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Abstract: Heterocyclic compounds are recognized to possess a high grade of structural diversity and a broad spectrum of therapeutic properties. About two-thirds of the New Chemical Entities approved by the FDA against cancer entail heterocyclic rings and are the foundation stone of medicinal chemistry. Pyrimidine being a major heterocyclic compound and a crucial base component of the genetic material, has emerged as the key structural component against cancer, the deadliest disease worldwide. Though many drugs are marketed against cancer, researchers are still investigating the more promising moieties against various malignancies due to the severity of this disease. In this review, an attempt has been made to assemble the reported literature of the previous five years on various synthetic procedures and the anti-cancer potential of various classes of fused pyrimidine analogs, which would help the researchers in designing new potent derivatives. Besides this, the review intends to focus on the comprehensive discussion on biological targets, modes of action, and structure-activity relationships of each class of fused pyrimidines as potential anticancer agents.

There has been considerable interest in the development of novel compounds with anticonvulsant, antioxidant, antibacterial, and antifungal activities. The present study explores the antimicrobial activity of some new arylidene hydrazide derivatives and correlates the effect on the antimicrobial potency by varying the substituents on hydrazide part of the arylidine hydrazide. Hydrazones possessing an azomethine–NHN=CH- proton constitute an important class of compounds for new drug developments; therefore, a series of arylidene hydrazides were synthesized with various aromatic aldehydes/ketones. The synthesis of title compounds was affected as outlined in the scheme. In this scheme O-chloro benzoic acid on reaction with aniline through Ullmann Reaction gave N-phenyl anthranilic acid. The esterification product of N-phenyl anthranilic acid followed by reaction with hydrazine hydrate yielded 2-phenyl amino benzoic acid hydrazide. These hydrazides were give arylidine hydrazide as title compounds. A total of 11 compounds were synthesized. The synthetic methods used are simple, rapid, and economical found to be accurate and reproducible. All the intermediates and title compounds were characterized by running TLC, determining M.P. and spectral studies such as IR and 1H-NMR. The synthesized compounds showed mild-to-moderate antibacterial activity against Gram-positive Bacillus subtilis (MTCC441), Bacillus cereus (MTCC-7190) and Gram-negative Escherichia coli and antifungal activity against Candida albicans and Aspergillus fumigates (ATTC 9197). The bio-screening data revealed that 4b, 4f, 4g, 4h, and 4j moiety exhibited good antibacterial activity against all where 4a and 4c showed good antifungal activity. Among the compounds, 4a and 4c exhibited good antioxidant activity too.

Supplementary Figure 4 - PDF file 1452K, Caspase-2 cleavage following treatment with mifepristone

Supplementary Figure 1 - PDF file 129K, In vitro analysis of MDA-MB-231, BT-20, and MDA-MB-468 total live cell counts following treatment

Supplementary Methods 1 - PDF file 64K, Annotated ImageJ macro for quantifying total cell numbers and apoptotic cells using digitally captured IncuCyte images

Supplementary Figure 6 - PDF file 1359K, Western analysis of GR isoforms from MDA-MB-231 xenografts

Supplementary Figure 7 - PDF file 126K, Representative images of clonogenic assay with MDA-MB-231 cells

Supplementary Figure Legends - PDF file 104K, Supplemental figure legends 1-7

Supplementary Figure 2 - PDF file 168K, Phase-contrast and fluorescent images of apoptotic MDA-MB-231 cells

Supplementary Methods 2 - PDF 64K, Annotated ImageJ macro for measuring GR+ and total cell counts in MDA-MB-231 xenografted mammary gland tumors

Supplementary Figure 3 - PDF file 83K, Trypan blue dye exclusion analysis of MDA-MB-231, BT-20 and MDA-MB-468 cells treated with dexamethasone +/-mifepristone and paclitaxel

Purpose: Triple-negative breast cancer (TNBC) accounts for 10% to 20% of newly diagnosed invasive breast cancer. Finding effective targets for chemotherapy-resistant TNBC has proven difficult in part because of TNBC's molecular heterogeneity. We have previously reported that likely because of the antiapoptotic activity of glucocorticoid receptor (GR) in estrogen receptor (ER)-negative breast epithelial and cancer cells, high GR expression/activity in early-stage TNBC significantly correlates with chemotherapy resistance and increased recurrence. We hypothesized that pretreatment with mifepristone, a GR antagonist, would potentiate the efficacy of chemotherapy in GR+ TNBCs by inhibiting the antiapoptotic signaling pathways of GR and increasing the cytotoxic efficiency of chemotherapy.Experimental Design: TNBC cell apoptosis was examined in the context of physiologic glucocorticoid concentrations, chemotherapy, and/or pharmacologic concentrations of mifepristone. We used high-throughput live microscopy with continuous recording to measure apoptotic cells stained with a fluorescent dye and Western blot analysis to detect caspase-3 and PARP cleavage. The effect of mifepristone on GR-mediated gene expression was also measured. TNBC xenograft studies were performed in female severe combined immunodeficient (SCID) mice and tumors were measured following treatment with vehicle, paclitaxel, or mifepristone/paclitaxel.Results: We found that although mifepristone treatment alone had no significant effect on TNBC cell viability or clonogenicity in the absence of chemotherapy, the addition of mifepristone to dexamethasone/paclitaxel treatment significantly increased cytotoxicity and caspase-3/PARP cleavage. Mifepristone also antagonized GR-induced SGK1 and MKP1/DUSP1 gene expression while significantly augmenting paclitaxel-induced GR+ MDA-MB-231 xenograft tumor shrinkage in vivo.Conclusions: These results suggest that mifepristone pretreatment could be a useful strategy for increasing tumor cell apoptosis in chemotherapy-resistant GR+ TNBC. Clin Cancer Res; 19(22); 6163–72. ©2013 AACR.

Abstract: The current world is plagued by unpredictability as a result of various COVID-19 variants. The current variants of concern (VOCs) are B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617/B.1.617.2(Delta). WHO classified two variants, delta (B.1.617.2) and omicron (B.1.1.529), as having highly mutable strikes. The WHO predicted that it would be more dangerous than previous variants due to its mutatable capability. The Omicron variant of coronavirus has caused widespread disruption, with countries struggling to manage the massive number of infections. Due to its unique properties, such as protein structure, symptoms, transmission, and epidemiology, this review aims to compare omicron to other variants. Furthermore, we have highlighted vaccines that have been used to combat this pandemic.

Using demographic, clinical, visual field, and optical coherence tomography (OCT) variables to study the association of 5-year glaucomatous progression in glaucoma suspect eyes.This is a retrospective longitudinal clinical study. Inclusion criteria consisted of glaucoma suspect eyes (i.e., concerning cup-to-disk ratio and/or intraocular pressure (IOP)21 mm Hg), age ≥ 30 years old, follow-up time of 5 years, best-corrected visual acuity (BCVA) of 20/100 or better, spherical equivalent (SE) higher than 8 diopters and an astigmatism less than 3 diopters. Eyes with glaucoma-determined by two consecutive, reliable visual field tests-were excluded, as well as any eyes with any clinically significant retinal or neurological disease. The percentage of glaucoma suspect eyes, which progressed to glaucoma within a 5-year period, was calculated. Study subjects were divided into the following groups: eyes that progressed to glaucoma and those that did not.In the 288 patients which we looked at, 365 total eyes, 323 eyes had concerning cup-to-disk ratio and 42 had ocular hypertension. Bivariate analysis showed that the eyes which progressed to glaucoma had significantly worse mean deviation, increased pattern standard deviation (PSD), and less visual field index (VFI). Our bivariate analysis also showed a thinner average, superior and inferior retinal nerve fiber layer thickness (RNFL), and more severe average, superior, and inferior RNFL damages (i.e., color grading scale) at baseline. Logistic regression analysis showed that only PSD and severe inferior RNFL damage (i.e., red color) to be significantly associated with 5-year glaucomatous progression.Segmental RNFL damage and pattern standard deviation are associated with 5-year glaucomatous progression in glaucoma suspect eyes.Nassiri N, Das S, Patel V

"Consensual ophthalmotonic reaction" refers to changes in intraocular pressure (IOP) in one eye, which is accompanied by a corresponding change in IOP in the contralateral eye. This study evaluates whether monocular administration of selective laser trabeculoplasty (SLT) leads to a consensual ophthalmotonic reaction and how long this effect lasts.A retrospective chart review was performed on patients receiving SLT at Kresge Eye Institute in Detroit, MI, from January 2015 to August 2016. Patients were excluded if they had previous history of glaucoma incisional and/or laser procedures; required additional laser trabeculoplasty; had glaucoma medication changes during the follow-up period; experienced no decrease in IOP during the follow-up period; or had a diagnosis of angle closure on gonioscopy. Various demographic, clinical, and surgical data were collected. IOP measurements were collected at baseline and postoperatively at 1-3 months, 4-9 months, and 12-15 months.At all follow-up periods, the IOP of the treated eye was decreased from baseline IOP (This study showed that monocular administration of SLT results in a consensual ophthalmotonic reaction. The consensual ophthalmotonic reaction appears to last for up to 4-9 months.Therefore, although SLT does lead to a consensual ophthalmotonic reaction, monocular administration of SLT is not a reliable method of long-term IOP control for the contralateral non-SLT-treated eye.Nassiri N, Mei F, Tokko H

Coumarin is a phenol, consisting of benzene ring and alpha-pyrone ring. Coumarins are prepared through Pechmann reaction, which involve condensation of phenol with ethyl acetoacetate in the presence of acid catalyst. Coumarins are being used widely due to their various biological activities in recent years, like anticoagulant, antibacterial, antitumoral, antitubercular, antifungal, MAO inhibitor activity, antioxidant, anti-inflammatory and as CNS active compounds. Methyl esters of amino acids and their di/tri and tetrapeptides derivatives were prepared using coupling agent DCC and a base NMM by stirring continuously for 36 hours. The compounds prepared were analyzed and the structures are elucidated by TLC, IR and 1H NMR spectral data. They were screened for antibacterial activity against three bacterial species and antifungal activity against one species

Isoniazid (INH) is one of the most successful tuberculosis medications in the market today. In particular, isoniazid is used as a prophylaxis medication to avoid resurgence of illness in those who have underlying Mycobacterium tuberculosis (MTB) infection. The mode of action of isoniazid is complicated and incorporates a number of distinct aspects in which various biomolecular routes are impacted, including mycolic acid production. Catalase-peroxidase (KatG) activates the prodrug isoniazid and enzymes such as β-ketoacyl ACP synthase (KasA) and enoyl acyl carrier protein (ACP) reductase target the active isoniazid products. Various genes in diverse biochemical networks and pathways are involved in the physiological mechanisms of isoniazid resistance. Isoniazid resistance is the most common of all clinical drug-resistant isolates, with incidence in some areas of up to 20 to 30%. In this review article, several existing components that may influence to the complexities of isoniazid function including mechanism of action, resistance mechanisms in MTB, along with their history, different synthetic procedures, uses, dosage forms, side effects, adverse drug reactions, physico-chemical characteristics, ADME properties, contraindications as well as future perspectives are discussed. Studies of pharmacokinetics have found that the cause of the drug mediated hepatotoxicity is possible by metabolism of isoniazid. Because of inter-individual heterogeneity of polymorphism that affect isoniazid metabolism rates, customized medicines may be required in various populations to prevent hepatotoxicity. The isoniazid multidrug combination treatment which would proved to be effective tuberculosis treatment in future. Further exploration is needed for better comprehension of pathogenesis mechanism of Mycobacterium tuberculosis (MTB) and drug resistance studies are required for building up better therapeutics and diagnostic against tuberculosis.

Abstract: Owing to the enhanced toxicity as well as consequences of allopathic medication, the research on herbal therapies is developing progressively. As a result, medicinal herbs are beginning to play a substantial role in the advancement of the dominant therapeutic medications. Since ancient times, the use of herbs has performed a vital part in human well-being as well in the invention of cutting-edge pharmaceuticals. Inflammation and related illnesses are a major health concern for the entire human population. Pain-inducing drugs including opiates, non-steroidal anti-inflammatory drugs, glucocorticoids, and corticosteroids have severe side effects and these therapies suffer from the recurrence of symptoms too after discontinuing the treatment. As a result, the diagnosis along with the advancement of medications with anti-inflammatory properties is the priority to conquer the drawbacks of the existing therapies. The present review article provides insight into the literature comprising promising phytochemicals from various medicinal plants tested through different model systems and employed for alleviating inflammation in several inflammatory disorders as well as clinical status of the herbal products.

Background: Heterocyclic scaffolds have gained exceptional devotion in the recent years due to their marked utility in bio-organic field. Among these, pyrazole remains a privileged scaffold as broad array of medicinally active agents encompasses this heterocycle as a core nucleus. Pyrazole is a five-membered, aromatic ring containing two nitrogen atoms at adjacent positions are readily able to show interactions with numerous receptor (s), enzymes located on the target cells in biological system. Pyrazole-containing compounds are acknowledged with anticyclooxygenases (anti-inflammatory), carbonic anhydrase inhibitor, α-glycosidase inhibitor, and cholinesterase enzymes inhibitor and anti-DNA gyrases activities. Noticeably, rimonabant, phenylbutazone, fipronil, difenamizole, celecoxib, antipyrine, fezolamide and betazole are few representatives of pyrazole containing drugs. Objectives: The manuscript aims to review the detailed synthetic approaches applied for the synthesis of pyrazole derivatives. In particular, we examine recent scientific finding on antimicrobial, anti-tubercular, antiviral, anticancer and anti-inflammatory perspectives of pyrazole containing analogues. Methods: Pyrazole analogues have been widely explored by scientific community as large number of papers has been published in this regard. Numerous pyrazole-containing analogues have been designed, synthesized, and screened for their in vitro and in vivo bio-efficacy and many of them endowed with commendable pharmacological activities. Pyrazole analogues with superior applications as antiviral, anticancer, and anti-inflammatory efficacy have also been well documented in patents granted to this heterocyclic nucleus. Results: This review outlines the recent advances in medicinal chemistry of pyrazole analogues with a special emphasize of structure-activity relationships to afford ideas for the rational drug-design and discovery and their impact on desired pharmacological applications. Conclusion: The information provided in this manuscript may help the medicinal chemists to generate robust pyrazole analogues with high efficacy.

Analyze practice patterns of glaucoma surgeons with and without fellowship training.Physician-specific 2017 Medicare data were obtained from the Centers for MedicareMedicaid Services website. Current Procedural Terminology codes identified procedures including iStent, tube shunts, trabeculectomy, complicated trabeculectomy, endoscopic cyclophotocoagulation, internal Xen Implant, external Xen or Express shunt, Gonioscopy-Assisted Transluminal Trabeculotomy, and Kahook Dual Blade Goniotomy. Physicians with fellowship training were identified via the American Glaucoma Society website.A total of 1547 glaucoma surgeons were identified, of which 319 had completed fellowship training. Overall, fellowship-trained glaucoma surgeons performed more services (50.4 ± 47.0 vs 40.5 ± 35.3, P .001) with a larger variety of procedures (1.8 ± 1.0 vs 1.3 ± 0.6, P .001) than those without fellowship training. Surgeons without fellowship training were more likely to perform iStent and endoscopic cyclophotocoagulation and less likely to perform the remaining procedures than their fellowship-trained counterparts. Medicare payments did not differ between groups and the number of Medicare beneficiaries only differed for internal Xen implant (P = .03). Patient comorbidity burden was similar between groups with about one-third of patients being diagnosed with ischemic heart disease.Surgeons without fellowship training can treat a similar volume of glaucoma patients as those with fellowship training. However, based on surgical procedures employed, their practices are skewed towards mild and moderate glaucoma and they are more limited in their breadth of procedures. In addition, ischemic heart disease was prevalent in the glaucoma patient population.

Objective Abrupt changes in ophthalmology education caused by the COVID-19 pandemic have resulted in novel online curriculum development. The aims of this study were to identify (1) the scope of online curricula implemented both prior to and during the COVID-19 pandemic; (2) perception of educators on these online modalities; and (3) early lessons from online implementation that may guide future curricular planning. Methods Implementation of online curricula was evaluated by using a national online survey of Ophthalmology Directors of Medical Student Education (DMSE) via Qualtrics software. Participants Medical Student Educators of the Association of University Professors of Ophthalmology (AUPO) were surveyed. Results Fifty responses were collected, representing a 64.9% response rate. Prior to the COVID-19 pandemic, 44% of institutions had no online components in their courses, but 78.3% of institutions reported increasing online components in response to the pandemic. Required courses were significantly associated both with having implemented online components before the pandemic and implementing online-only versions of these courses in response to the pandemic. The three most popular modalities used for online teaching were lectures, interactive cases, and problem-based learning, with a median satisfaction of 4.0, 4.32, and 4.35, (out of five) respectively. The least popular modalities used were online teaching of physical exam skills and telemedicine, both with a median satisfaction of 2.5. Median overall educator satisfaction with online teaching was four (out of five). The most common weakness related to online teaching was the lack of effective physical exam skills training. Conclusion Our data demonstrate that most institutions successfully shifted their ophthalmology curriculum to a virtual and online version in response to the COVID-19 pandemic. DMSEs adapted quickly, transitioning in-person clinical courses, and extracurricular activities to online formats. Overall, educator satisfaction with online curricula was high. Integration of online curricula provides the opportunity to enrich institutional curriculums and overcome limitations imposed by decreasing curriculum time. This study reveals an early window into the utilization, strengths, and weaknesses of online ophthalmology education, which can serve as a guiding point to enhance ophthalmology curriculum development.

A clinically useful drug may have limitations in practice because of undesirable side effects, poor solubility, and poor bioavailability, short duration of action, first-pass effect, poor absorption & adverse effects. There are increased efforts in research to increase the therapeutic efficacy of drugs by eliminating or minimizing the undesirable properties of drug molecules. Some of the problems can be solved using a formulation development approach but in some cases, chemical modification in the molecule is necessary to correct the pharmacokinetic parameters. One of the approaches to convert the existing molecule to a more efficient molecule is prodrug design. Mutual Prodrug is the molecule in which an active drug molecule is attached to a carrier molecule having pharmacological activity. So a mutual prodrug consists of two pharmacologically active molecules connected by a bio labile linkage. Both molecules in this act as a pro moiety of each other. The design of mutual prodrug is very fruitful in the area of research & has given successful results in increasing the clinical & therapeutic effectiveness of the drugs. The present article takes a review of various applications of mutual prodrugs & development in this field in the last few decades.

Alzheimer's disease (AD) is a neurodegenerative age related brain disease which diminishes learning and memory. Two common cholinesterases (ChEs), first acetylcholinesterase (AChE) and second one butyrylcholinesterase (BChE) are the main targets to treat this disease. In the current paper, six novel pyrazolo-benzothiazole analogs were systematically planned, synthesized, and biological tested for their ChEs activities, antioxidant, enzyme kinetic, self induced Aβ modulation, PAMPA-BBB, and docking and molecular simulation study. Among all derivatives,4a bearing 3,4-dimethoxypyrazolo-benzothiazole molecules was the potential inhibitor of AChE (IC50 = 8.69 ± 0.42 µM), Aβ modulator and good antioxidant. Docking studies also clearly revealed that compound 4a fit into the active sites of hAChE.

Herbs are an effective source of Ayurvedic medicine and other traditional medicines as well as modern medicine. Faced with the challenges of modern medicine, the world is shifting toward Ayurvedic theories of health management. In the treatment of the disease, the use of drugs is not limited. This increases the demand for raw materials exponentially. However, production growth is still linear. Rapid depletion of resources creates major problems. To fill the deficit, advances in adulteration and substitution are becoming more prevalent. This adulteration and substitution are a burning problem in an industry that threatens the integrity of Ayurvedic system of medicine. Imprecise knowledge, misidentification, deforestation, and personal gain have led to adulteration. Therefore, an understanding of all ways of adulteration and substitutions is needed to amend this illegal act and maximize consumer safety. This article focuses on adulteration, its types and various methods of adulteration, as well as the concept of substitution, reasoning, and its types. Attempts have also been made to differentiate these two related terms.

Vision loss and blindness are among the top ten disabilities in the United States, yet access and utilization of eye care remains low. Vision Detroit aimed to address eye-care disparities via community-based screenings. By investigating burden of eye disease and barriers to eye-care utilization in an underserved urban community, we may direct efforts to improve access.Twenty-three screenings were conducted from March 2015-November 2017. Patient information gathered at screenings were demographics, medical and social history, eye exam/referral history, insurance status, primary care physician (PCP) status, and patient-perceived eye-care barriers.Three-hundred-eighty patients were screened, 42% African American and 51% Hispanic. Average age was 53 ± 16.4 years, 70% reported vision problems, 50% reported over two years of vision problems, and average habitual visual acuity in best-seeing eye was 20/37. Eye-care underutilization was reported in 61% of type-2 diabetics. Older age and PCP recommendations/referrals were associated with increased utilization in all patients. Insurance was the most common barrier (53%); of the 55% insured, 31% reported financial barriers. Employed patients were more likely than unemployed to report a time barrier (odds ratio = 1.76, 95% confidence interval 1.03-3.01). Those with high school or less education reported "unaware of need", "unsure where to go", "transportation", and "insurance" as barriers more often.Visual burden was pervasive, yet access was suboptimal. Financial, logistical, and awareness barriers were common. PCP referral and older age were associated with increased utilization. Those less educated reported more barriers, highlighting the need to address fiscal concerns and eye-health education.