Valsartan: An Angiotensin Receptor Blocker Modulates BDNF Expression and Provides Neuroprotection Against Cerebral Ischemic Reperfusion Injury.

AT1 receptor blockers (ARBs) are commonly used drugs to treat cardiovascular disease and hypertension, but research on their impact on brain disorders is unattainable. Valsartan (VAL) is a drug that specifically blocks AT1 receptor. Despite the previous evidence for VAL to provide neuroprotection in case of ischemic reperfusion injury, evaluation of their potential in mitigating mitochondrial dysfunction that causes neuronal cell death and neurobehavioral impairment remains unknown. The aim of this study was to evaluate the therapeutic effect of repurposed drug VAL against ischemic reperfusion injury-induced neuronal alternation. tMCAO surgery was performed to induce focal cerebral ischemic reperfusion injury. Following ischemic reperfusion injury, we analyzed the therapeutic efficacy of VAL by measuring the infarct volume, brain water content, mitochondrial oxidative stress, mitochondrial membrane potential, histopathological architecture, and apoptotic marker protein. Our results showed that VAL administrations (5 and 10 mg/kg b.wt.) mitigated the brain damage, enhanced neurobehavioral outcomes, and alleviated mitochondrial-mediated oxidative damage. In addition to this, our findings demonstrated that VAL administration inhibits neuronal apoptosis by restoring the mitochondrial membrane potential. A follow-up investigation demonstrated that VAL induces BDNF expression and promoted ischemic tolerance via modulating the Akt/p-Creb signaling pathway. In summary, our results suggested that VAL administration provided neuroprotection, ameliorated mitochondrial dysfunction, preserved the integrity of neurons, and lead to functional improvement after ischemic reperfusion injury.

Innovative approaches to Alzheimer's therapy: Harnessing the power of heterocycles, oxidative stress management, and nanomaterial drug delivery system.

Alzheimer's disease (AD) presents a complex pathology involving amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, and cholinergic deficits. Oxidative stress exacerbates AD progression through pathways like macromolecular peroxidation, mitochondrial dysfunction, and metal ion redox potential alteration linked to amyloid-beta (Aß). Despite limited approved medications, heterocyclic compounds have emerged as promising candidates in AD drug discovery. This review highlights recent advancements in synthetic heterocyclic compounds targeting oxidative stress, mitochondrial dysfunction, and neuroinflammation in AD. Additionally, it explores the potential of nanomaterial-based drug delivery systems to overcome challenges in AD treatment. Nanoparticles with heterocyclic scaffolds, like polysorbate 80-coated PLGA and Resveratrol-loaded nano-selenium, show improved brain transport and efficacy. Micellar CAPE and Melatonin-loaded nano-capsules exhibit enhanced antioxidant properties, while a tetra hydroacridine derivative (CHDA) combined with nano-radiogold particles demonstrates promising acetylcholinesterase inhibition without toxicity. This comprehensive review underscores the potential of nanotechnology-driven drug delivery for optimizing the therapeutic outcomes of novel synthetic heterocyclic compounds in AD management. Furthermore, the inclusion of various promising heterocyclic compounds with detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) data provides valuable insights for planning the development of novel drug delivery treatments for AD.

Targeted Cancer Stem Cell Therapeutics: An Update.

Cancer stem cells (CSCs) have become a key player in the growth of tumors, the spread of cancer, and the resistance to therapeutic interventions. Targeting these elusive cell populations has the potential to fundamentally alter cancer treatment plans. CSCs, also known as tumor-initiating cells (TICs), are thought to play a role in both medication resistance and cancer recurrence. This is explained by their capacity to regenerate themselves and change into different kinds of cancer cells. Due to their higher expression of ATP-binding cassette (ABC) membrane transporters, enhanced epithelial to mesenchymal (EMT) characteristics, improved immune evasion, activation of survival signaling pathways, and improved DNA repair mechanisms, CSCs exhibit extraordinary resistance to therapies. This comprehensive analysis delves into advancements in the domain of Targeted Cancer Stem Cell Therapeutics, concentrating on unraveling the distinctive traits of CSCs and the therapeutic methods devised to eliminate them.

Targeting Various Pathogenic Pathways for the Development of Antialzheimer's Drugs: An Update.

Alzheimer's disease (AD) has been recognized as the most important cause of dementia, which is estimated to contribute more than 2 trillion USD in medical costs. AD patients encounter progressive neurodegenerative dementia associated with behavioural, linguistic, and visuospatial deficits. Although studies on the discovery of amyloid ß (Aß) and tau (the essential elements of plaques and tangles in AD) have shed light on the molecular pathological processes of AD, the exact cause of the condition is still largely unknown. The involvement of various proteins, such as amyloid-ß, prion protein, tau, and α-synuclein has been linked to AD pathogenesis. The current AD treatments are mainly based on symptomatic management and restoration of neurotransmitters' balance. There is a significant need to develop medications that can alter the underlying disease process and prevent its progression. The present manuscript provides a review of various hypotheses that have been proposed for AD pathogenesis. The manuscript has also explored the development of novel anti-AD drugs based on various pathogenic pathways, which are recently under various clinical trial phases.

Unravelling of molecular biomarkers in synaptic plasticity of Alzheimer's disease: Critical role of the restoration of neuronal circuits.

Learning and memory storage are the fundamental activities of the brain. Aberrant expression of synaptic molecular markers has been linked to memory impairment in AD. Aging is one of the risk factors linked to gradual memory loss. It is estimated that approximately 13 million people worldwide will have AD by 2050. A massive amount of oxidative stress is kept under control by a complex network of antioxidants, which occasionally fails and results in neuronal oxidative stress. Increasing evidence suggests that ROS may affect many pathological aspects of AD, including Aß accumulation, tau hyperphosphorylation, synaptic plasticity, and mitochondrial dysfunction, which may collectively result in neurodegeneration in the brain. Further investigation into the relationship between oxidative stress and AD may provide an avenue for effective preservation and pharmacological treatment of this neurodegenerative disease. In this review, we briefly summarize the cellular mechanism underlying Aß induced synaptic dysfunction. Since oxidative stress is common in the elderly and may contribute to the pathogenesis of AD, we also shed light on the role of antioxidant and inflammatory pathways in oxidative stress adaptation, which has a potential therapeutic target in neurodegenerative diseases.

Caenorhabditis elegans: A transgenic model for studying age-associated neurodegenerative diseases.

Neurodegenerative diseases (NDs) are a heterogeneous group of aging-associated ailments characterized by interrupting cellular proteostasic machinery and the misfolding of distinct proteins to form toxic aggregates in neurons. Neurodegenerative diseases, which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and others, are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Over the past decades, Caenorhabditis eleganshas beenwidely used as a transgenic model to investigate biological processes related to health and disease. The nematode Caenorhabditis elegans (C. elegans) has developed as a powerful tool for studying disease mechanisms due to its ease of genetic handling and instant cultivation while providing a whole-animal system amendable to several molecular and biochemical techniques. In this review, we elucidate the potential of C. elegans as a versatile platform for systematic dissection of the molecular basis of human disease, focusing on neurodegenerative disorders, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.

Melatonin Mitigates Rotenone-Induced Oxidative Stress and Mitochondrial Dysfunction in the Drosophila melanogaster Model of Parkinson's Disease-like Symptoms.

Parkinson's disease (PD) is the second most common neurodegenerative disorder; however, its etiology remains elusive. Antioxidants are considered to be a promising approach for decelerating neurodegenerative disease progression owing to extensive examination of the relationship between oxidative stress and neurodegenerative diseases. In this study, we investigated the therapeutic effect of melatonin against rotenone-induced toxicity in the Drosophila model of PD. The 3-5 day old flies were divided into four groups: control, melatonin alone, melatonin and rotenone, and rotenone alone groups. According to their respective groups, flies were exposed to a diet containing rotenone and melatonin for 7 days. We found that melatonin significantly reduced the mortality and climbing ability of Drosophila because of its antioxidative potency. It alleviated the expression of Bcl 2, tyrosine hydroxylase (TH), NADH dehydrogenase, mitochondrial membrane potential, and mitochondrial bioenergetics and decreased caspase 3 expression in the Drosophila model of rotenone-induced PD-like symptoms. These results indicate the neuromodulatory effect of melatonin, and that it is likely modulated against rotenone-induced neurotoxicity by suppressing oxidative stress and mitochondrial dysfunctions.

SAR based Review on Diverse Heterocyclic Compounds with Various Potential Molecular Targets in the Fight against COVID-19: A Medicinal Chemist Perspective.

Coronavirus disease (COVID-19) was reported to be transmitted from bats to humans and, became a pandemic in 2020. COVID-19 is responsible for millions of deaths worldwide and still, the numbers are increasing. Further, despite the availability of vaccines, mutation in the virus continuously poses a threat of re-emergence of the more lethal form of the virus. So far, the repurposing of drugs has been exercised heavily for the identification of therapeutic agents against COVID-19, which led FDA to approve many drugs for the same e.g., remdesivir, favipiravir, ribavirin, etc. The anti-COVID drugs explored via other approaches include nirmatrelvir (used in combination with ritonavir as Paxlovid), tixagevimab and cilgavimab (both used in combination with each other) and others. However, these approved drugs failed to achieve a significant clinical outcome. Globally, natural bioactive have also been explored for anti-COVID-19 effects, based on their traditional medicinal values. Although the clinical findings suggest that FDA-approved drugs and natural bioactives can help reducing the overall mortality rate but the significant clinical outcome was not achieved. Therefore, the focus has been shifted towards new drug development. In line with that, a lot of work has been done and still going on to explore heterocyclic compounds as potent anti- COVID-19 drugs. Several heterocyclic scaffolds have been previously reported with potent antiinflammatory, anticancer, anti-viral, antimicrobial and anti-tubercular effects. Few of them are under consideration for clinical trials whereas others are under preclinical investigation. Hence, this review discusses the evidence of rationally designed and tested heterocyclic compounds acting on different targets against COVID-19. The present article will help the researches and will serve as a pivotal resource in the design and development of novel anti-COVID-19 drugs.

Pregnenolone Attenuates the Ischemia-Induced Neurological Deficit in the Transient Middle Cerebral Artery Occlusion Model of Rats.

Neurosteroids are apparent to be connected in the cerebral ischemic injury for their potential neuroprotective effects. We previously demonstrated that progesterone induces neuroprotection via the mitochondrial cascade in the cerebral ischemic stroke of rodents. Here, we sought to investigate whether or not pregnenolone, a different neurosteroid, can protect the ischemic injury in the transient middle cerebral artery occlusion (tMCAO) rodent model. Male Wistar rats were chosen for surgery for inducing stroke using the tMCAO method. Pregnenolone (2 mg/kg b.w.) at 1 h postsurgery was administered. The neurobehavioral tests and (TTC staining) 2, 3, 5-triphenyl tetrazolium chloride staining were performed after 24 h of the surgery. The mitochondrial membrane potential and reactive oxygen species (ROS) were measured using flow cytometry. Oxygraph was used to examine mitochondrial bioenergetics. The spectrum of neurobehavioral tests and 2, 3, 5-triphenyltetrazolium chloride staining showed that pregnenolone enhanced neurological recovery. Pregnenolone therapy after a stroke lowered mitochondrial ROS following ischemia. Our data demonstrated that pregnenolone was not able to inhibit mitochondrial permeability transition pores. There was no effect on mitochondrial bioenergetics such as oxygen consumption and respiratory coupling. Overall, the findings demonstrated that pregnenolone reduced the neurological impairments via reducing mitochondria ROS but not through the inhibition of the mitochondria permeability transition pore (mtPTP).

Dodging blood brain barrier with "nano" warriors: Novel strategy against ischemic stroke.

Ischemic stroke (IS) is one of the leading causes of death and disability resulting in inevitable burden globally. Ischemic injury initiates cascade of pathological events comprising energy dwindling, failure of ionic gradients, failure of blood brain barrier (BBB), vasogenic edema, calcium over accumulation, excitotoxicity, increased oxidative stress, mitochondrial dysfunction, inflammation and eventually cell death. In spite of such complexity of the disease, the only treatment approved by US Food and Drug Administration (FDA) is tissue plasminogen activator (t-PA). This therapy overcome blood deficiency in the brain along with side effects of reperfusion which are responsible for considerable tissue injury. Therefore, there is urgent need of novel therapeutic perspectives that can protect the integrity of BBB and salvageable brain tissue. Advancement in nanomedicine is empowering new approaches that are potent to improve the understanding and treatment of the IS. Herein, we focus nanomaterial mediated drug delivery systems (DDSs) and their role to bypass and cross BBB especially via intranasal drug delivery. The various nanocarriers used in DDSs are also discussed. In a nut shell, the objective is to provide an overview of use of nanomedicine in the diagnosis and treatment of IS to facilitate the research from benchtop to bedside.

Heterocyclic Moieties as HDAC Inhibitors: Role in Cancer Therapeutics.

'Epigenetic' regulation of genes via post-translational modulation of proteins is a wellexplored approach for disease therapies, particularly cancer chemotherapeutics. Histone deacetylases (HDACs) are one of the important epigenetic targets and are mainly responsible for balancing the acetylation/deacetylation of lysine amino acids on histone/nonhistone proteins along with histone acetyltransferase (HAT). HDAC inhibitors (HDACIs) have become important biologically active compounds for the treatment of cancers due to cell cycle arrest, differentiation, and apoptosis in tumor cells, thus leading to anticancer activity. Out of the four classes of HDAC, i.e., Class I, II, III, and IV, HDACIs act on Class IV (Zinc dependent HDAC), and various FDA-approved drugs belong to this category. The required canonical pharmacophore model (zinc-binding group, surface recognition cap, and appropriate linker) supported by HDACIs, various heterocyclic moieties containing compounds exhibiting HDAC inhibitory activity, and structure-activity relationship of different synthetic derivatives reported during the last twelve years have been summarized in this review.

In silico strategies for probing novel DPP-IV inhibitors as anti-diabetic agents.

Identification of new DPP-IV inhibitors by integrating validated in silico approach is being presented herein. Novel hits were identified by combining pharmacophore and structure based virtual screening of ZINC and Knowledge Base in house database followed by ADME profiling, consensus docking studies. Six potential hits were identified and analysed for their synthetic accessibility score, novelty analysis and pan assay interference compounds filtration. Out of six, three hits viz., ZINC25060187, ZINC53746227 and KB-10 were analysed for stability studies using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and Molecular Dynamics (MD) simulation. The simulation studies of the identified hits revealed that these hits have good selectivity and stability in DPP-IV binding pocket. Important interactions with amino acids viz., Tyr547, Glu205 and Glu206 similar to co-crystallized ligand were also observed. One of the hits viz., KB-10 was synthesized and evaluated for its biological potential. The compound KB-10 showed good DPP-IV inhibition in both in vitro and in vivo studies with IC50: 22.69 µM. This study supports the fact that these techniques hold potential for efficient screening of compounds with unknown affinity for DPP-IV that could serve as candidates for therapeutic development.Communicated by Ramaswamy H. Sarma.

Design and synthesis of pyrazole-pyrazoline hybrids as cancer-associated selective COX-2 inhibitors.

In continuation of our previous work on cancer and inflammation, 15 novel pyrazole-pyrazoline hybrids (WSPP1-15) were synthesized and fully characterized. The formation of the pyrazoline ring was confirmed by the appearance of three doublets of doublets in 1 H nuclear magnetic resonance spectra exhibiting an AMX pattern for three protons (HA , HM , and HX ) of the pyrazoline ring. All the synthesized compounds were screened for their in vitro anticancer activity against five cell lines, that is, MCF-7, A549, SiHa, COLO205, and HepG2 cells, using the MTT growth inhibition assay. 5-Fluorouracil was taken as the positive control in the study. It was observed that, among them, WSPP11 was found to be active against A549, SiHa, COLO205, and HepG2 cells, with IC50 values of 4.94, 4.54, 4.86, and 2.09 µM. All the derivatives were also evaluated for their cytotoxicity against HaCaT cells. WSPP11 was also found to be nontoxic against normal cells (cell line HaCaT), with an IC50 value of more than 50 µM. The derivatives were also evaluated for their in vitro anti-inflammatory activity by the protein (egg albumin) denaturation assay and the red blood cell membrane stabilizing assay, using diclofenac sodium and celecoxib as standard. Compounds that showed significant anticancer and anti-inflammatory activities were further studied for COX-2 inhibition. The manifestation of a higher COX-2 selectivity index of WSPP11 as compared with other derivatives and an in vitro anticancer activity against four cell lines further established that compounds that were more selective toward COX-2 also exhibited a better spectrum of activity against various cancer cell lines.

Synthesis, ADMET prediction and reverse screening study of 3,4,5-trimethoxy phenyl ring pendant sulfur-containing cyanopyrimidine derivatives as promising apoptosis inducing anticancer agents.

Cancer remains considered as one of the leading global health problems either due to meagre and suboptimal therapeutic response of chemotherapeutic agents or due to the emergence of spontaneous complex multidrug resistance in cancer cells. This created a persistent need for the development of new anticancer agents. Enthralled by the high success rate for natural product-based drug discovery and current research scenario, we synthesized a new series of 3,4,5-trimethoxy phenyl ring pendant sulfur-containingcyanopyrimidine derivatives clubbed with different amines intending to search an anticancer lead compound. To probe the anti-proliferative spectrum of the synthesized derivatives, an in-vitro evaluation was piloted against a panel of 60 cancer cell lines at the National Cancer Institute (NCI) representing major types of cancer diseases. Most of the derivatives showed good to moderate anti-proliferative activity. The results revealed that compound 4e displayed the most promising broad-spectrum anticancer activity with high growth inhibition of various cell lines representing multiple cancers diseases. Mechanistic investigation of compound 4e in human breast cancer MDA-MB-231 cells showed that compound 4e triggers cell death through the induction of apoptosis. ADMET studies and reverse screening were also performed to identify the potential targets of designed molecules. It was concluded that 3,4,5-trimethoxy phenyl ring pendant sulfur-containingcyanopyrimidine derivative 4e could act as a promising hit molecule for further development of novel anticancer therapeutics.

Computational prediction and experimental validation of the activator function of C2-ß-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone on pancreatic and hepatic hexokinase.

This study identifies and validates hexokinase type 4 (HK4), an isozyme of hexokinase in the liver and pancreas, as an important target of C2-ß-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone (ßdGT), a xanthone glucoside suggested to have antidiabetic property. In the study, we applied the computational pipeline of molecular docking followed by the molecular dynamics simulations to shortlist potential ßdGT protein targets. The analysis of protein dynamics and the binding free energy (ΔG) led us to the identification of HK4 as a key ßdGT target, whereby the binding mode and domain dynamics suggested the activator function of ßdGT. ßdGT bound to the allosteric site of the isozyme ∼13 Å away from the substrate (glucose)-binding site. The binding free energy of the ligand-protein complex was energetically feasible (ΔG, -41.61 kcal/mol) and the cleft angle deviation between the two (small and large) domains of HK4 revealed differential HK4 dynamics in response to ßdGT binding. 3D structure analysis of the isozyme-ligand complex highlighted the role of Arg63, Glu67 and Lys458 in ligand stabilization and hydrophobic interactions mediated by Tyr214 and Met235. Experimental validation of the results of computational analysis confirmed the activator function of ßdGT on HK4. The study has implication in diabetes as ßdGT may be used to lower the blood glucose level by activating hepatic and pancreatic hexokinase without the risk of hypoglycemia.Communicated by Ramaswamy H. Sarma.

Mining of potential dipeptidyl peptidase-IV inhibitors as anti-diabetic agents using integrated in silico approaches.

The dipeptidyl peptidase-IV (DPP-IV) family of receptors possesses a large binding cavity that imparts promiscuity for number of ligand binding which is not common to other receptors. This feature increases the challenge of using computational methods to identify DPP-IV inhibitors, therefore using both pharmacophore and structure-based screening seems to be a reliable approach. Mining of novel DPP-IV inhibitors by integrating both of these in silico techniques was reported. Pharmacophore model (Model_008) obtained from structurally diverse reported compounds was used as a template for screening of MolMall database followed by structure-based screening against PDB ID: 5T4E. After absorption, distribution, metabolism and excretion (ADME) analysis of shortlisted compounds, consensus docking and molecular mechanics/generalized born surface area studies were carried out. The results of the docking studies obtained were comparable to that of the reference ligand. Out of nine hits identified, only one hit (ID MolMall-20062) was available which was procured through exchange program. Molecular dynamic simulation studies of the procured hit revealed its good selectivity and stability in DPP-IV binding pocket and interactions observed with important amino acids viz., Trp629, Lys544 and Arg125. Biological testing of the compound MolMall-20062 showed promising DPP-IV inhibition activity with IC50: 6.2 µM. Compound MolMall-20062 could be taken as a good lead for the development of DPP-IV inhibitors.AbbreviationsADMEabsorption, distribution, metabolism and excretionChEBIchemical entities of biological interestDPP-IVdipeptidyl peptidase IVDISCOtechdistance comparisonsHTVShigh throughput virtual screeningMDmolecular dynamicsMM-GBSAmolecular mechanics-generalized born surface areaOGTToral glucose tolerance testPBVSpharmacophore-based virtual screeningPDBprotein data bankRMSDroot mean square deviationROCreceiver operating characteristicsSPstandard precisionSBVSstructure-based virtual screeningVSvirtual screeningXPextra precisionCommunicated by Ramaswamy H. Sarma.

Combretastatin-based compounds with therapeutic characteristics: a patent review.

Introduction: Combretastatins represent a potent class of phenolic-stilbene natural products that function as colchicine binding site inhibitors of tubulin polymerization and have been advanced as promising anticancer lead compounds. Among them, combretastatin A-4 is the most potent lead molecule due to its broad spectrum cytotoxicity against a variety of tumors. However, low water solubility due to its high lipophilic nature and inter-conversion of olefinic double bond from more active cis to less active trans-conformation poses limitations to its clinical utility. However, different approaches including prodrugs, salt formations, structural modifications, prevention of inter-conversion of the olefinic bond and changes to the substitution pattern on the rings of combretastatin A-4 were investigated and successfully resulted in different combretastatin-based molecules that demonstrated varying levels of potency against different types of tumors during their in-vitro and in-vivo studies. Areas covered: This review covers the patents over a period of 2008-2018. Expert opinion: Molecular hybridization and prodrug designing imparted multi-targeted actions to combretastatin derivatives. Currently, various combretastatin derivatives are under clinical trials. These derivatives could be used to treat disorders other than cancer, due to their vascular disrupting action.

Dibenzepinones, dibenzoxepines and benzosuberones based p38α MAP kinase inhibitors: Their pharmacophore modelling, 3D-QSAR and docking studies.

In the present study, a series of dibenzepinones, dibenzoxepines, and benzosuberones targeting p38α MAP kinase were subjected to pharmacophore modelling, 3D-QSAR and molecular docking studies. The IC50 values for these 67 compounds ranged between 0.003 and 6.80 µM. A five-point model (DDHHR.8) was generated using these compounds. This model was found to be statistically significant and was found to have high correlation (R2 = 0.98), cross-validation coefficient (Q2 = 0.95) and F (330) values at six component PLS factor. Tests were performed to ascertain the efficacy of the generated model. These tests included external validation, Tropsha's test for predictive ability, Y-randomisation test and domain of applicability (APD). In order to check the restrictivity of the model, enrichment studies were performed with inactive compounds by using decoy set molecules. To evaluate the effectiveness of the docking protocol, the co-crystallised ligand was extracted from the ligand-binding domain of the protein and was re-docked into the same position. Both the conformers were then superimposed, suggesting satisfactory docking parameters with an RMSD value of less than 1.0 Š(0.853 Å). A 10 ns molecular dynamics simulation confirmed the docking results of the 3UVP-ligand complex and the presumed active conformation. The outcome of the present study provides insight into the molecular features that promote bioactivity and can be exploited for the prediction of novel potent p38α MAP kinase inhibitors before carrying out their synthesis and anticancer evaluation.

Targeting malaria and leishmaniasis: Synthesis and pharmacological evaluation of novel pyrazole-1,3,4-oxadiazole hybrids. Part II.

In continuance with earlier reported work, an extension has been carried out by the same research group. Mulling over the ongoing condition of resistance to existing antimalarial agents, we had reported synthesis and antimalarial activity of certain pyrazole-1,3,4-oxadiazole hybrid compounds. Bearing previous results in mind, our research group ideated to design and synthesize some more derivatives with varied substitutions of acetophenone and hydrazide. Following this, derivatives 5a-r were synthesized and tested for antimalarial efficacy by schizont maturation inhibition assay. Further, depending on the literature support and results of our previous series, certain potent compounds (5f, 5n and 5r) were subjected to Falcipain-2 inhibitory assay. Results obtained for these particular compounds further strengthened our hypothesis. Here, in this series, compound 5f having unsubstituted acetophenone part and a furan moiety linked to oxadiazole ring emerged as the most potent compound and results were found to be comparable to that of the most potent compound (indole bearing) of previous series. Additionally, depending on the available literature, compounds (5a-r) were tested for their antileishmanial potential. Compounds 5a, 5c and 5r demonstrated dose-dependent killing of the promastigotes. Their IC50 values were found to be 33.3 ±â€¯1.68, 40.1 ±â€¯1.0 and 19.0 ±â€¯1.47 µg/mL respectively. These compounds (5a, 5c and 5r) also had effects on amastigote infectivity with IC50 of 44.2 ±â€¯2.72, 66.8 ±â€¯2.05 and 73.1 ±â€¯1.69 µg/mL respectively. Further target validation was done using molecular docking studies. Acute oral toxicity studies for most active compounds were also performed.

Revealing quinquennial anticancer journey of morpholine: A SAR based review.

Morpholine, a six-membered heterocycle containing one nitrogen and one oxygen atom, is a moiety of great significance. It forms an important intermediate in many industrial and organic syntheses. Morpholine containing drugs are of high therapeutic value. Its wide array of pharmacological activity includes anti-diabetic, anti-emetic, growth stimulant, anti-depressant, bronchodilator and anticancer. Multi-drug resistance in cancer cases have emerged in the last few years and have led to the failure of many chemotherapeutic drugs. Newer treatment methods and drugs are being developed to overcome this problem. Target based drug discovery is an effective method to develop novel anticancer drugs. To develop newer drugs, previously reported work needs to be studied. Keeping this in mind, last five year's literature on morpholine used as anticancer agents has been reviewed and summarized in the paper herein.