A Comprehensive Update of Anti-COVID-19 Activity of Heterocyclic Compounds.

The Coronavirus disease 2019 (COVID-19) pandemic is one of the most considerable health problems across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the major causative agent of COVID-19. The severe symptoms of this deadly disease include shortness of breath, fever, cough, loss of smell, and a broad spectrum of other health issues such as diarrhea, pneumonia, bronchitis, septic shock, and multiple organ failure. Currently, there are no medications available for coronavirus patients, except symptom-relieving drugs. Therefore, SARS-CoV-2 requires the development of effective drugs and specific treatments. Heterocycles are important constituents of more than 85% of the physiologically active pharmaceutical drugs on the market now. Several FDA-approved drugs have been reported including molnupiravir, remdesivir, ritonavir, oseltamivir, favipiravir, chloroquine, and hydroxychloroquine for the cure of COVID-19. In this study, we discuss potent anti-SARS-CoV-2 heterocyclic compounds that have been synthesized over the past few years. These compounds included; indole, piperidine, pyrazine, pyrimidine, pyrrole, piperazine, quinazoline, oxazole, quinoline, isoxazole, thiazole, quinoxaline, pyrazole, azafluorene, imidazole, thiadiazole, triazole, coumarin, chromene, and benzodioxole. Both in vitro and in silico studies were performed to determine the potential of these heterocyclic compounds in the fight against various SARS-CoV-2 proteins.

Comparison of Efficacy of Topical Betamethasone Dipropionate and Topical Minoxidil in Patients With Alopecia Areata.

Background and objective Alopecia areata (AA) is a reiterative and nonscarring type of hair loss that can affect any hairy area of the body, particularly the scalp. It manifests as patchy or confluent hair loss with variations in demographics and ethnicity. There are numerous treatment options available, including topical and systemic steroids, topical minoxidil, dithranol, tacrolimus, psoralen and ultraviolet therapy (PUVA), contact immunotherapy, and oral immunosuppressive drugs. However, no previous contrast for efficacy is present between the topical betamethasone versus topical minoxidil alone in our population. This study aims to compare the efficacy of topical betamethasone dipropionate versus topical minoxidil in patients with AA. Methodology A nonrandomized controlled study was conducted at the Department of Dermatology, Jinnah Hospital Lahore, incorporating the data of patients between July 26, 2016, and January 26, 2017, after obtaining institutional ethical approval. One hundred patients with alopecia, either on the scalp or any other hairy part, from both genders, aged between 18 and 50 years, were included in the study. Two groups were created, and patients were assigned to these groups based on the clinician's choice. Group A patients were administered betamethasone dipropionate (0.05%) lotion twice daily on affected areas for 12 weeks. Group B patients were administered minoxidil (5%) solution twice daily on affected areas for 12 weeks. A four-week follow-up plan was followed. A five-point scale score system was used for alopecia grading. After 12 weeks, the hair regrowth score (RGS) was used to compare the efficacy of treatment between the two groups. Results A total of 100 patients with grades S1 to S3 AA of less than three months duration were enrolled. Two groups were created, with 50 patients in each group. The mean age in Group A was 29.08 ± 6.51 years, while in Group B, it was 29.38 ± 6.62 years. In Group A, there were 76% males and 24% females, while in Group B, there were 74% males and 26% females. Comparison of efficacy of topical betamethasone dipropionate versus topical minoxidil in patients with AA demonstrated a greater efficacy of 74% (Grade 3 and Grade 4 responses) in Group A, while in Group B, only 42% of patients showed efficacy. A statistically significant difference was found, with a P-value of 0.001. No serious side effects were noted. Conclusions Our study concluded that topical betamethasone dipropionate (0.05%) lotion has statistically significantly higher efficacy compared to topical minoxidil (5%) solution in patients with AA.

"Advanced" Parkinson's disease: A review.

There is no consensus driven definition of "advanced" Parkinson's disease (APD) currently. APD has been described in terms of emergence of specific clinical features and clinical milestones of the disease e.g., motor fluctuations, time to increasing falls, emergence of cognitive decline, etc. The pathological burden of disease has been used to characterize various stages of the disease. Imaging markers have been associated with various motor and nonmotor symptoms of advancing disease. In this review, we present an overview of clinical, pathologic, and imaging markers of APD. We also propose a model of disease definition involving longitudinal assessments of these markers as well as quality of life metrics to better understand and predict disease progression in those with Parkinson's disease.

Deep brain stimulation in PD: risk of complications, morbidity, and hospitalizations: a systematic review.

Introduction: Parkinson's disease (PD) is a progressive and debilitating neurological disorder. While dopaminergic medication improves PD symptoms, continued management is complicated by continued symptom progression, increasing medication fluctuations, and medication-related dyskinesia. Deep brain stimulation (DBS) surgery is a well-accepted and widespread treatment often utilized to address these symptoms in advanced PD. However, DBS may also lead to complications requiring hospitalization. In addition, patients with PD and DBS may have specialized care needs during hospitalization. Methods: This systematic review seeks to characterize the complications and risk of hospitalization following DBS surgery. Patient risk factors and modifications to DBS surgical techniques that may affect surgical risk are also discussed. Results: It is found that, when candidates are carefully screened, DBS is a relatively low-risk procedure, but rate of hospitalization is somewhat increased for DBS patients. Discussion: More research is needed to determine the relative influence of more advanced disease vs. DBS itself in increased rate of hospitalization, but education about DBS and PD is important to insure effective patient care within the hospital.

Unveiling the Role of Nonionic Surfactants in Enhancing Cefotaxime Drug Solubility: A UV-Visible Spectroscopic Investigation in Single and Mixed Micellar Formulations.

This study reports the interfacial phenomenon of cefotaxime in combination with nonionic surfactants, Triton X-100 (TX-100) and Tween-80 (TW-80), and their mixed micellar formulations. Cefotaxime was enclosed in a micellar system to improve its solubility and effectiveness. TX-100 and TW-80 were used in an amphiphilic self-assembly process to create the micellar formulation. The effect of the addition of TX-100, a nonionic surfactant, on the ability of TW-80 to solubilize the drug was examined. The values of the critical micelle concentration (CMC) were determined via UV-Visible spectroscopy. Gibbs free energies (ΔGp and ΔGb), the partition coefficient (Kx), and the binding constant (Kb) were also computed. In a single micellar system, the partition coefficient (Kx) was found to be 33.78 × 106 and 2.78 × 106 in the presence of TX-100 and TW-80, respectively. In a mixed micellar system, the value of the partition coefficient for the CEF/TW-80 system is maximum (5.48 × 106) in the presence of 0.0019 mM of TX-100, which shows that TX-100 significantly enhances the solubilizing power of micelles. It has been demonstrated that these surfactants are effective in enhancing the solubility and bioavailability of therapeutic compounds. This study elaborates on the physicochemical characteristics and solubilization of reactive drugs in single and mixed micellar media. This investigation, conducted in the presence of surfactants, shows a large contribution to the binding process via both hydrogen bonding and hydrophobic interactions.

White Matter Microstructural Differences between Essential Tremor and Parkinson Disease, Evaluated Using Advanced Diffusion MRI Biomarkers.

BACKGROUND: Essential tremor (ET) is a common slowly-progressive neurologic disorder. It is predominantly characterized by kinetic tremors involving bilateral upper limbs. Although ET shares motor similarities with Parkinson disease (PD), there is no known relationship between ET and PD. METHODS: We studied white matter differences between 17 ET and 68 PD patients using standard diffusion tensor imaging and fixel-based analysis (FBA). Diffusion magnetic resonance imaging data were acquired from two scanners (General Electric (GE) and Philips) with different numbers of diffusion directions. Fractional anisotropy maps were generated by the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL), and FBA was performed using MRtrix3 to obtain fiber density, fiber bundle, and fiber density bundle cross-section. RESULTS: Compared with PD, significantly lower values of fiber density, fiber bundle, and fiber density bundle cross-section were found in the corpus callosum and left tapetum of the ET group. Additionally, significantly lower functional anisotropy values were found in the ET compared to the PD group, principally in the corpus callosum, corona radiata, and cingulum. In conclusion, differences in white matter integrity between ET and PD were observed by both FBA-based metrics and diffusion tensor imaging. CONCLUSIONS: Advanced diffusion-based metrics may provide a better understanding of the white matter microstructural characteristics in disparate motor-associated diseases with different underlying phenotypes, such as ET and PD.

A Comprehensive Update of Various Attempts by Medicinal Chemists to Combat COVID-19 through Natural Products.

The ongoing COVID-19 pandemic has resulted in a global panic because of its continual evolution and recurring spikes. This serious malignancy is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the outbreak, millions of people have been affected from December 2019 till now, which has led to a great surge in finding treatments. Despite trying to handle the pandemic with the repurposing of some drugs, such as chloroquine, hydroxychloroquine, remdesivir, lopinavir, ivermectin, etc., against COVID-19, the SARS-CoV-2 virus continues its out-of-control spread. There is a dire need to identify a new regimen of natural products to combat the deadly viral disease. This article deals with the literature reports to date of natural products showing inhibitory activity towards SARS-CoV-2 through different approaches, such as in vivo, in vitro, and in silico studies. Natural compounds targeting the proteins of SARS-CoV-2-the main protease (Mpro), papain-like protease (PLpro), spike proteins, RNA-dependent RNA polymerase (RdRp), endoribonuclease, exoribonuclease, helicase, nucleocapsid, methyltransferase, adeno diphosphate (ADP) phosphatase, other nonstructural proteins, and envelope proteins-were extracted mainly from plants, and some were isolated from bacteria, algae, fungi, and a few marine organisms.

Recent synthetic approaches towards thienothiophenes: a potential template for biologically active compounds.

Heterocyclic compounds are attractive candidates because of their vast applications in natural and physical sciences. Thienothiophene (TT) is an annulated ring of two thiophene rings with a stable and electron-rich structure. Thienothiophenes (TTs) fully represent the planar system, which can drastically alter or improve the fundamental properties of organic, π-conjugated materials when included into a molecular architecture. These molecules possessed many applications including, pharmaceutical as well as optoelectronic properties. Different isomeric forms of thienothiophene showed various applications such as antiviral, antitumor, antiglaucoma, antimicrobial, and as semiconductors, solar cells, organic field effect transistors, electroluminiscents etc. A number of methodologies were adopted to synthesize thienothiophene derivatives. In this review, we have addressed different synthetic strategies of various isomeric forms of thienothiophene that have been reported during last seven years, i.e., 2016-2022.

Study of Interactions Between 3-benzoyl-4-hydroxy-2-methyl-2H-1, 2-benzothiazine and Human DNA by Theoretical, Spectroscopic and Viscometric measurements.

From the last few years mode of interactions between drugs and DNA is an attractive research area as it bridges chemistry, molecular biology and medicinal science. Interactions between small heterocyclic molecules and human DNA is a noteworthy feature in pharmacology for investigation of drugs mechanism and designing of more effective and target specific drugs with fewer side effects. The present research work focuses on the theoretical investigations of 3-benzoyl-4-hydroxy-2-methyl-2H-1, 2-benzothiazine (SASA) by using Gaussian (16 W) software to predict optimized geometry, HOMO-LUMO gap, bond length, bond angle, dihedral angle, electronic and vibrational spectra. Possible reaction site observed in SASA was C7, C9 and C18 as these atoms show maximum charge density. Later the interactions of SASA with human DNA was explored spectroscopic investigations and viscometric investigations at physiological buffers of pH of 4.7 (stomach pH) and 7.4 (blood pH) respectively. Maximum absorbance between SASA-DNA complex was observed in buffer solution of pH 3.4 at wavelength of 370 nm, whereas at 7.4 has maximim absorbance between. Spectroscopic results reflects the bathochromic and hyperchromic shift succeeding the addition of human DNA. During viscosity measurement, intercalation and electrostatic mode of interaction were detected at low and high concentration of drug in solution respectively. Increase in the value of rate constant was observed with the increase in concentration of drug. Larger values of rate constant were observed at pH 7.4 in comparison to pH 3.5. Rate constant, thermodynamic parameters and viscometric analysis prefers the intake of SASA via blood.

Cyclooxygenase-2 (COX-2) as a Target of Anticancer Agents: A Review of Novel Synthesized Scaffolds Having Anticancer and COX-2 Inhibitory Potentialities.

Cancer is a serious threat to human beings and is the second-largest cause of death all over the globe. Chemotherapy is one of the most common treatments for cancer; however, drug resistance and severe adverse effects are major problems associated with anticancer therapy. New compounds with multi-target inhibitory properties are targeted to surmount these challenges. Cyclooxygenase-2 (COX-2) is overexpressed in cancers of the pancreas, breast, colorectal, stomach, and lung carcinoma. Therefore, COX-2 is considered a significant target for the synthesis of new anticancer agents. This review discusses the biological activity of recently prepared dual anticancer and COX-2 inhibitory agents. The most important intermolecular interactions with the COX-2 enzyme have also been presented. Analysis of these agents in the active area of the COX-2 enzyme could guide the introduction of new lead compounds with extreme selectivity and minor side effects.

Clinicopathologic Correlations of Jaw Tremor in a Longitudinal Aging Study.

Background and Objectives: The aim of this study is to assess clinical and pathologic correlations of jaw tremor in 3 cohorts enrolled in a long-term aging study. Jaw/lip tremor has been described in various movement disorders but the impact of seeing a jaw tremor on clinician diagnosis and whether the presence of isolated jaw tremor is correlated with subsequent phenoconversion to a different movement disorder are unclear. Methods: Data from the Arizona Study of Aging and Neurodegenerative Disease, a longitudinal clinicopathologic study, were used. Control subjects (n = 708) did not have any tremor or parkinsonism. At initial evaluation, 276 subjects who had jaw tremor were categorized as isolated jaw tremor (jaw tremor without limb action tremor or parkinsonism), suspect/possible PD (1 or 2 cardinal features of PD without a history of dopaminergic treatment), parkinsonism (probable PD and other parkinsonian disorders), or nonparkinsonian tremor (e.g., essential tremor). Initial clinical diagnosis was compared with "final diagnosis" based on longitudinal assessments and with clinicopathologic diagnosis when available. Results: In subjects with jaw tremor, we identified 45 isolated jaw tremor, 92 nonparkinsonian tremor, 56 suspect/possible PD, and 83 parkinsonism cases at baseline and followed longitudinally. Neuropathologic diagnosis was available for 137 cases. The mean time from initial to final assessment or autopsy was 6.8 years (SD 4.4). Of the subjects with follow-up data, only 15.4% of those with isolated jaw tremor (6/39) and 8.8% of those with nonparkinsonian tremor (6/68) evolved into a clinical parkinsonian disorder. Neither of these groups was associated with clinicopathologic PD: isolated jaw tremor (1/18) and nonparkinsonian tremor (1/43). Those with jaw tremor initially classified into a parkinsonian group were more highly associated with clinicopathologic PD: 27 of 51 subjects with parkinsonism other and 4 of 25 possible PD. Discussion: The presence of either jaw tremor in isolation or associated with nonparkinsonian tremor does not portend a neurodegenerative diagnosis.

Synthesis of Novel N-Methylmorpholine-Substituted Benzimidazolium Salts as Potential α-Glucosidase Inhibitors.

The α-glucosidase enzyme, located in the brush border of the small intestine, is responsible for overall glycemic control in the body. It hydrolyses the 1,4-linkage in the carbohydrates to form blood-absorbable monosaccharides that ultimately increase the blood glucose level. α-Glucosidase inhibitors (AGIs) can reduce hydrolytic activity and help to control type 2 diabetes. Aiming to achieve this, a novel series of 1-benzyl-3-((2-substitutedphenyl)amino)-2-oxoethyl)-2-(morpholinomethyl)-1H-benzimidazol-3-ium chloride was synthesized and screened for its α-glucosidase inhibitory potential. Compounds 5d, 5f, 5g, 5h and 5k exhibited better α-glucosidase inhibitions compared to the standard drug (acarbose IC50 = 58.8 ± 0.012 µM) with IC50 values of 15 ± 0.030, 19 ± 0.060, 25 ± 0.106, 21 ± 0.07 and 26 ± 0.035 µM, respectively. Furthermore, the molecular docking studies explored the mechanism of enzyme inhibitions by different 1,2,3-trisubstituted benzimidazolium salts via significant ligand-receptor interactions.

Parental perception of silver diamine fluoride for the management of dental caries.

Objectives: This study aims to identify and extract parental perception and acceptance of silver diamine fluoride (SDF) application in treating dental caries with the objective of a) evaluating parental acceptability of SDF as a treatment choice for dental caries in their children and b) investigating parental concerns regarding the use of SDF for childhood caries. Methods: A cross-sectional survey using a reliable questionnaire was conducted among parents of children aged 2-10 years, who reported to the department of paediatric dentistry at two dental hospitals between June 2020 and January 2021. Results: 197 participants/guardians were included in the study and 128 showed acceptability towards SDF, out of which, 99 preferred upper posterior teeth for the treatment. The dentists' advice became a major factor affecting treatment option for 108 participants. Parental age also impacted the choice of SDF as a treatment option (i.e., those aged 31-40 years were more aware of SDF treatment than younger or older age groups). Conclusion: Parental acceptance of SDF in comparison to other dental caries treatment options in children was found to be higher when more invasive treatment choices were provided. Aesthetic appearance and cost of treatment were significant concerns for the parents.

Knowledge, attitude, and practice of artificial intelligence among doctors and medical students in Pakistan: A cross-sectional online survey.

Background: The use of Artificial intelligence (AI) has gained popularity during the last few decades and its use in medicine is increasing globally. Developing countries like Pakistan are lagging in the implementation of AI-based solutions in healthcare. There is a need to incorporate AI in the health system which may help not only in expediting diagnosis and management but also injudicious resource allocation. Objective: To determine the knowledge, attitude, and practice of AI among doctors and medical students in Pakistan. Materials and methods: We conducted a cross-sectional study using an online questionnaire-based survey regarding demographic details, knowledge, perception, and practice of AI. A sample of 470 individuals including doctors and medical students were selected using the convenient sampling technique. The chi-square test was applied for the comparison of variables. Results: Out of 470 individuals, 223(47.45%) were doctors and 247(52.55%) were medical students. Among these, 165(74%) doctors and 170(68.8%) medical students had a basic knowledge of AI but only 61(27.3%) doctors and 48(19.4%) students were aware of its medical applications. Regarding attitude, 237(76.7%) individuals supported AI's inclusion in curriculum, 368(78.3%) and 305(64.9%), 281(59.8%) and 269(57.2%) acknowledged its necessity in radiology, pathology, and COVID-19 pandemic respectively. Conclusion: The majority of doctors and medical students lack knowledge about AI and its applications, but had a positive view of AI in the field of medicine and were willing to adopt it.

In-silico modeling and in-vitro studies of 2,1-benzothiazine-2,2-dioxide based hydrazone derivatives as α-glucosidase inhibitors.

Diabetes mellitus (DM) is a metabolic disorder characterized by frequent urination, hunger and high blood sugar level. α-glucosidase inhibitors are considered as a frontline treatment for the DM. This research article deals with the identification of benzothiazine derivatives as α-glucosidase inhibitors through in-silico techniques and then the confirmation through in-vitro analysis. Molecular docking studies were carried out to find out the binding interactions of targeted molecules with receptor molecule i.e., α-glucosidase enzyme. The synthetic compounds 1 (a-n), 2 (a-d) and 3 (a-b) were evaluated for in-vitro alpha glucosidase inhibitory activities that resulted in the discovery of various potent molecules. Majority of the compounds (1c, 1f, 1g, 1k-n, 2a-d and 3a-b) exhibited good inhibitory activity against α-glucosidase. Compounds 1c, 1g, 1k and 1m appeared as the potent active compounds with the IC50 values 17.44, 27.64, 24.43, 42.59 and 16.90 µM respectively. Compounds 1c & 2c were found almost 3-folds more active than the standard acarbose. The study may lead to discover potent drug candidates with less complication for the treatment of the type II diabetes mellitus.

Synthesis and α-Glucosidase Inhibition Activity of 2-[3-(Benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl]-N-arylacetamides: An In Silico and Biochemical Approach.

Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c, 12a, 12d, 12e, and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good in vitro α-glucosidase inhibitions with IC50 values of 30.65, 18.25, 20.76, 35.14, and 24.24 µM, respectively, which were better than the standard drug, acarbose (IC50 = 58.8 µM). Furthermore, a good agreement was observed between in silico and in vitro modes of study.

Synthesis, molecular docking and anti-diabetic studies of novel benzimidazole-pyrazoline hybrid molecules.

Pyrazoline and benzimidazoles derivatives have been widely studied due to their potential applications in the medicinal field. In this research project, we have hybridized these two heterocyclic systems in the same molecule. A new series of compounds, 2-((3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-1H-benzo[d]imidazole (5a-i) were synthesized through a multistep reaction. In the first step, chalcones 3a-i were prepared by coupling of various acetophenones and benzaldehydes under alkaline conditions. These chalcones were cyclized with hydrazine hydrate to form a series of pyrazolines which were finally coupled with 2-chloromethyl-1H-benzimidazole to get a new series of titled hybrid molecules. The structures of these compounds were elucidated by spectral (1H NMR and 13C NMR) analysis. The anti-diabetic potential of these compounds was studied by screening them for their α-glucosidase inhibition activity. The SAR was established through molecular docking analysis. Compound 5d appeared as effective inhibitor with IC50 = 50.06µM as compared to reference drug (acarbose) having IC50 = 58.8µM.

Synthesis, characterization and antimicrobial activity of norfloxacin based acetohydrazides.

The drug resistance phenomenon in microbes is resulting in the ineffectiveness of available drugs to treat the infections. Thus, there is a continued need to discover new molecules to combat the drug resistance phenomenon. Norfloxacin is a fluoroquinolone antibiotic that is used for the treatment of urinary tract infections. In this research work, norfloxacin is structurally modified by hybridizing with a range of substituted acetohydrazidic moieties through a multistep reaction. The first step involves the coupling of norfloxacin 1 with methyl chloroacetate followed by the treatment with hydrazine hydrate to result in corresponding acetohydrazide 3. A range of substituted benzaldehydes were reacted with the acetohydrazide to form the targeted series of norfloxacin derivatives 4a-i. The final compounds were screened for antimicrobial activity. Among the tested compounds, 4c, 4d, 4e and 4f displayed better antifungal activity against F.avenaceum, while compound 4c and 4e were active against F. bubigeum.