Publications by authors named "Mudasir Maqbool"

18 Publications

  • Page 1 of 1

Depression and anxiety in women with polycystic ovarian syndrome: a literature survey.

Int J Adolesc Med Health 2021 Aug 23. Epub 2021 Aug 23.

Regional Research Institute of Unani Medicine, Srinagar, Jammu and Kashmir, India.

Polycystic ovarian syndrome (PCOS) is the most frequent endocrine disorder among women of reproductive age. Some of the indications and symptoms of PCOS include amenorrhoea, hirsutism, infertility, obesity, acne vulgaris and androgenic alopecia. PCOS is a crippling condition that affects a woman's identity, mental health and overall quality of life (QOL). In persons with PCOS, anxiety and sadness are assumed to be multifactorial. According to some specialists, physical symptoms like acne, hirsutism and obesity have been linked to psychiatric morbidities. Many aspects of it remain unknown, including its cause, progression throughout life, symptom spectrum and level of morbidity. PCOS is a complex disease that has an impact on many aspects of a person's health, including their mental health. Anxiety and depression are three times as common in PCOS patients as in non-PCOS people. Anxiety and depression symptoms are also more common and more intense in those with PCOS. There isn't enough research on the prevalence of anxiety and depression in patients with PCOS. It's unclear what causes persons with PCOS to be more anxious and depressed. It could be the result of PCOS symptoms, hormonal changes, or a combination of factors that are currently unclear. Our review article will help to highlight the most recent research on anxiety and depression in PCOS women.
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http://dx.doi.org/10.1515/ijamh-2021-0092DOI Listing
August 2021

Acute neurological conditions during pregnancy and their management: a review.

Int J Adolesc Med Health 2021 Aug 23. Epub 2021 Aug 23.

Regional Research Institute of Unani Medicine, Srinagar, Jammu and Kashmir, India.

Less vascular resistance, higher vascular permeability and improved cardiac output include anatomical and physiological changes related to pregnancy. These are needed to accommodate an increase in plasma volume and ensure significant organ infusion. Nevertheless, increases in oestrogen levels may lead to an increase in the risk of coagulation and thrombosis. Increased levels of progesterone increase the risk of thrombosis due to vasodilation, vascular stasis and edoema in these situations. The increased resistance in preeclampsia maternal systemic blood arteries can create high blood pressure that can interfere with blood flow in numerous organs (including liver, kidneys, brain and placenta). The risk of issues such as pulmonary edoema, placental abruption, pneumonia of aspiration, renal failure, hepatic failure and stroke in pregnant women is increased by Preeclampsia and eclampsia. Some peripheral neuropathies (carpal tunnel syndrome, peripheral facial palsy) and central neurological conditions (seizure, migraine, stroke, epilepsy) may become more common during pregnancy because of the exacerbation of the pre-existing neurologic condition or the onset of neurological disturbance caused by pregnancy physiological changes (such as headache or vascular disorders). During the three trimesters of pregnancy, neurological disorders are both peripheral and central. Therefore, an early and correct diagnosis is required to improve pregnancy care, treatment and perinatal outcomes. The aims of this paper are to identify, define and manage the most prevalent peripheral and centrally occurring neurological disorders in the pregnancy.
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http://dx.doi.org/10.1515/ijamh-2021-0084DOI Listing
August 2021

Polycystic ovary syndrome and infertility: an update.

Int J Adolesc Med Health 2021 Jul 22. Epub 2021 Jul 22.

Regional Research Institute of Unani Medicine, Srinagar, Jammu and Kashmir, India.

Polycystic ovarian syndrome is the most well-known endocrine condition among women of this generation (PCOS). Symptoms of hyperandrogenism, irregular menstrual periods, and insulin resistance are all traits associated with PCOS. In women with PCOS, the chance of having problems including infertility, insulin resistance, and type 2 diabetes increases. The PCOS board hopes to reduce body weight and insulin levels, restore fertility, control excessive hair growth on the body or scalp, re-establish the regular feminine cycle, and avoid misunderstandings. Insulin sensitizers have been one of the most common metabolic modulators, but their effectiveness has been sporadic. Insulin resistance, followed by thiazolidinediones, is central to the pathophysiology of PCOS, with metformin having nearly similar efficacy. In the management of PCOS, statins and incretins are newer therapies with obvious metabolic targets. Vitamin D, acarbose, and myoinositol are just a few of the reciprocal and optional clinical treatments that have been proved to be useful in the treatment of PCOS. The number of viable methods for dealing with PCOS-related infertility has increased as well. Despite the fact that clomiphene citrate (CC) has long been the gold standard for ovulation induction in the event of ovulatory infertility, aromatase inhibitors can induce ovulation with results that are nearly identical to or better than those reported with CC, aromatase inhibitors can cause ovulation with results that are nearly identical to or better than those reported with CC. Ovarian incitement conventions that intelligently utilize gonadotropins, gonadotropin-delivering hormone rivals, the approach of ovarian boring, and assisted conceptive advancements with oocyte development indicate an expanding level of therapeutic progress.
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http://dx.doi.org/10.1515/ijamh-2021-0073DOI Listing
July 2021

Menstrual distress in females of reproductive age: a literature review.

Int J Adolesc Med Health 2021 Jul 22. Epub 2021 Jul 22.

Regional Research Institute of Unani Medicine, Srinagar, Jammu and Kashmir, India.

Menstrual-related issues have significant public-health ramifications. Women who are having menstruation troubles should get their mental health checked by healthcare specialists. In young women, a menstrual-related condition has serious health implications. Young females who have menstrual issues miss job and school, and their behavioural and mental development suffers as a result. Depression and anxiety have an impact on women's menstrual periods in adults. Symptoms like as cramps, tiredness, backache, swelling abdomen, and painful breasts have also been described in women with menstrual misery. Menstrual distress has been shown to impair women's daily activities, as well as their reproductive and psychological health, according to research. Menstrual periods are frequently accompanied by a variety of unpleasant symptoms, such as premenstrual syndrome, which includes symptoms such as mild cramping and exhaustion. The severity of these symptoms, on the other hand, differs from woman to woman, depending on their health, food, way of life, and other factors. Women with menstrual-related issues have also reported smoking, alcohol intake, and an increase in hunger. Furthermore, young women experience emotional disturbances such as melancholy, restlessness, and despair. It is a sign of an atypical menstrual cycle if there is no cycle or if the bleeding is atypical or light. As a result, it is critical to maintain contact with a gynaecologist in order to detect any significant changes in a regular menstrual cycle.
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http://dx.doi.org/10.1515/ijamh-2021-0081DOI Listing
July 2021

Correlation between obesity, gestational diabetes mellitus, and pregnancy outcomes: an overview.

Int J Adolesc Med Health 2021 Jun 16. Epub 2021 Jun 16.

Regional Research Institute of Unani Medicine, Srinagar, Jammu and Kashmir, India.

Obesity has been identified mainly as a raise in the body's adiposity leading to prolonged overshoot of caloric intake over expenditure. Obesity has significant health-altering implications which have been shown to be implicated in the pathogenesis and progression of other diseases through its extensive physiological assaults. The prevalence of overweight and obesity has been an increasing epidemic worldwide. The number of obese births was even on the increase, with an increasing number of women of reproductive age registering as obese. Obesity is related to adverse perinatal outcomes and increased morbidity and mortality in pregnant women. The potential risk for multiple antenatal, postpartum, intrapartum, and neonatal complications is maternal obesity. Greater risk of developing Gestational Diabetes Mellitus (GDM), pregnancy induced hypertension (PIH), pre-eclampsia, risk of venous embolism, increased need for labor induction, and cesarean sections in the mother have been recorded in a comprehensive analysis of pregnancy complications associated with obesity. The link between obesity, gestational diabetes, and pregnancy outcomes will be briefly shown in this article.
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http://dx.doi.org/10.1515/ijamh-2021-0058DOI Listing
June 2021

Polycystic ovary syndrome and reproductive health of women: a curious association.

Int J Adolesc Med Health 2021 Apr 21. Epub 2021 Apr 21.

Regional Research Institute of Unani Medicine, Srinagar, Jammu and Kashmir, India.

Reproductive health is a broad concept that encompasses mortality, morbidity, and quality of life associated with the reproductive system, mechanism, and incidents encountered at all ages by men and women. Orthodox Indian society finds the conversation on reproductive health to be a taboo and discourages open conversations about it. Polycystic ovary syndrome (PCOS) is a reproductive-age metabolic endocrine disorder found in females. Females suffering from PCOS are prone to reproductive, metabolic, and cardiovascular disorders. In this paper, we will systematically review about effect of PCOS on Reproductive Health of Women. The numerous electronic databases such as: BMJ, LANCET, PUBMED, Unicef Website, WHO Website and Google Scholar have been comprehensively searched for studies linked to PCOS, its various effects and effect on women's reproductive health. For additional analyses, we have reviewed reference lists of reviews and collected papers. The effects of PCOS on women's reproductive health have been verified by several scientific reports worldwide. PCOS is a hormonal condition, as per multiple reports, with the ability to lead to different outcomes. It still appears to be a common cause among females of infertility. An integral aspect of the treatment of this disease is the early diagnosis of long-term morbidities by effective screening tests. In the future, studies must concentrate on the missing holes in our growing perception of this disease. Several studies have confirmed that reproductive morbidity, including irregular uterine bleeding, abortion, miscarriage, and other risk of pregnancy during reproductive years, is associated with PCOS. PCOS is an amalgam of physiological and psychosocial dysfunction, not just an endocrine disorder.
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http://dx.doi.org/10.1515/ijamh-2021-0031DOI Listing
April 2021

Unravelling the potency of triazole analogues for inhibiting α-synuclein fibrillogenesis and disaggregation.

Org Biomol Chem 2021 02;19(7):1589-1603

Drug Design and Synthesis Lab., Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India.

A series of triazole-based compounds was synthesized using a click chemistry approach and evaluated for the inhibition of α-synuclein (α-syn) fibrillogenesis and its disaggregation. Compounds Tr3, Tr7, Tr12, Tr15, and Tr16 exhibited good effect in inhibiting α-syn fibrillogenesis confirmed by Thioflavin-T assay and fluorescence microscopy and α-syn disaggregation confirmed by fluorescence microscopy. Molecular docking was used to understand the plausible mechanism of the test compounds for inhibiting the α-syn fibrillogenesis and to verify the in vitro results. Compounds Tr3, Tr7, Tr12, Tr15 and Tr16 showed good binding interactions with the essential amino acid residues of α-syn. The compounds which were found to be good inhibitors or disaggregators had no toxic effects on the SH-SY5Y cell line. These compounds have the potential to be developed as therapeutic interventions against synucleinopathies including Parkinson's disease and Lewy body dementia.
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http://dx.doi.org/10.1039/d0ob02226hDOI Listing
February 2021

Quinoline carboxamide core moiety-based compounds inhibit P. falciparumfalcipain-2: Design, synthesis and antimalarial efficacy studies.

Bioorg Chem 2021 03 24;108:104514. Epub 2020 Nov 24.

Drug Design and Synthesis Lab., Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India. Electronic address:

Targeting Falcipain-2 (FP2) for the development of antimalarials is a promising and established concept in antimalarial drug discovery and development. FP2, a member of papain-family cysteine protease of the malaria parasite Plasmodium falciparum holds an important role in hemoglobin degradation pathway. A new series of quinoline carboxamide-based compounds was designed, synthesized and evaluated for antimalarial activity. We integrated molecular hybridization strategy with in-silico drug design to develop FP2 inhibitors. In-vitro results of FP2 inhibition by Qs17, Qs18, Qs20 and Qs21 were found to be in low micromolar range with IC 4.78, 7.37, 2.14 and 2.64 µM, respectively. Among the 25 synthesized compounds, four compounds showed significant antimalarial activities. These compounds also depicted morphological and food-vacuole abnormalities much better than that of E-64, an established FP2 inhibitor. Overall these aromatic substituted quinoline carboxamides can serve as promising leads for the development of novel antimalarial agents.
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http://dx.doi.org/10.1016/j.bioorg.2020.104514DOI Listing
March 2021

Diphenyl triazine hybrids inhibit α-synuclein fibrillogenesis: Design, synthesis and in vitro efficacy studies.

Eur J Med Chem 2020 Dec 22;207:112705. Epub 2020 Aug 22.

Drug Design and Synthesis Lab., Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India. Electronic address:

Aggregation of α-synuclein (α-syn) is one of the central hypotheses for Parkinson's disease (PD), therefore, its inhibition and disaggregation is an optimistic approach for the treatment of PD. Here, we report design, synthesis and in-vitro efficacy studies of a series of diphenyl triazine hybrids as potential inhibitors of α-syn fibrillogenesis. From the docking studies, we concluded that compounds A1, A2, A4, A8 and A9 display promising binding affinity with the essential residues of α-syn with binding energy values: -6.0, -7.0, -6.3, -6.6 and -6.7 kcal/mol respectively. The target compounds were synthesized using multistep organic synthesis reactions. Compounds A1, A2 A4, A8 and A9 showed a significant lowering of the α-syn fibril formation during Thioflavin-T assay and fluorescence microscopy. In addition, these compounds A1, A2, A4, A8 and A9 also proved to be good disaggregators in the pre-aggregated form of α-syn. Most of the compounds exhibited no cytotoxicity in mouse embryonic fibroblast (MEF) and human adenocarcinomic alveolar basal epithelial cells (A549) except A2. Overall, diphenyl triazine-based compounds can be further investigated for the treatment of synucleinopathies and for Lewy body dementia in which α-syn is predominantly observed.
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http://dx.doi.org/10.1016/j.ejmech.2020.112705DOI Listing
December 2020

Deciphering the robustness of pyrazolo-pyridine carboxylate core structure-based compounds for inhibiting α-synuclein in transgenic C. elegans model of Synucleinopathy.

Bioorg Med Chem 2020 09 11;28(17):115640. Epub 2020 Jul 11.

Drug Design and Synthesis Lab, Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India. Electronic address:

Parkinson's disease (PD), a calamitous neurodegenerative disorder with no cure till date, is closely allied with the misfolding and aggregation of α-Synuclein (α -Syn). Inhibition of α-Syn aggregation is one of the optimistic approaches for the treatment for PD. Here, we carried out hypothesis-driven studies towards synthesising a series of pyrazolo-pyridine carboxylate containing compounds (7a-7m) targeted at reducing deleterious α-Syn aggregation. The target compounds were synthesized through multi-step organic synthesis reactions. From docking studies, compounds 7b, 7g and 7i displayed better interaction with the key residues of α-Syn with values: -6.8, -8.9 and -7.2 Kcal/mol, respectively. In vivo transgenic C. elegans model of Synucleinopathy was used to evaluate the ability of the designed and synthesized compounds to inhibit α-Syn aggregation. These lead compounds 7b, 7g and 7i displayed 1.7, 2.4 and 1.5-fold inhibition of α-Syn with respect to the control. Further, the strategy of employing pyrazolo-pyridine-based compounds worked with success and these scaffolds could be further modified and validated for betterment of endpoints associated with PD.
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http://dx.doi.org/10.1016/j.bmc.2020.115640DOI Listing
September 2020

Drug Use Evaluation of Beta-Blockers in Medical Wards of Nedjo General Hospital, Western Ethiopia.

Cardiovasc Ther 2020 22;2020:2509875. Epub 2020 May 22.

Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal Srinagar, 190006 Jammu and Kashmir, India.

Introduction: Beta-blocker use evaluation is a performance method that focuses on the evaluation of beta-blocker use processes to achieve optimal patient outcomes. Several studies conducted in different hospitals revealed a high incidence of inappropriate prescription of beta-blockers among hospitalized patients. Therefore, it is important to identify inappropriate beta-blocker prescribing since they may increase the risk of hospitalizations. Despite this, there was no study conducted related to drug use evaluation of beta-blockers in Nedjo general hospital (NGH). Thus, this study was aimed at assessing the use evaluation of beta-blockers in medical wards of NGH.

Methods: A retrospective cross-sectional study was conducted at medical wards of NGH from January 1, 2016, to December 31, 2017.

Results: Out of the total of 149 medical record of patients that contains beta-blockers, 84 (56.37%) were males and about one-third (31.54%) of the patients ages were between 41 and 50 years. Propranolol was the most commonly prescribed beta-blocker (62.76%), and 94.56% of beta-blockers were prescribed with correct indication. There were about 51%, 46.31%, 64.43%, and 46.98% of beta-blockers prescribed with the correct dose, duration, frequency, and route of administration, respectively. Regarding the routes of administration, 70 (46.98%) of them were prescribed with the correct route. Most drugs interacting were propranolol with cimetidine 26 (68.42%), and the most frequent condition for which beta-blockers were prescribed was hypertension (32.89%).

Conclusion: Overall, there was an inappropriate use of beta-blockers in terms of dosage and durations. So, prescribers of NGH should strictly adhere to the national treatment guideline when prescribing medications. Additionally, drug information centers have proved useful and effective in promoting rational drug use. Hence, it should be recommended for general use.
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http://dx.doi.org/10.1155/2020/2509875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284961PMC
July 2020

GSK3 Inhibitors in the Therapeutic Development of Diabetes, Cancer and Neurodegeneration: Past, Present and Future.

Curr Pharm Des 2017 Nov;23(29):4332-4350

Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi 110025, India.

GSK3 has gained a considerable attention of researchers in the late 1970s as an inevitable drug target to treat diabetes. Furthermore, it was found to have a key role in the development of diseases like cancer and neurodegeneration (ND). A broad spectrum of GSK3 inhibitors have been discovered from time to time in order to curb these diseases. Inhibition of GSK3 by insulin boosts the dephosphorylation of glycogen synthase, hence its activation to convert UDP glucose into glycogen. Lack of insulin and insulin-resistance is supposed to be the cause of type 2 diabetes (Diabetes mellitus). Additionally, GSK3 stabilizes the components of beta-catenin complex, hence promotes oncogenesis. Phosphorylation of GSK3 by Akt and some other kinases also favours the carcinogenesis. However, in some cases GSK3 has tumor supressing character. GSK3 has been found to have a prominent role in the formation of amyloid plaques and neurofibrillary tangles (abnormal protein accumulations) which are the main suspects of Alzheimer's disease (AD). GSK3 inhibitors have been reported to have amyloidbeta disaggregation property and have been found to promote the adult hippocampal neurogenesis in vivo as well as in vitro. This manuscript thoroughly reviews the involvement of GSK3 in diabetes, cancer and ND. Furthermore, development of GSK3 inhibitors as antidiabetes, anticancer and antineurodegenerative agents focusing mainly on lead optimization has been discussed.
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http://dx.doi.org/10.2174/1381612823666170714141450DOI Listing
November 2017

Rational design, synthesis and biological screening of triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents.

Eur J Med Chem 2017 Aug 24;136:36-51. Epub 2017 Apr 24.

Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India; Kusuma School of Biological Sciences, IIT Delhi, New Delhi 110016, India; Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi, New Delhi 110016, India.

In our endeavor towards the development of potent multitarget ligands for the treatment of Alzheimer's disease, a series of triazine-triazolopyrimidine hybrids were designed, synthesized and characterized by various spectral techniques. Docking and scoring techniques were used to design the inhibitors and to display their interaction with key residues of active site. Organic synthesis relied upon convergent synthetic routes were mono and di-substituted triazines were connected with triazolopyrimidine using piperazine as a linker. In total, seventeen compounds were synthesized in which the di-substituted triazine-triazolopyrimidine derivatives 9a-d showed better acetylcholinesterase (AChE) inhibitory activity than the corresponding tri-substituted triazine-triazolopyrimidine derivatives 10a-f. Out of the disubstituted triazine-triazolopyrimidine based compounds, 9a and 9b showed encouraging inhibitory activity on AChE with IC values 0.065 and 0.092 μM, respectively. Interestingly, 9a and 9b also demonstrated good inhibition selectivity towards AChE over BuChE by ∼28 folds. Furthermore, kinetic analysis and molecular modeling studies showed that 9a and 9b target both catalytic active site as well as peripheral anionic site of AChE. In addition, these derivatives effectively modulated Aβ self-aggregation as investigated through CD spectroscopy, ThT fluorescence assay and electron microscopy. Besides, these compounds exhibited potential antioxidants (2.15 and 2.91 trolox equivalent by ORAC assay) and metal chelating properties. In silico ADMET profiling highlighted that, these novel triazine derivatives have appropriate drug like properties and possess very low toxic effects in the primarily pharmacokinetic study. Overall, the multitarget profile exerted by these novel triazine molecules qualified them as potential anti-Alzheimer drug candidates in AD therapy.
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http://dx.doi.org/10.1016/j.ejmech.2017.04.064DOI Listing
August 2017

Corrigendum to 'Dihydroorotate dehydrogenase: A drug target for the development of antimalarials' [Eur. J. Med. Chem. 125 (2017) 640-651].

Eur J Med Chem 2017 03;128:346-347

Department of Chemistry, Jamia Millia Islamia, New Delhi, 110025, India. Electronic address:

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http://dx.doi.org/10.1016/j.ejmech.2017.02.023DOI Listing
March 2017

Dihydroorotate dehydrogenase: A drug target for the development of antimalarials.

Eur J Med Chem 2017 Jan 27;125:640-651. Epub 2016 Sep 27.

Department of Chemistry, Jamia Millia Islamia, New Delhi, 110025, India. Electronic address:

Malaria is a critical human disease with extensive exploration yet unestablished due to occurrence of frequent drug resistance. This aspect of malaria pharmacology calls for the introduction of new antimalarial. The drugs reported till date targeted different stages of the parasites in order to stop their growth and proliferation. Beside this, various drugs that could inhibit the imperative enzymes of the parasite have also been reported. Amid them, dihydroorotate dehydrogenase (DHODH) has a key worth. DHODH is involved in the de novo pyrimidine biosynthesis of the malarial parasite which acts as a primary source of energy for its survival. Since life of the parasite utterly depends on pyrimidine biosynthesis, so it can be used as an apt drug target for malaria eradication. In addition to this, DHODH is also present in human and their active sites have significant structural dissimilarities, so the development of selective inhibitors may prove to be a milestone in search of new antimalarials. Inhibitors of human DHODH have been used to treat autoimmune diseases such as, rheumatoid arthritis or multiple sclerosis and have been investigated in the treatment of cancer, viral diseases, as well as in plant pathology. Here, we have reviewed the important role of DHODH as a viable drug target against malaria, its importance for the survival of the parasite, and DHODH inhibitors reported so far. The rate of success of the reported DHODH inhibitors and further required improvements have also been accounted.
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http://dx.doi.org/10.1016/j.ejmech.2016.09.085DOI Listing
January 2017

Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer's disease therapies.

Eur J Med Chem 2016 Aug 26;119:260-77. Epub 2016 Apr 26.

Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India; Kusuma School of Biological Sciences, IIT Delhi, New Delhi 110016, India; Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi, New Delhi 110016, India.

In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aβ aggregation and antioxidant activity.
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http://dx.doi.org/10.1016/j.ejmech.2016.04.053DOI Listing
August 2016

Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents.

Bioorg Med Chem 2016 06 22;24(12):2777-88. Epub 2016 Apr 22.

Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India; Kusuma School of Biological Sciences, IIT Delhi, New Delhi 110016, India; Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi, New Delhi 110016, India.

A series of new cyanopyridine-triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimer's agents. These molecules were designed while using computational techniques and were synthesized via a feasible concurrent synthetic route. Inhibition potencies of synthetic compounds 4a-4h against cholinesterases, Aβ1-42 disaggregation, oxidative stress, cytotoxicity, and neuroprotection against Aβ1-42-induced toxicity of the synthesized compounds were evaluated. Compounds 4d and 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC50 values 0.059 and 0.080μM, respectively, along with good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modelling studies revealed that these compounds interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The mixed type inhibition of compound 4d further confirmed their dual binding nature in kinetic studies. Furthermore, the results from neuroprotection studies of most potent compounds 4d and 4h indicate that these derivatives can reduce neuronal death induced by H2O2-mediated oxidative stress and Aβ1-42 induced cytotoxicity. In addition, in silico analysis of absorption, distribution, metabolism and excretion (ADME) profile of best compounds 4d and 4h revealed that they have drug like properties. Overall, these cyanopyridine-triazine hybrids can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy.
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http://dx.doi.org/10.1016/j.bmc.2016.04.041DOI Listing
June 2016

Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease.

Eur J Med Chem 2016 Jan 21;107:63-81. Epub 2015 Oct 21.

Department of Chemistry, Jamia Millia Islamia, Central University, New Delhi 110025, India. Electronic address:

Neurodegenerative diseases are among the most challenging diseases with poorly known mechanism of cause and paucity of complete cure. Out of all the neurodegenerative diseases, Alzheimer's disease is the most devastating and loosening of thinking and judging ability disease that occurs in the old age people. Many hypotheses came forth in order to explain its causes. In this review, we have enlightened Glycogen Synthase Kinase-3 which has been considered as a concrete cause for Alzheimer's disease. Plaques and Tangles (abnormal structures) are the basic suspects in damaging and killing of nerve cells wherein Glycogen Synthase Kinase-3 has a key role in the formation of these fatal accumulations. Various Glycogen Synthase Kinase-3 inhibitors have been reported to reduce the amount of amyloid-beta as well as the tau hyperphosphorylation in both neuronal and nonneuronal cells. Additionally, Glycogen Synthase Kinase-3 inhibitors have been reported to enhance the adult hippocampal neurogenesis in vivo as well as in vitro. Keeping the chemotype of the reported Glycogen Synthase Kinase-3 inhibitors in consideration, they may be grouped into natural inhibitors, inorganic metal ions, organo-synthetic, and peptide like inhibitors. On the basis of their mode of binding to the constituent enzyme, they may also be grouped as ATP, nonATP, and allosteric binding sites competitive inhibitors. ATP competitive inhibitors were known earlier inhibitors but they lack efficient selectivity. This led to find the new ways for the enzyme inhibition.
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http://dx.doi.org/10.1016/j.ejmech.2015.10.018DOI Listing
January 2016
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