Search

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), β-secretase-1 (BACE-1), and inhibition of amyloid β (Aβ) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Finger millet ( Eluesine coracana L.) is gaining importance as a food crop with the increasing emphasis on nutritional aspects and drought resilience. However, the average productivity of the crop has stagnated at around 2,000 kg ha -1 in India. Recently released nutrient responsive high yielding varieties are reported to respond better to application of fertilizers/manures. Further, substitution of chemical fertilizers with organic manures to maintain sustainable yields and improve soil health is gaining attention in recent years. Therefore, identifying the appropriate rate and source of nutrition is important to enhance the productivity of finger millet while improving the soil health. A field experiment was conducted during two rainy seasons (July-November, 2018 and 2019) to study the response of finger millet varieties to chemical fertilizers and farmyard manure (FYM) on growth, yields, N use efficiency, N uptake and on soil properties. Two varieties MR-1 and MR-6 were tested with four nutrient management practices viz. , unamended control, 100% recommended dose of fertilizers (RDF; 40-20-20 kg NPK ha -1 ), 50% RDF + 50% recommended dose of nitrogen (RDN) as FYM and 100% RDN as FYM. Among the varieties, MR-6 outperformed MR-1 in terms of growth, yield, N use efficiency and N uptake. The yield enhancement was up to 22.6% in MR-6 compared to MR-1 across the nutrient management practices. Substituting FYM completely or half of the fertilizer dose increased the growth and yield of finger millet compared to application of chemical fertilizers alone. Similarly, the average biomass yield, ears m -2 , grain yield, total N uptake and N use efficiency in response to nutrient management practices followed the order of 100% RDN as FYM > 50% RDF + 50% RDN as FYM > 100% RDF. The soil organic carbon, available N, P, K, and S improved by 25.0, 12.9, 5.7, 6.1, and 22.6%, respectively in the plots under higher rate of FYM application (8 Mg ha -1 ) compared to plots under chemical fertilizers alone. We conclude that substituting chemical fertilizers either completely or by up to 50% with organic manures supplies adequate amounts of nutrients, improves the yield of finger millet, economic returns, and soil properties., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor AC declared a past co-authorship with the author VS., (Copyright © 2023 Prabhakar, Gopinath, Sai Sravan, Srasvan Kumar, Thirupathi, Samba Siva, Meghalakshmi, Ravi Kumar and Singh.)

Aim: This study reports the designing of BChE inhibitors through machine learning (ML), followed by in silico and in vitro evaluations. Methodology: ML technique was used to predict the virtual hit, and its derivatives were synthesized and characterized. The compounds were evaluated by using various in vitro tests and in silico methods. Results: The gradient boosting classifier predicted N-phenyl-4-(phenylsulfonamido) benzamide as an active BChE inhibitor. The derivatives of the inhibitor, i.e., compounds 34 , 37 and 54 were potent BChE inhibitors and displayed blood-brain barrier permeability with no significant AChE inhibition. Conclusion: The ML prediction was effective, and the synthesized compounds showed the BChE inhibitory activity, which was also supported by the in silico studies.

The abundance, low cost, high density of functional groups and ease of purification of carbohydrates are among the most important features that make them a prime candidate for designing therapeutics. Several carbohydrate-based molecules, of both natural and synthetic origin, are known for their wide range of therapeutic activities. The incorporation of a carbohydrate moiety not only retains the pharmacological characteristics of a molecule but also improves its activity. Several sugar conjugates have been designed and reported to inhibit acetylcholinesterase, β-amyloid and tau aggregation. This systematic review provides a brief overview of carbohydrate-based bioactive molecules having anti-Alzheimer's activity along with improved therapeutic potential. Most importantly, several reported carbohydrate-based molecules for Alzheimer's disease act on β-amyloid aggregation, tau protein, cholinesterase and oxidative stress, with enhanced pharmacokinetic and mechanistic properties. The prospect of designing carbohydrate-based molecules for Alzheimer's disease will definitely provide potential opportunities to discover novel carbohydrate-based drugs.

The outbreak of existing public health distress is threatening the entire world with emergence and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel coronavirus disease 2019 (COVID-19) is mild in most people. However, in some elderly people with co-morbid conditions, it may progress to pneumonia, acute respiratory distress syndrome (ARDS) and multi organ dysfunction leading to death. COVID-19 has caused global panic in the healthcare sector and has become one of the biggest threats to the global economy. Drug discovery researchers are expected to contribute rapidly than ever before. The complete genome sequence of coronavirus had been reported barely a month after the identification of first patient. Potential drug targets to combat and treat the coronavirus infection have also been explored. The iterative structure-based drug design (SBDD) approach could significantly contribute towards the discovery of new drug like molecules for the treatment of COVID-19. The existing antivirals and experiences gained from SARS and MERS outbreaks may pave way for identification of potential drug molecules using the approach. SBDD has gained momentum as the essential tool for faster and costeffective lead discovery of antivirals in the past. The discovery of FDA approved human immunodeficiency virus type 1 (HIV-1) inhibitors represent the foremost success of SBDD. This systematic review provides an overview of the novel coronavirus, its pathology of replication, role of structure based drug design, available drug targets and recent advances in in-silico drug discovery for the prevention of COVID-19. SARSCoV- 2 main protease, RNA dependent RNA polymerase (RdRp) and spike (S) protein are the potential targets, which are currently explored for the drug development., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. NGB, SR, GG and AS are thankful to Indian Institute of Technology ( Banaras Hindu University) Varanasi for providing teaching assistantships to them., (© 2021 The Author(s).)

Cancer, characterized by uncontrolled malignant neoplasm, is a leading cause of death in both advanced and emerging countries. Although, ample drugs are accessible in the market to intervene with tumor progression, none are totally effective and safe. Natural anthraquinone (AQ) equivalents such as emodin, aloe-emodin, alchemix and many synthetic analogs extend their antitumor activity on different targets including telomerase, topoisomerases, kinases, matrix metalloproteinases, DNA and different phases of cell lines. Nano drug delivery strategies are advanced tools which deliver drugs into tumor cells with minimum drug leakage to normal cells. This review delineates the way AQ derivatives are binding on these targets by abolishing tumor cells to produce anticancer activity and purview of nanoformulations related to AQ analogs.

Drug discovery and development have gained momentum due to the rational drug design by engaging computational tools and bioinformatics methodologies. Bioisosteric replacements and hybrid molecular approaches are the other inventive processes, used by medicinal chemists for the desired modifications of leads for clinical drug candidates. SERMs, ought to produce inhibitory activity in breast, uterus and agonist activity in other tissues, are beneficial for estrogen-like actions. ER subtypes α and β are hormone dependent modulators of intracellular signaling and gene expression, and development of ER selective ligands could be an effective approach for treatment of breast cancer. This report has critically investigated the possible designing considerations of SERMs, their in silico interactions, and potent pharmacophore generation approaches viz. indole, restricted benzothiophene [3, 2-b] indole, carborane, xanthendione, combretastatin A-4, organometallic heterocycles, OBHS-SAHA hybrids, benzopyranones, tetrahydroisoquinolines, Dig G derivatives and their specifications in drug design and development, to rationally improve the understanding in drug discovery. This also includes various strategies for the development of dual inhibitors for the management of antiestrogenic resistance., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: A breakthrough in modern medicine, in terms of treatment of Alzheimer's disease, is yet to be seen, as the scene is currently plagued with numerous clinical trial failures. Here, we are exploring multifunctional hybrid sulfonamides for their anti-Alzheimer activity due to the complex nature of the disease. Results & methodology: Compound 41 showed significant inhibition of MMP-2 (IC 50 : 18.24 ± 1.62 nM), AChE (IC 50 : 4.28 ± 0.15 μM) and BuChE (IC 50 : 1.32 ± 0.02 μM). It also exhibited a metal-chelating property, as validated by an in vitro metal-induced Aβ aggregation assay using confocal fluorescence imaging. Whereas, MTT and DPPH assays revealed it to be nontoxic and neuroprotective with substantial antioxidant property. Conclusion: The present study puts forth potent yet nontoxic lead molecules, which foray into the field of multitargeted agents for the treatment of Alzheimer's disease.

Cholinergic hypothesis of Alzheimer's disease has been advocated as an essential tool in the last couple of decades for the drug development. Here in, we report de novo fragment growing strategy for the design of novel 3,5-diarylpyrazoles and hit optimization of spiropyrazoline derivatives as acetyl cholinesterase inhibitors. Both type of scaffolds numbering forty compounds were synthesized and evaluated for their potencies against AChE, BuChE and PAMPA. Introduction of lipophilic cyclohexane ring in 3,5-diarylpyrazole analogs led to spiropyrazoline derivatives, which facilitated and improved the potencies. Compound 44 (AChE = 1.937 ± 0.066 µM; BuChE = 1.166 ± 0.088 µM; hAChE = 1.758 ± 0.095 µM; P e  = 9.491 ± 0.34 × 10 -6  cm s 1 ) showed positive results, which on further optimization led to the development of compound 67 (AChE = 0.464 ± 0.166 µM; BuChE = 0.754 ± 0.121 µM; hAChE = 0.472 ± 0.042 µM; P e  = 13.92 ± 0.022 × 10 -6  cm s 1 ). Compounds 44 and 67 produced significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE. They were found to be safer to MC65 cells and decreased metal induced Aβ 1-42 aggregation. Further, in-vivo behavioral studies, on scopolamine induced amnesia model, the compounds resulted in better percentage spontaneous alternation scores and were safe, had no influence on locomotion in tested animal groups at dose of 3 mg/kg. Early pharmacokinetic assessment of optimized hit molecules was supportive for further drug development., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To analyze the outcomes of long segment coronary anastomoses in patients with diffusely diseased coronary arteries and compare them with medically managed patients., Methods: We retrospectively studied patients with diffusely diseased coronary arteries who underwent complete revascularization with long segment coronary reconstruction (> 2 cm in length) from February 2015 to November 2016. During the same time, patients who opted medical management for diffuse coronary artery disease were also studied., Results: Forty-one patients underwent long segment coronary anastomoses for diffuse coronary artery disease with either left internal thoracic artery (LITA) or saphenous vein conduits. In 15 (36.58%) patients, the anastomosis length was more than 4 cm. In 41 patients, left anterior descending (LAD) artery had long segment anastomosis and in four patients, posterior descending artery (PDA) had long segment anastomosis. Twenty-one patients were operated off-pump and the rest were operated on cardiopulmonary bypass. The post-operative recovery of all the patients was uneventful. There were no procedural complications. There was one mortality due to cerebrovascular accident (2.43%). During the study period, 50 patients with diffuse coronary artery disease were under medical management. In the medically managed group, there were seven death during the follow-up, with mortality rate of 14%., Conclusion: Patients with diffuse disease coronary diseases, who are surgically managed, have a better outcome when compared to the medically managed patients with acceptable morbidity and mortality., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Indian Association of Cardiovascular-Thoracic Surgeons 2019.)