Exploration of multifaceted molecular mechanism of angiotensin-converting enzyme 2 (ACE2) in pathogenesis of various diseases.

Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE (a transmembrane bound dipeptidyl peptidase enzyme). ACE2 converts angiotensinogen to the heptapeptide angiotensin-(1-7). ACE2 and its product, angiotensin-(1-7), have counteracting effects against the adverse actions of other members of renin-angiotensin system (RAS). ACE2 and its principal product, angiotensin-(1-7), were considered an under recognized arm of the RAS. The COVID-19 pandemic brought to light this arm of RAS with special focus on ACE2. Membrane bound ACE2 serves as a receptor for SARS-CoV-2 viral entry through spike proteins. Apart from that, ACE2 is also involved in the pathogenesis of various other diseases like cardiovascular disease, cancer, respiratory diseases, neurodegenerative diseases and infertility. The present review focuses on the molecular mechanism of ACE2 in neurodegenerative diseases, cancer, cardiovascular disease, infertility and respiratory diseases, including SARS-CoV-2. This review summarizes unveiled roles of ACE2 in the pathogenesis of various diseases which further provides intriguing possibilities for the use of ACE2 activators and RAS modulating agents for various diseases.

Insights into the structural requirements of triazole derivatives as promising DPP IV inhibitors: computational investigations.

Diabetes is one of the leading causes of death globally as per World Health Organization 2019. To cope up with side effects of current diabetes therapy, researchers have found several novel targets for the treatment of diabetes. Currently, dipeptidyl peptidase IV (DPP IV) has emerged as a target in modulating the diabetes physiology. In the present work, various 3D-Quantitative structure activity relationship (QSAR) techniques namely comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis, topomer CoMFA and molecular hologram QSAR are used to explore the structural requirements of triazole derivatives as DPP IV inhibitors. Different models generated by 3D QSAR studies had acceptable statistical values for further prediction of molecules. From the contour maps of QSAR results, important structural features are deduced. Substitutions on N1 and N2 of triazole ring with H-bond donor group enhances the biological activity. Aliphatic side chain, less bulky group, H-bond donor group and -COOH group on N3 of triazole ring are vital for the DPP IV inhibition. Moreover, electron withdrawing side chain on the triazole ring improves the biological activity. Further, novel triazole derivatives were designed and docking results of these compounds proved the efficiency of the developed 3D QSAR model. In future, results of this study may provide promising DPP IV inhibitors for the treatment of diabetes. Communicated by Ramaswamy H. Sarma.

Investigations on substituted (2-aminothiazol-5-yl)(imidazo[1,2-a]pyridin-3-yl)methanones for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease majorly affecting old age populations. Various factors that affect the progression of the disease include, amyloid plaque formation, neurofibrillary tangles, inflammation, oxidative stress, etc. Herein we report of a new series of substituted (2-aminothiazol-5-yl)(imidazo[1,2-a]pyridin-3-yl)methanones. The designed compounds were synthesized and characterized by spectral data. In vivo anti-inflammatory activity was carried out for screening of anti-inflammatory potential of synthesized compounds. All the compounds were tested for acute inflammatory activity by using carrageenan induced acute inflammation model. Compounds 10b, 10c, and 10o had shown promising acute anti-inflammatory activity and they were further tested for formalin induced chronic inflammation model. Compound 10c showed both acute and chronic anti-inflammatory activity. Compound 10c also showed promising results in AlCl3 induced AD model. Studies on various behavioral parameters suggested improved amnesic performance of compound 10c treated rats. Compound 10c treated rats also exhibited excellent antioxidant and neuroprotective effect with inherent gastrointestinal safety.

In silico studies on therapeutic agents for COVID-19: Drug repurposing approach.

AIMS: The severe acute respiratory syndrome coronavirus 2, better known as COVID-19 has become the current health concern to the entire world. Initially appeared in Wuhan, China around December 2019, it had spread to almost 187 countries due to its high contagious nature. Precautionary measures remain the sole obliging tactic to cease the person to person transmissions till any effective method of treatment or vaccine is developed. Amidst the pandemic, research and development of new molecule is labour-intensive and tedious process. Drug repurposing is the concept of identifying therapeutically potent molecule from the library of pre-existing molecules. MATERIALS AND METHODS: In the present study, 61 molecules that are already being used in clinics or under clinical scrutiny as antiviral agents are surveyed via docking study. Docking study was performed using Maestro interface (Schrödinger Suite, LLC, NY). KEY FINDINGS: Out of these 61 molecules, 37 molecules were found to interact with >2 protein structures of COVID-19. The docking results indicate that amongst the reported molecules, HIV protease inhibitors and RNA-dependent RNA polymerase inhibitors showed promising features of binding to COVID-19 enzyme. Along with these, Methisazone an inhibitor of protein synthesis, CGP42112A an angiotensin AT2 receptor agonist and ABT450 an inhibitor of the non-structural protein 3-4A might become convenient treatment option as well against COVID-19. SIGNIFICANCE: The drug repurposing approach provide an insight about the therapeutics that might be helpful in treating corona virus disease.

Pharmacological investigation of quinoxaline-bisthiazoles as multitarget-directed ligands for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent disease of old age leading to dementia. Complex AD pathogenesis involves multiple factors viz. amyloid plaque formation, neurofibrillary tangles and inflammation. Herein we report of a new series of quinoxaline-bisthiazoles as multitarget-directed ligands (MTDLs) targeting BACE-1 and inflammation concurrently. Virtual screening of a library of novel quinoxaline-bisthiazoles was performed by docking studies. The most active molecules from the docking library were taken up for synthesis and characterized by spectral data. Compounds 8a-8n showed BACE-1 inhibition in micro molar range. One of the compounds, 8n showed BACE-1 inhibition at IC50 of 3 ±â€¯0.07 µM. Rat paw edema inhibition in acute and chronic models of inflammation were obtained at 69 ±â€¯0.45% and 55 ±â€¯0.7%, respectively. Compound 8n also showed noteworthy results in AlCl3 induced AD model. The treated rats exhibited excellent antiamnesic, antiamyloid, antioxidant, and neuroprotective properties. Behavioural parameters suggested improved cognitive functions which further validates the testimony of present study. Moreover, compound 8n was found to have inherent gastrointestinal safety. This new string of quinoxaline-bisthiazoles were identified as effective lead for the generation of potent MTDLs and compound 8n was found to showcase qualities to tackle AD pathogenesis.

Thiazolyl-thiadiazines as Beta Site Amyloid Precursor Protein Cleaving Enzyme-1 (BACE-1) Inhibitors and Anti-inflammatory Agents: Multitarget-Directed Ligands for the Efficient Management of Alzheimer's Disease.

Alzheimer's disease (AD) is associated with multiple neuropathological events including ß-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibition and neuronal inflammation, ensuing degeneracy, and death to neuronal cells. Targeting such a complex disease via a single target directed treatment was found to be inefficacious. Hence, with an intention to incorporate multiple therapeutic effects within a single molecule, multitarget-directed ligands (MTDLs) have been evolved. Herein, for the first time, we report the discovery of novel thiazolyl-thiadiazines that can serve as MTDLs as evident from the in vitro and in vivo studies. These MTDLs exhibited BACE-1 inhibition down to micromolar range, and results from the in vivo studies demonstrated efficient anti-inflammatory activity with inherent gastrointestinal safety. Moreover, compound 6d unveiled noteworthy antioxidant, antiamyloid, neuroprotective, and antiamnesic properties. Overall, results of the present study manifest the potential outcome of thiazolyl-thiadiazines for AD treatment.

Design, synthesis and biological evaluation of novel pyrazolo-pyrimidinones as DPP-IV inhibitors in diabetes.

We report the design, synthesis, biological activity and docking studies of series of novel pyrazolo[3,4-d]pyrimidinones as DPP-IV inhibitors in diabetes. Molecules were synthesized and evaluated for their DPP-IV inhibition activity. Compounds 5e, 5k, 5o and 6a were found to be potent inhibitors of DPP-IV enzyme. Amongst all the synthesized compounds, 6-methyl-5-(4-methylpyridin-2-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (5k) was found to be the most active based on in vitro DPP-IV studies and also exhibited promising in vivo blood glucose lowering activity in male Wistar rats.