showed good drug-likeness properties and can be developed as an oral drug candidate.

In vitro and in vivo assessment of newer quinoxaline-oxadiazole hybrids as antimicrobial and antiprotozoal agents.

A new series of N-(substituted-phenyl)-2-[5-(quinoxalin-2-yloxymethyl)-[1,3,4] oxadiazol-2-ylsulfanyl]-acetamides (5a-o) was designed and synthesised from the parent compound 2-hydroxy quinoxaline (1) through a multistep reaction sequence and was characterised by spectral and elemental analyses. All of the compounds synthesised were evaluated for their antimicrobial and antiprotozoal activities. The results revealed that quinoxaline-based 1,3,4-oxadiazoles displayed promising antibacterial, antifungal and anti-Trypanosoma cruzi activities compared with reference drugs, particularly the lead compound 5l in a short-term in vivo model in T. cruzi.