Co(III)-Catalyzed Regioselective Functionalization of Isoquinolones with Naphthoquinones.

A strategy for Co(III)-catalyzed C(sp2)-H alkenylation of N-protected isoquinolones with 1,4-naphthoquinones has been disclosed. The developed protocol was efficiently applied for diversely substituted isoquinolones. Preliminary mechanistic experiments revealed the involvement of a five-membered cobaltacycle as an intermediate. Deuterium labeling experiments suggested the reversible nature of the C-H activation step. The scale-up reaction was also carried out, and the product was utilized as a chemosensor to detect Fe3+ ions.

ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma.

Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We screen clinically relevant small molecules for DSBR inhibition with the aim of identifying improved GBM combination therapy regimens. We identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor that suppresses radiation-induced phosphorylation of DSBR proteins, blocks DSB end resection, and enhances the cytotoxic effects of TMZ in treatment-naïve and treatment-resistant GBMs with TP53 mutation. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.

Bystander effects, pharmacokinetics, and linker-payload stability of EGFR-targeting antibody-drug conjugates Losatuxizumab vedotin and Depatux-M in glioblastoma models.

PURPOSE: Antibody-drug conjugates (ADCs) are targeted therapies with robust efficacy in solid cancers, and there is intense interest in using EGFR-specific ADCs to target EGFR-amplified glioblastoma (GBM). Given the molecular heterogeneity of GBM, bystander activity of ADCs may be important for determining treatment efficacy. In this study, the activity and toxicity of two EGFR-targeted ADCs, Losatuxizumab vedotin (ABBV-221) and Depatuxizumab mafodotin (Depatux-M), with similar auristatin toxins, were compared in GBM patient-derived xenografts (PDXs) and normal murine brain following direct infusion by convection enhanced delivery (CED). METHODS: EGFRviii-amplified and non-amplified GBM PDXs were used to determine in vitro cytotoxicity, in vivo efficacy, and bystander activities of ABBV-221 and Depatux-M. Non-tumor bearing mice were used to evaluate pharmacokinetics and toxicity of ADCs using LC-MS/MS and immunohistochemistry. RESULTS: CED improved intracranial efficacy of Depatux-M and ABBV-221 in three EGFRviii-amplified GBM PDX models (Median survival: 125 to >300 days vs 20-49 days with isotype-control AB095). Both ADCs had comparable in vitro and in vivo efficacy. However, neuronal toxicity and CD68+ microglia/macrophage infiltration were significantly higher in brains infused with ABBV-221, with the cell-permeable MMAE, as compared to Depatux-M, with the cell-impermeant MMAF. CED infusion of ABBV-221 into brain or incubation of ABBV-221 with normal brain homogenate resulted in significant release of MMAE, which is consistent with linker instability in the brain microenvironment. CONCLUSION: EGFR-targeting ADCs are promising therapeutic options for GBM when delivered intra-tumorally by CED. However, the linker and payload for the ADC must be carefully considered to maximize the therapeutic window.

Fragility of overactive bladder medication clinical trials: A systematic review.

PURPOSE: Overactive bladder (OAB) syndrome significantly impairs quality of life, often necessitating pharmacological interventions with associated risks. The fragility of OAB trial outcomes, as measured by the fragility index (FI: smallest number of event changes to reverse statistical significance) and quotient (FQ: FI divided by total sample size expressed as a percentage), is critical yet unstudied. MATERIALS AND METHODS: We conducted a systematic search for randomized controlled trials on OAB medications published between January 2000 and August 2023. Inclusion criteria were trials with two parallel arms reporting binary outcomes related to OAB medications. We extracted trial details, outcomes, and statistical tests employed. We calculated FI and FQ, analyzing associations with trial characteristics through linear regression. RESULTS: We included 57 trials with a median sample size of 211 participants and a 12% median lost to follow-up. Most studies investigated anticholinergics (37/57, 65%). The median FI/FQ was 5/3.5%. Larger trials were less fragile (median FI 8; FQ 1.0%) compared to medium (FI: 4; FQ 2.5%) and small trials (FI: 4; FQ 8.3%). Double-blinded studies exhibited higher FQs (median 2.9%) than unblinded trials (6.7%). Primary and secondary outcomes had higher FIs (median 5 and 6, respectively) than adverse events (FI: 4). Each increase in 10 participants was associated with a +0.19 increase in FI (p < 0.001). CONCLUSIONS: A change in outcome for a median of five participants, or 3.5% of the total sample size, could reverse the direction of statistical significance in OAB trials. Studies with larger sample sizes and efficacy outcomes from blinded trials were less fragile.

An integrative approach for management of post-traumatic dorsal foot wounds - A case report.

Crush injuries to the foot have become increasingly prevalent in contemporary settings, primarily arising from incidents such as the impact of large objects falling onto the foot or involvement in traffic accidents. The complexity of treating these injuries is compounded by the intricate anatomy of the foot. In specific scenarios, the implementation of an integrated management approach could prove advantageous. In this report, we depict the case of a 23-year-old male who visited the Shalya OPD with a wound on his left foot caused by trauma. The wound covered the medial portion of the foot, involving the dorsal area, and measured roughly 20 cm by 9 cm and was unable to walk. We successfully managed the case by adopting an integrative approach. The Ayurvedic treatment included Panchavalkala kashaya for wound irrigation, as well as oral administration of Amalaki rasayana, Triphala guggulu, Shatavari churna and Ashwagandha churna. Jatyadi taila was topically applied. For the first seven days, in addition to these ayurvedic medications, we also employed analgesics and antibiotics to treat infection and pain. To accomplish early closure, we employed a split-thickness skin graft after sufficient granulation tissue had appeared. The wound was completely healed within three months and the patient was able to walk freely without any support. The combined approach yielded a promising result in this case.

Hidden hunger in patients with type 2 diabetes (T2D) and its effect on glycaemic control: a protocol for systematic review and meta-analysis.

INTRODUCTION: Hidden hunger or micronutrient deficiencies are quite common in many parts of the world, particularly in the countries of sub-Saharan Africa and South Asia. Micronutrient deficiencies may impact insulin signalling pathways and glucose metabolism, potentially accelerating the onset and development of type 2 diabetes (T2D). This review aims to estimate the prevalence of multiple micronutrient deficiencies among patients with T2D and assess the effect of their deficiency on glycaemic control. METHODOLOGY: The review follows the Cochrane Handbook and PRISMA 2020 guidelines. It includes all eligible studies reporting the prevalence of micronutrient deficiencies and their effect on glycaemic control in T2D patients. We would undertake a comprehensive literature search across databases: PubMed, Scopus, EMBASE, LILACS, ProQuest, Google Scholar and grey literature, and identify the studies meeting the inclusion criteria. We would perform data extraction using a prepiloted data extraction sheet and record relevant study characteristics and outcomes. ANALYSIS: Data will be analysed using JBI Sumari software and R software. Pooled prevalence/incidence of micronutrient deficiency will be estimated, and variance will be stabilised using logit transformation and a double-arcsine transformation of the data. The OR and risk ratio of glycaemic control among T2D cases with and without micronutrient deficiency will be estimated using the 'rma' function under the 'meta' and 'metafor' packages.The study findings will have implications for diabetes management strategies and may inform interventions targeting improved glycaemic control through addressing micronutrient deficiencies. ETHICS AND DISSEMINATION: This systematic review will be based on the scientific information available in the public domain; therefore, ethics approval is not required. We will share the study findings at national and international conferences and submit them for publication in relevant scientific journals. PROSPERO REGISTRATION NUMBER: CRD42023439780.

Musculoskeletal Comorbidities among known Diabetes Patients, their Quality of Life, and Healthcare Costs: A Comparative Study From a Tertiary Care Hospital in Uttarakhand.

Introduction: Diabetes is a chronic disorder with long-term sequelae and multisystem manifestation. Burden of diabetes in on the rise. Presence of other morbidities can not only have a detrimental effect on the disease treatment and recovery course, but also on the financial burden and quality of life. Present study aims to investigate how musculoskeletal conditions affect individuals with diabetes compared to those without the condition. Material and Methods: A comparative study was conducted among patients attending the outpatient department of a tertiary care hospital in North India to assess the burden of musculoskeletal disorders in people with and without diabetes. A total of 195 diabetes patients and an equal number of individuals without diabetes were sequentially enrolled from the outpatient department (OPD). Results: Burden of musculoskeletal comorbidities was significantly higher (46.2%) among people with diabetes than the comparison group (25.1%). The overall odds ratio (OR) for comorbidities of musculoskeletal system was 2.5 times higher in diabetes cases as compared to individuals without diabetes. The OR for rheumatoid arthritis, chronic backache, and osteoarthritis was found to be 3.6, 2.9, and 1.7 respectively. Poor quality of life and higher direct cost of treatment were found among diabetes cases with musculoskeletal comorbidities as against those without these comorbidities. Conclusion: Presence of musculoskeletal comorbidity is high among diabetes patients, and it has an impact on the quality of life and treatment cost. Screening for musculoskeletal comorbidities should be included as part of the diabetes complication assessment to allow for early detection and treatment.

Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization.

ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G0-G1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53-mutant tumors but not in TP53-WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53-mutant, but not in TP53-WT, PDXs. In plasmid-based reporter assays, GBM43 (TP53-mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53-mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53-mutant cells to ATM inhibitor-mediated radiosensitization.

Differential Distribution of the DNA-PKcs Inhibitor Peposertib Selectively Radiosensitizes Patient-derived Melanoma Brain Metastasis Xenografts.

Radioresistance of melanoma brain metastases limits the clinical utility of conventionally fractionated brain radiation in this disease, and strategies to improve radiation response could have significant clinical impact. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is critical for repair of radiation-induced DNA damage, and inhibitors of this kinase can have potent effects on radiation sensitivity. In this study, the radiosensitizing effects of the DNA-PKcs inhibitor peposertib were evaluated in patient-derived xenografts of melanoma brain metastases (M12, M15, M27). In clonogenic survival assays, peposertib augmented radiation-induced killing of M12 cells at concentrations ≥100 nmol/L, and a minimum of 16 hours exposure allowed maximal sensitization. This information was integrated with pharmacokinetic modeling to define an optimal dosing regimen for peposertib of 125 mpk dosed just prior to and 7 hours after irradiation. Using this drug dosing regimen in combination with 2.5 Gy × 5 fractions of radiation, significant prolongation in median survival was observed in M12-eGFP (104%; P = 0.0015) and M15 (50%; P = 0.03), while more limited effects were seen in M27 (16%, P = 0.04). These data support the concept of developing peposertib as a radiosensitizer for brain metastases and provide a paradigm for integrating in vitro and pharmacokinetic data to define an optimal radiosensitizing regimen for potent DNA repair inhibitors.

Maternal healthcare seeking and determinants of adequate antenatal care and institutional childbirth among Indian tribes: A cross-sectional study from nine districts.

OBJECTIVE: To report the utilisation of maternal healthcare services and factors associated with adequate antenatal care and institutional childbirths among mothers in the tribal communities from nine districts in India. METHODS: Cross-sectional data were collected from 2636 tribal women who had a childbirth experience in the past 12 months. Socio-demographic, maternal healthcare services and health system-related details were collected. Multiple logistic regression analyses were done to identify factors associated with adequate antenatal care (receiving at least four antenatal care visits, the first visit being in the first trimester and receiving a minimum of 100 iron-folic acid tablets) and institutional childbirth (mother giving birth in a health facility). RESULTS: Only 23% of the mothers received adequate antenatal care. 82% were institutional childbirths. The logistic regression revealed that particularly vulnerable tribal groups (PVTGs), those lacking all-weather roads, and women of advanced age were at risk of inadequate antenatal care. Mother's education, health worker's home visits during pregnancy and reception of advice on antenatal care were significantly associated with the reception of adequate antenatal care. Having all-weather roads, and education of the mother and head of the household were positively associated with institutional childbirths, whereas PVTGs, children of birth order three or above, and working mothers were more likely to give childbirth at home. CONCLUSION: PVTGs are at risk of foregoing adequate antenatal care and are more likely to give childbirth at home. Having all-weather roads is a strong correlate of adequate maternal care. Outreach activities by the health workers are to be strengthened as they are positively and significantly associated with the reception of adequate antenatal care. Investing in education and other social determinants and addressing certain socio-cultural practices is important to improve maternal health.

Experimental and Computational Studies on RuII -Catalyzed C7-Allylation of Indolines with Allyl Bromide.

The selective C7-allylation of indolines with allyl bromide under ruthenium catalysis has been revealed here. Under established reaction conditions, C7-allylation of various indolines, including drug compounds, was accomplished with good selectivity and yields. Based on combined experimental and density functional theory (DFT) studies, the olefin insertion route was energetically favorable among four possible pathways. Experimental and DFT studies further revealed that the C-H activation is a reversible rate-limiting step.

Vaccination and associated factors among tribal children of 1 year age in nine Indian districts: A cross-sectional study.

OBJECTIVE: To report on vaccination status by 12 months of age among tribal children from nine districts of India. METHODS: Cross-sectional study of 2631 tribal women having a child aged 12 months or below from nine Indian districts with a considerable proportion of the tribal population. Socio-demographic details, reception of various vaccines by 12 months of age, mother's antenatal care utilisation and health system-related details were collected through a pre-tested, interviewer-administered questionnaire from mothers. Multiple logistic regression analysis was used to identify the factors associated with complete vaccination by 12 months of age. RESULTS: Only 52% of children were fully vaccinated by the age of 12 months among the tribal populations; 11% did not receive any vaccine, and 37% of the tribal children received some vaccines. The age-appropriate vaccination was unsatisfactory as only 75% of the infants received all birth dose vaccines, and only 60.5% received all doses by 14 weeks. Only 73% were vaccinated against measles. Illness of the child, home births and communication gaps concerning vaccination were the main reasons for an infant not being vaccinated appropriately. Frequency of health worker's visits to the village, hospital birth, reception of advice on vaccination and educational status of the head of the households were significantly associated with full vaccination status. CONCLUSION: A relatively low proportion of children were fully vaccinated among the tribal populations. Health systems factors, mainly the outreach services and advice by the health workers, were positively and significantly associated with a child being fully vaccinated by 12 months of age. Improving outreach services is crucial to improve vaccination coverage in tribal areas, and there is a need to address the social determinants in the long run.

Key factors influencing public health students and curricula in India: Recommendations from a mixed methods analysis.

BACKGROUND: Building on a distinguished history of community medicine training, public health programs have been expanding in India in recent years. The COVID-19 pandemic has brought additional attention to the importance of public health programs and the need for a strong workforce. This paper aims to assess the current capacity for public health education and training in India and provide recommendations for improved approaches to meet current and future public health needs. METHODS: We conducted a desk review of public health training programs via extensive internet searches, literature reviews, and expert faculty consultations. Among those programs, we purposively selected faculty members to participate in in-depth interviews. We developed summary statistics based on the desk review. For qualitative analysis, we utilized a combination of deductive and inductive coding to identify key themes and systematically reviewed the strengths and weaknesses of each theme. RESULTS: The desk review captured 59 institutions offering public health training across India. The majority of training programs were graduate level degrees including Master of Public Health and Master of Science degrees. Key factors impacting these programs included collaborations, mentorship, curriculum standardization, tuition and funding, and student demand for public health education and careers. Collaborations and mentorship were highly valued but varied in quality across institutions. Curricula lacked standardization but also contained substantial flexibility and innovation as a result. Public sector programs were perceived to be affordable though fees and stipends varied across institutions. Further development of career opportunities in public health is needed. CONCLUSION: Public health education and training in India have a strong foothold. There are numerous opportunities for continued expansion and strengthening of this field, to support a robust multi-disciplinary public health workforce that will contribute towards achieving the sustainable development goals.

Photoredox Minisci-Type Hydroxyfluoroalkylation of Isoquinolines with N-Trifluoroethoxyphthalimide.

A straightforward photocatalytic approach has been demonstrated to incorporate a trifluoroethanol unit onto the isoquinolines. Herein, we report N-trifluoroethoxyphthalimide as a hydroxyfluoroalkyl radical precursor, enabling efficient synthesis of trifluoroethanol-substituted heteroarenes. Radical quenching experiments confirmed the involvement of a free-radical pathway under developed photocatalytic conditions. The DFT calculations confirmed the intramolecular 1,2-HAT reactivity of the O-centered trifluoroethoxy radical (generated from N-trifluoroethoxyphthalimide under photocatalytic condition) to the C-centered trifluoroethanol radical. Fluorescence quenching studies suggested that isoquinoline was responsible for the quenching of Ir-photocatalyst emission. A catalytic cycle involving trifluoroethanol radical reaction with isoquinolines has been proposed.

Convection enhanced delivery of EGFR targeting antibody-drug conjugates Serclutamab talirine and Depatux-M in glioblastoma patient-derived xenografts.

Background: EGFR targeting antibody-drug conjugates (ADCs) are highly effective against EGFR-amplified tumors, but poor distribution across the blood-brain barrier (BBB) limits their efficacy in glioblastoma (GBM) when administered systemically. We studied whether convection-enhanced delivery (CED) can be used to safely infuse ADCs into orthotopic patient-derived xenograft (PDX) models of EGFRvIII mutant GBM. Methods: The efficacy of the EGFR-targeted ADCs depatuxizumab mafodotin (Depatux-M) and Serclutamab talirine (Ser-T) was evaluated in vitro and in vivo. CED was performed in nontumor and tumor-bearing mice. Immunostaining was used to evaluate ADC distribution, pharmacodynamic effects, and normal cell toxicity. Results: Dose-finding studies in orthotopic GBM6 identified single infusion of 2 µg Ser-T and 60 µg Depatux-M as safe and effective associated with extended survival prolongation (>300 days and 95 days, respectively). However, with serial infusions every 21 days, four Ser-T doses controlled tumor growth but was associated with lethal toxicity approximately 7 days after the final infusion. Limiting dosing to two infusions in GBM108 provided profound median survival extension of over 200 days. In contrast, four Depatux-M CED doses were well tolerated and significantly extended survival in both GBM6 (158 days) and GBM108 (310 days). In a toxicity analysis, Ser-T resulted in a profound loss in NeuN+ cells and markedly elevated GFAP staining, while Depatux-M was associated only with modest elevation in GFAP staining. Conclusion: CED of Depatux-M is well tolerated and results in extended survival in orthotopic GBM PDXs. In contrast, CED of Ser-T was associated with a much narrower therapeutic window.

Central Nervous System Distribution of the Ataxia-Telangiectasia Mutated Kinase Inhibitor AZD1390: Implications for the Treatment of Brain Tumors.

Effective drug delivery to the brain is critical for the treatment of glioblastoma (GBM), an aggressive and invasive primary brain tumor that has a dismal prognosis. Radiation therapy, the mainstay of brain tumor treatment, works by inducing DNA damage. Therefore, inhibiting DNA damage response (DDR) pathways can sensitize tumor cells to radiation and enhance cytotoxicity. AZD1390 is an inhibitor of ataxia-telangiectasia mutated kinase, a critical regulator of DDR. Our in vivo studies in the mouse indicate that delivery of AZD1390 to the central nervous system (CNS) is restricted due to active efflux by P-glycoprotein (P-gp). The free fraction of AZD1390 in brain and spinal cord were found to be low, thereby reducing the partitioning of free drug to these organs. Coadministration of an efflux inhibitor significantly increased CNS exposure of AZD1390. No differences were observed in distribution of AZD1390 within different anatomic regions of CNS, and the functional activity of P-gp and breast cancer resistance protein also remained the same across brain regions. In an intracranial GBM patient-derived xenograft model, AZD1390 accumulation was higher in the tumor core and rim compared with surrounding brain. Despite this heterogenous delivery within tumor-bearing brain, AZD1390 concentrations in normal brain, tumor rim, and tumor core were above in vitro effective radiosensitizing concentrations. These results indicate that despite being a substrate of efflux in the mouse brain, sufficient AZD1390 exposure is anticipated even in regions of normal brain. SIGNIFICANCE STATEMENT: Given the invasive nature of glioblastoma (GBM), tumor cells are often protected by an intact blood-brain barrier, requiring the development of brain-penetrant molecules for effective treatment. We show that efflux mediated by P-glycoprotein (P-gp) limits central nervous system (CNS) distribution of AZD1390 and that there are no distributional differences within anatomical regions of CNS. Despite efflux by P-gp, concentrations effective for potent radiosensitization are achieved in GBM tumor-bearing mouse brains, indicating that AZD1390 is an attractive molecule for clinical development of brain tumors.

Maternal depression: Technology enabled self screening in real time.

The first step toward providing treatment, is getting the right diagnosis in real time; before it is too late. Without this, resource deployment may appear to be comparable to the scale and scope of the problem, while in reality it may just be a drop in the ocean. Maternal depression, during pregnancy is a debilitating risk to both the mother and the child, but the bigger problem is, it goes unnoticed, undetected, and therefore untreated. If mobile technology can be deployed to screen for depression in real time by the pregnant mother herself, it will go miles in creating a HOPE for health.

Strengthening institutions for public health education: results of an SWOT analysis from India to inform global best practices.

BACKGROUND: Developing public health educational programs that provide workers prepared to adequately respond to health system challenges is an historical dilemma. In India, the focus on public health education has been mounting in recent years. The COVID-19 pandemic is a harbinger of the increasing complexities surrounding public health challenges and the overdue need to progress public health education around the world. This paper aims to explore strengths and challenges of public health educational institutions in India, and elucidate unique opportunities to emerge as a global leader in reform. METHODS: To capture the landscape of public health training in India, we initiated a web-based desk review of available offerings and categorized by key descriptors and program qualities. We then undertook a series of in-depth interviews with representatives from a purposively sample of institutions and performed a qualitative SWOT analysis. RESULTS: We found that public health education exists in many formats in India. Although Master of Public Health (MPH) and similar programs are still the most common type of public health training outside of community medicine programs, other postgraduate pathways exist including diplomas, PhDs, certificates and executive trainings. The strengths of public health education institutions include research capacities, financial accessibility, and innovation, yet there is a need to improve collaborations and harmonize training with well-defined career pathways. Growing attention to the sector, improved technologies and community engagement all hold exciting potential for public health education, while externally held misconceptions can threaten institutional efficacy and potential. CONCLUSIONS: The timely need for and attention to public health education in India present a critical juncture for meaningful reform. India may also be well-situated to contextualize and scale the types of trainings needed to address complex challenges and serve as a model for other countries and the world.

Pyrazole Containing Anti-HIV Agents: An Update.

BACKGROUND: Pyrazole scaffolds have gained importance in drug discovery and development for various pharmacological activities like antiviral, antifungal, anticancer, antidepressant, antiinflammatory, antibacterial, etc. Additionally, the pyrazole moiety has shown potent anti-HIV activity as a core heterocycle or substituted heterocycles derivatives (mono, di, tri, tetra, and fused pyrazole derivatives). To assist the development of further potential anti-HIV agents containing pyrazole nucleus, here we have summarized pyrazole containing anti-HIV compounds that have been reported by researchers all over the world for the last two decades. OBJECTIVE: The present review concentrates on an assortment of pyrazole containing compounds, particularly for potential therapeutic activity against HIV. METHODS: Google Scholar, Pubmed, and SciFinder were searched databases with ''pyrazol'' keywords. Further, the year of publication and keywords ''Anti-HIV'' filter was applied to obtain relevant reported literature for anti-HIV agents containing pyrazole as a core or substituted derivatives. RESULTS: This review article has shown the comprehensive compilation of 220 compounds containing pyrazole nucleus and possessing anti-HIV activity by sorting approximately 40 research articles from 2001 to date. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin- 3-yl)ethane-1,2-dione (13), 3-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-fluoro-1H-pyrrolo[2,3- c]pyridin-7-yl)-1H-pyrazole-5-carboxamide (31), 3-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4- fluoro-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide (88), 3-cyanophenoxypyrazole derivative (130), and 4-(4-chlorophenyl)-5-(4-methyl-5-((4-nitrophenyl)diazenyl)thiazol-2-yl)-3- phenyl-5,6-dihydro-4H-pyrazolo[4,3-d]isoxazole (178) were the most potent mono-, di-, tri-, tetrasubstituted, and fused pyrazole derivatives, respectively, which have shown potent anti-HIV activity among all the described derivatives as compared with standard anti-HIV drugs. CONCLUSION: This review article provides an overview of the potential therapeutic activity of pyrazole derivatives against HIV that will be helpful for designing pyrazole containing compounds for anti-HIV activity.