Publications by authors named "Brijesh Rathi"

39 Publications

Multi-targeting approach for nsp3, nsp9, nsp12 and nsp15 proteins of SARS-CoV-2 by Diosmin as illustrated by molecular docking and molecular dynamics simulation methodologies.

Methods 2021 Feb 25. Epub 2021 Feb 25.

Department of Chemistry, Miranda House, University of Delhi, Delhi 110007, India. Electronic address:

Novel coronavirus SARS-CoV-2continues tospread rapidly worldwide and causing serious health and economic loss. In the absence of any effective treatment, various in-silico approaches are being explored towards the therapeutic discovery against COVID-19. Targeting multiple key enzymes of SARS-CoV-2 with a single potential drug could be an important in-silico strategy to tackle the therapeutic emergency. A number of Food and Drug Administration (FDA) approved drugs entered into clinical stages were originated from multi-target approaches with an increased rate, 16-21% between 2015 and 2017. In this study, we selected an FDA-approved library (Prestwick Chemical Library of 1520 compounds) and implemented in-silico virtual screening against multiple protein targets of SARS-CoV-2 on the Glide module of Schrödinger software (release 2020-1). Compounds were analyzed for their docking scores and the top-ranked against each targeted protein were further subjected to Molecular Dynamics (MD) simulations to assess the binding stability of ligand-protein complexes. A multi-targeting approach was optimized that enabled the analysis of several compounds' binding efficiency with more than one protein targets. It was demonstrated that Diosmin (6) showed the highest binding affinity towards multiple targets with binding free energy (kcal/mol) values of -63.39 (nsp3); -62.89 (nsp9); -31.23 (nsp12); and -65.58 (nsp15). Therefore, our results suggests that Diosmin (6) possesses multi-targeting capability, a potent inhibitor of various non-structural proteins of SARS-CoV-2, and thus it deserves further validation experiments before using as a therapeutic against COVID-19 disease.
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http://dx.doi.org/10.1016/j.ymeth.2021.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904494PMC
February 2021

In silico identification of potential inhibitor for TP53-induced glycolysis and apoptosis regulator in head and neck squamous cell carcinoma.

3 Biotech 2021 Mar 7;11(3):117. Epub 2021 Feb 7.

Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec-125, Noida, 201313 India.

Head and neck squamous cell carcinoma (HNSCC) is the six most common cancer globally and most common cancer in men in India. The metabolic regulation is highly altered and is considered as a hall mark of HNSCC. TP53-induced glycolysis and apoptosis regulator (TIGAR) plays very important role in the development and progression of HNSCC. The aim of our study is to identify a novel FDA approved anticancer inhibitor against mutated TP53-induced glycolysis and apoptosis regulator (TIGAR) through drug repurposing approach. A library of 105 FDA approved anticancer compounds were screened using molecular docking approach against TIGAR (PDB: 3DCY) both Wild-Type (WT) and mutated (Mut). Specific mutations in TIGAR were identified using cBioPortal, a cancer genomics database and mutated structure was modelled using SWISS-MODEL. Out of 510 sequenced cases/patients samples, 17(3%) patients showed alteration in TIGAR [TIGAR and TIGAR]. The virtual drug screening showed 45 drugs out of 105 high binding affinity with TIGAR, Trabectedin showed highest binding affinity with both TIGAR (- 13.3 kcal/mol) as well as TIGAR (- 13.8 kcal/mol). The molecular docking studies were validated using molecular dynamics simulation (MD Simulation) of protein-ligand complex of TIGAR and Trabectedin for 100 ns. The MD Simulation of Trabectedin complex showed more stable with TIGAR compared to TIGAR. Moreover, the string analysis revealed that metabolic-related genes, HK2, PFKFB1, PFKM, PFKP, PFKL, FBP1 are closely associated with TIGAR in HNSCC. Our findings suggest that Trabectedin can be proposed as an inhibitor for [TIGAR] which can be used to target metabolic signalings in HNSCC. However, further investigation and in vitro and in vivo validation our findings required to understand the molecular mechanisms of regulation of Trabectedin in HNSCC.
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http://dx.doi.org/10.1007/s13205-021-02665-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868312PMC
March 2021

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening pipeline and in-vitro validation assays.

Methods 2021 Jan 14. Epub 2021 Jan 14.

Loyola University Chicago Stritch School of Medicine, Chicago, IL 60153, USA; Department of Medicine, Loyola University Medical Center, Chicago, IL 60153, USA. Electronic address:

SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2'-O-MT. For virtual screening, energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard (Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs and investigational molecules (n = 5903). The screening was performed against viral targets using three sequential docking modes (i.e., HTVS, SP, and XP). Virtual screening identified ∼290 potential inhibitors based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. The top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. The resulting top eight hits were tested for their SARS-CoV-2 anti-viral activity in-vitro. Among these, a known inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), was found to be a potent inhibitor of SARS-CoV-2. Further, target validation through enzymatic assays confirmed 3CLpro to be the target. This is the first study that has showcased BIM IX as a COVID-19 inhibitor thereby validating our pipeline.
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http://dx.doi.org/10.1016/j.ymeth.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807167PMC
January 2021

Computationally validated SARS-CoV-2 CTL and HTL Multi-Patch vaccines, designed by reverse epitomics approach, show potential to cover large ethnically distributed human population worldwide.

J Biomol Struct Dyn 2020 Nov 6:1-20. Epub 2020 Nov 6.

Parasite-Host Biology Group, Protein Biochemistry & Engineering Lab, ICMR-National Institute of Malaria Research, New Delhi, India.

The SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is responsible for the COVID-19 outbreak. The highly contagious COVID-19 disease has spread to 216 countries in less than six months. Though several vaccine candidates are being claimed, an effective vaccine is yet to come. A novel reverse epitomics approach, 'overlapping-epitope-clusters-to-patches' method is utilized to identify the antigenic regions from the SARS-CoV-2 proteome. These antigenic regions are named as 'Ag-Patch or Ag-Patches', for Antigenic Patch or Patches. The identification of Ag-Patches is based on the clusters of overlapping epitopes rising from SARS-CoV-2 proteins. Further, we have utilized the identified Ag-Patches to design Multi-Patch Vaccines (MPVs), proposing a novel method for the vaccine design. The designed MPVs were analyzed for immunologically crucial parameters, physiochemical properties and cDNA constructs. We identified 73 CTL (Cytotoxic T-Lymphocyte) and 49 HTL (Helper T-Lymphocyte) novel Ag-Patches from the proteome of SARS-CoV-2. The identified Ag-Patches utilized to design MPVs cover 768 overlapping epitopes targeting 55 different HLA alleles leading to 99.98% of world human population coverage. The MPVs and Toll-Like Receptor ectodomain complex shows stable complex formation tendency. Further, the cDNA analysis favors high expression of the MPVs constructs in a human cell line. We identified highly immunogenic novel Ag-Patches from the entire proteome of SARS CoV-2 by a novel reverse epitomics approach and utilized them to design MPVs. We conclude that the novel MPVs could be a highly potential novel approach to combat SARS-CoV-2, with greater effectiveness, high specificity and large human population coverage worldwide. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1838329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651196PMC
November 2020

Author Correction: Synergistic blending of high-valued heterocycles inhibits growth of Plasmodium falciparum in culture and P. berghei infection in mouse model.

Sci Rep 2020 Aug 24;10(1):14146. Epub 2020 Aug 24.

Department of Chemistry, Hansraj College University Enclave, University of Delhi, Delhi, 110007, India.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-70608-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445261PMC
August 2020

Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2.

J Biomol Struct Dyn 2020 Aug 24:1-14. Epub 2020 Aug 24.

Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, India.

Drug re-purposing might be a fast and efficient way of drug development against the novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We applied a bioinformatics approach using molecular dynamics and docking to identify FDA-approved drugs that can be re-purposed to potentially inhibit the non-structural protein 9 (Nsp9) replicase and spike proteins in SARS-CoV-2. We performed virtual screening of FDA-approved compounds, including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis, and active phytochemicals against the Nsp9 replicase and spike proteins. Selected hit compounds were identified based on their highest binding energy and favorable absorption, distribution, metabolism and excretion (ADME) profile. Conivaptan, an arginine vasopressin antagonist drug exhibited the highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present at the active site of the Nsp9 replicase. Tegobuvir, a non-nucleoside inhibitor of the hepatitis C virus, also exhibited maximum stability along with the highest binding energy (-8.1 Kcal/mol) at the active site of the spike proteins. Molecular docking scores were further validated by molecular dynamics using Schrodinger, which supported the strong stability of ligands with the proteins at their active sites through water bridges, hydrophobic interactions, and H-bonding. Our findings suggest Conivaptan and Tegobuvir as potential therapeutic agents against SARS-CoV-2. Further and validation and evaluation are warranted to establish how these drug compounds target the Nsp9 replicase and spike proteins.
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http://dx.doi.org/10.1080/07391102.2020.1811773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484568PMC
August 2020

Experimental and Computational Studies of Microwave-Assisted, Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines in Nitromethane.

ACS Omega 2020 Aug 21;5(30):18746-18757. Epub 2020 Jul 21.

Department of Chemistry, Miranda House, University of Delhi, Delhi 110007, India.

Nucleophilic ring opening reactions of epoxides with aromatic amines are in the forefront of the synthetic organic chemistry research to build new bioactive scaffolds. Here, convenient, green, and highly efficient regioselective ring opening reactions of sterically hindered (2,3)-3-(-Boc-amino)-1-oxirane-4-phenylbutane with various poorly reactive aromatic amines are accomplished under microwave irradiation in nitromethane. All the reactions effectively implemented for various aromatic amines involve the reuse of nitromethane that supports its dual role as a solvent and catalyst. The corresponding new β-alcohol analogs of hydroxyethylamine (HEA) are isolated in 41-98% yields. The reactions proceed under mild conditions for a broad range of less reactive and sterically hindered aromatic amines. Proton NMR experiments suggest that the nucleophilicity of amines is influenced by nitromethane, which is substantiated by the extensive computational studies. Overall, this methodology elucidates the first-time use of nitromethane as a solvent for the ring opening reactions under microwave conditions involving an equimolar ratio of epoxide and aromatic amine without any catalyst, facile ring opening of complex epoxide by less reactive aromatic amines, low reaction time, less energy consumption, recycling of the solvent, and simple workup procedures.
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http://dx.doi.org/10.1021/acsomega.0c01760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408245PMC
August 2020

Oseltamivir analogs with potent anti-influenza virus activity.

Drug Discov Today 2020 08 15;25(8):1389-1402. Epub 2020 Jun 15.

Department of Chemistry, Miranda House University Enclave, University of Delhi, Delhi, 110007, India. Electronic address:

Influenza A and B viruses cause seasonal worldwide influenza epidemics each winter, and are a major public health concern and cause of morbidity and mortality. A substantial reduction in influenza-related deaths can be attributed to both vaccination and administration of oseltamivir (OS), which is approved for oral administration and inhibits viral neuraminidase (NA), a transmembrane protein. OS carboxylate (OSC), the active form of OS, is formed by the action of endogenous esterase, which targets NA and is shown to significantly reduce influenza-related deaths. However, the development of resistance in various viral variants, including H3N2 and H5N1, has raised concern about the effectiveness of OS. This comprehensive review covers a range of OS analogs shown to be effective against influenza virus, comparing different types of substituent group that contribute to the activity and bioavailability of these compounds.
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http://dx.doi.org/10.1016/j.drudis.2020.06.004DOI Listing
August 2020

Discovery of New Hydroxyethylamine Analogs against 3CL Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation, and Structure-Activity Relationship Studies.

J Chem Inf Model 2020 12 18;60(12):5754-5770. Epub 2020 Jun 18.

Laboratory for Translational Chemistry and Drug Discovery, Hansraj College, University of Delhi, Delhi 110007, India.

The novel coronavirus, SARS-CoV-2, has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of a vaccine and potential therapeutics are critically essential. The crystal structure for the main protease (M) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CL), was recently made available and is considerably similar to the previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, a computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against the 3-chymotrypsin-like cysteine protease (3CL) enzyme was accomplished, and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus, a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound with a docking score of -8.955 adhered to drug-like parameters, and the structure-activity relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular dynamics (MD) simulation analysis performed at 100 ns supported the stability of within the binding pocket. Largely, our results supported that this novel compound binds with domains I and II, and the domain II-III linker of the 3CL protein, suggesting its suitability as a strong candidate for therapeutic discovery against COVID-19.
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http://dx.doi.org/10.1021/acs.jcim.0c00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304236PMC
December 2020

Bioactive Chemical Entities: Pre-clinical and Clinical Aspects - Part-II.

Curr Top Med Chem 2020;20(8):606

Department of Medicine Loyola University Health Sciences Division 2160 South 1st Avenue Chicago, IL 60153, United States.

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http://dx.doi.org/10.2174/156802662008200331074457DOI Listing
December 2020

Bioactive Chemical Entities: Pre-Clinical and Clinical Aspects - Part-VIII.

Curr Top Med Chem 2020;20(5):336

Department of Medicine Loyola University Health Sciences Division 2160 South 1st Avenue Chicago, IL 60153, United States.

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http://dx.doi.org/10.2174/156802662005200304123756DOI Listing
December 2020

Fluorinated scaffolds for antimalarial drug discovery.

Expert Opin Drug Discov 2020 06 21;15(6):705-718. Epub 2020 Mar 21.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College University Enclave, University of Delhi , Delhi, India.

Introduction: The unique physicochemical properties and chemical diversity of organofluorine compounds have remarkably contributed for their wide utility in the area of pharmaceuticals, materials and agrochemicals. The noteworthy characteristics of fluorine include high electron affinity, lipophilicity and bioavailability, extending the half-life of the drugs. The incorporation of fluorine substituents, particularly trifluoromethyl groups, into organic molecules has led to their high potency against various diseases, including malaria. Hence, organofluorinated molecules offer valuable avenues for the design of new drug candidates against malaria.

Areas Covered: In this review, the authors discuss the importance of fluorine substituents present in the chemical compounds, and their potential applications for antimalarial drug discovery.

Expert Opinion: Fluorinated molecules represent a reliable strategy to develop new antimalarial drugs. Fluorine or fluorinated groups have been identified as a promising precursor, and their presence in approximately twenty-five percent of approved drugs is notable. Selective fluorination of chemical entities has the potential to be applied not only to improve the activity profile against the malaria parasite, but could be extrapolated for favorable pharmacological applications. Hazardous reagents such as HF, F and SF used for fluorination, are not considered as safe, and therefore, this process remains challenging, particularly for the pharmaceutical industry.
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http://dx.doi.org/10.1080/17460441.2020.1740203DOI Listing
June 2020

Mimicking neuromelanin nanoparticles as a selective Pb probe.

Anal Chim Acta 2020 Apr 24;1105:208-213. Epub 2020 Jan 24.

Key Laboratory of Control of Quality and Safety for Aquatic Products, Ministry of Agriculture, Chinese Academy of Fishery Sciences, Beijing, 100141, China. Electronic address:

Exposure to even very low concentration of Pb can cause neurological and developmental disorders, and affects children more severely. Neuromelanin (NM) in the substantial nigra can trap endogenous and environmental toxins and immobilize them as stable adducts, thus protecting brain against toxicity. Until now, the structure and Pb-chelating ability of NM is still little understood. Here, we prepare a mimicking NM by amino acid and dopamine. The prepared NM has strong fluorescent and its fluorescence can be quenched by Pb. This study offers a novel way to synthetic NM and provides an effective method to detect Pb.
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http://dx.doi.org/10.1016/j.aca.2020.01.051DOI Listing
April 2020

Coronavirus Disease COVID-19: A New Threat to Public Health.

Curr Top Med Chem 2020;20(8):599-600

Laboratory For Translational Chemistry and Drug Discovery Hansraj College, University of Delhi Delhi-110007, India.

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http://dx.doi.org/10.2174/1568026620999200305144319DOI Listing
May 2020

Synthesis and Bioactivity of Phthalimide Analogs as Potential Drugs to Treat Schistosomiasis, a Neglected Disease of Poverty.

Pharmaceuticals (Basel) 2020 02 3;13(2). Epub 2020 Feb 3.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi 110007, India.

The neglected tropical disease, schistosomiasis, is caused by trematode blood flukes of the genus and infects approximately 200 million people worldwide. With just one partially effective drug available for disease treatment, new drugs are urgently needed. Herein, a series of 47 phthalimide (Pht) analogues possessing high-value bioactive scaffolds (i.e., benzimidazole and 1,2,3,-triazoles) was synthesized by click-chemistry. Compounds were evaluated for anti-schistosomal activity in culture against somules (post-infective larvae) and adults of Schistosoma mansoni, their predicted ADME (absorption, distribution, metabolism, and excretion) properties, and toxicity vs. HepG2 cells. The majority showed favorable parameters for surface area, lipophilicity, bioavailability and Lipinski score. Thirteen compounds were active at 10 µM against both somules and adults (, , -, -, , , and ). Against somules, the majority caused degeneracy and/or death after 72 h; whereas against adult parasites, five compounds (, , , and ) elicited degeneracy, tegumental (surface) damage and/or death. Strongest potency against both developmental stages was recorded for compounds possessing n-butyl or isobutyl as a linker, and a pentafluorophenyl group on triazole. Apart from five compounds for which anti-parasite activity tracked with toxicity to HepG2 cells, there was apparently no toxicity to HepG2 cells (EC values ≥50 µM). The data overall suggest that phthaloyl-triazole compounds are favorable synthons for additional studies as anti-schistosomals.
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http://dx.doi.org/10.3390/ph13020025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169845PMC
February 2020

Photoinitiated Thiol-Ene Reactions of Various 2,3-Unsaturated O-, C- S- and N-Glycosides - Scope and Limitations Study.

Chem Asian J 2020 Mar 25;15(6):876-891. Epub 2020 Feb 25.

Department of Pharmaceutical Chemistry, University of Debrecen, 4032, Debrecen, Egyetem tér 1, Hungary.

The photoinitiated thiol-ene addition reaction is a highly stereo- and regioselective, and environmentally friendly reaction proceeding under mild conditions, hence it is ideally suited for the synthesis of carbohydrate mimetics. A comprehensive study on UV-light-induced reactions of 2,3-unsaturated O-, C-, S- and N-glycosides with various thiols was performed. The effect of experimental parameters and structural variations of the alkenes and thiols on the efficacy and regio- and stereoselectivity of the reactions was systematically studied and optimized. The type of anomeric heteroatom was found to profoundly affect the reactivity of 2,3-unsaturated sugars in the thiol-ene couplings. Hydrothiolation of 2,3-dideoxy O-glycosyl enosides efficiently produced the axially C2-S-substituted addition products with high to complete regioselectivity. Moderate efficacy and varying regio- and stereoselectivity were observed with 2,3-unsaturated N-glycosides and no addition occurred onto the endocyclic double bond of C-glycosides. Upon hydrothiolation of 2,3-unsaturated S-glycosides, the addition of thiyl radicals was followed by elimination of the thiyl aglycone resulting in 3-S-substituted glycals.
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http://dx.doi.org/10.1002/asia.201901560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154673PMC
March 2020

Outwitting an Old Neglected Nemesis: A Review on Leveraging Integrated Data-Driven Approaches to Aid in Unraveling of Leishmanicides of Therapeutic Potential.

Curr Top Med Chem 2020 ;20(5):349-366

Department of Medicine, Loyola University Chicago, Loyola University Medical Center, Maywood, IL 60153, United States.

The global prevalence of leishmaniasis has increased with skyrocketed mortality in the past decade. The causative agent of leishmaniasis is Leishmania species, which infects populations in almost all the continents. Prevailing treatment regimens are consistently inefficient with reported side effects, toxicity and drug resistance. This review complements existing ones by discussing the current state of treatment options, therapeutic bottlenecks including chemoresistance and toxicity, as well as drug targets. It further highlights innovative applications of nanotherapeutics-based formulations, inhibitory potential of leishmanicides, anti-microbial peptides and organometallic compounds on leishmanial species. Moreover, it provides essential insights into recent machine learning-based models that have been used to predict novel leishmanicides and also discusses other new models that could be adopted to develop fast, efficient, robust and novel algorithms to aid in unraveling the next generation of anti-leishmanial drugs. A plethora of enriched functional genomic, proteomic, structural biology, high throughput bioassay and drug-related datasets are currently warehoused in both general and leishmania-specific databases. The warehoused datasets are essential inputs for training and testing algorithms to augment the prediction of biotherapeutic entities. In addition, we demonstrate how pharmacoinformatics techniques including ligand-, structure- and pharmacophore-based virtual screening approaches have been utilized to screen ligand libraries against both modeled and experimentally solved 3D structures of essential drug targets. In the era of data-driven decision-making, we believe that highlighting intricately linked topical issues relevant to leishmanial drug discovery offers a one-stop-shop opportunity to decipher critical literature with the potential to unlock implicit breakthroughs.
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http://dx.doi.org/10.2174/1568026620666200128160454DOI Listing
December 2020

A new aptamer/black phosphorous interdigital electrode for malachite green detection.

Anal Chim Acta 2020 Feb 13;1099:39-45. Epub 2019 Nov 13.

College of Information, North China University of Technology, Beijing, 100043, China.

Malachite Green (MG), a cationic triphenylmethane dye, has adverse effects on the immune and reproductive system. Thus, it is essential to develop a rapid, sensitive and high-selective method for determination of MG. Black phosphorus (BP) has high charge-carrier mobility (∼1000 cm V s) and high adsorption capacity for cationic dyes (i.e. MG) through both electrostatic and hydrophobic interactions. Thus, it potentially plays as a high-sensitive sensing platform for detecting MG. However, BP degrades within 12 h under humid condition, which limits its applications. To overcome this issue, cysteine (CYS) is used for protecting BP from oxidation and ceasing its degradation. To the best of our knowledge, it is the first time that CYS is used to functionalize BP, and a silicon interdigital electrode is fabricated with the functionalized BP and aptamer. The BP-based interdigital electrode shows a lowest detection limit of 0.3 ng L toward MG. This work provides a new route to prepare a large scale and selective biosensor for MG monitoring on site in future.
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http://dx.doi.org/10.1016/j.aca.2019.11.026DOI Listing
February 2020

Compounds based on 5-(perylen-3-ylethynyl)uracil scaffold: High activity against tick-borne encephalitis virus and non-specific activity against enterovirus A.

Eur J Med Chem 2019 Jun 16;171:93-103. Epub 2019 Mar 16.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, Moscow 117997, Russia. Electronic address:

Rigid amphipathic fusion inhibitors (RAFIs) are potent antivirals based on a perylene core linked with a nucleoside moiety. Sugar-free analogues of RAFIs, 5-(perylen-3-ylethynyl)uracil-1-acetic acid 1 and its amides 2, were synthesized using combined protection group strategy. Compounds 1 and 2 appeared to have low toxicity on porcine embryo kidney (PEK) or rhabdomiosarcoma (RD) cells together with remarkable activity against enveloped tick-borne encephalitis virus (TBEV): EC values vary from 0.077 μM to subnanomolar range. Surprisingly, 3-pivaloyloxymethyl (Pom) protected precursors 7 and 8 showed even more pronounced activity. All the compounds showed no activity against several non-enveloped enteroviruses, except 4-hydroxybutylamides 2d,g, which inhibited the reproduction of enterovirus A71 with EC 50-100 μM, with a non-specific mode of action. The results suggest that the carbohydrate moiety of RAFI nucleosides does not play a crucial role in their antiviral action, and biological activity of the 5-(perylen-3-ylethynyl)uracil scaffold can be effectively modulated by substituents in positions 1 and 3. The high antiviral activity of these new compounds, coupled with low toxicity advocate their potential role in antiviral therapy.
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http://dx.doi.org/10.1016/j.ejmech.2019.03.029DOI Listing
June 2019

Molecules Effective against Infectious Diseases - Part II.

Curr Top Med Chem 2019 ;18(23):2007

Department of Chemistry Miranda House, University of Delhi Delhi-110007, India.

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http://dx.doi.org/10.2174/156802661823190110114126DOI Listing
March 2020

Anti-infectious Drugs: Approaches and Achievements - Part I.

Curr Top Med Chem 2018 ;18(22):1925

Department of Chemistry Miranda House, University of Delhi Delhi-110007, India.

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http://dx.doi.org/10.2174/156802661822190110105011DOI Listing
January 2019

Fast-Acting Small Molecules Targeting Malarial Aspartyl Proteases, Plasmepsins, Inhibit Malaria Infection at Multiple Life Stages.

ACS Infect Dis 2019 02 2;5(2):184-198. Epub 2019 Jan 2.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry , Hansraj College University Enclave, University of Delhi , Delhi 110007 , India.

The eradication of malaria remains challenging due to the complex life cycle of Plasmodium and the rapid emergence of drug-resistant forms of Plasmodium falciparum and Plasmodium vivax. New, effective, and inexpensive antimalarials against multiple life stages of the parasite are urgently needed to combat the spread of malaria. Here, we synthesized a set of novel hydroxyethylamines and investigated their activities in vitro and in vivo. All of the compounds tested had an inhibitory effect on the blood stage of P. falciparum at submicromolar concentrations, with the best showing 50% inhibitory concentrations (IC) of around 500 nM against drug-resistant P. falciparum parasites. These compounds showed inhibitory actions against plasmepsins, a family of malarial aspartyl proteases, and exhibited a marked killing effect on blood stage Plasmodium. In chloroquine-resistant Plasmodium berghei and P. berghei ANKA infected mouse models, treating mice with both compounds led to a significant decrease in blood parasite load. Importantly, two of the compounds displayed an inhibitory effect on the gametocyte stages (III-V) of P. falciparum in culture and the liver-stage infection of P. berghei both in in vitro and in vivo. Altogether, our findings suggest that fast-acting hydroxyethylamine-phthalimide analogs targeting multiple life stages of the parasite could be a valuable chemical lead for the development of novel antimalarial drugs.
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http://dx.doi.org/10.1021/acsinfecdis.8b00197DOI Listing
February 2019

Antimalarials: Review of Plasmepsins as Drug Targets and HIV Protease Inhibitors Interactions.

Curr Top Med Chem 2019 ;18(23):2022-2028

Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, PMB LG 77, Legon, Accra, Ghana.

Malaria is a major global health concern with the majority of cases reported in regions of South-East Asia, Eastern Mediterranean, Western Pacific, the Americas, and Sub-Saharan Africa. The World Health Organization (WHO) estimated 216 million worldwide reported cases of malaria in 2016. It is an infection of the red blood cells by parasites of the genus Plasmodium with most severe and common forms caused by Plasmodium falciparum (P. falciparum or Pf) and Plasmodium vivax (P. vivax or Pv). Emerging parasite resistance to available antimalarial drugs poses great challenges to treatment. Currently, the first line of defense includes artemisinin combination therapies (ACTs), increasingly becoming less effective and challenging to combat new occurrences of drug-resistant parasites. This necessitates the urgent need for novel antimalarials that target new molecular pathways with a different mechanism of action from the traditional antimalarials. Several new inhibitors and potential drug targets of the parasites have been reported over the years. This review focuses on the malarial aspartic proteases known as plasmepsins (Plms) as novel drug targets and antimalarials targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins Plm I, Plm II, Plm IV and Histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins.
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http://dx.doi.org/10.2174/1568026619666181130133548DOI Listing
January 2019

Small Molecules Effective Against Liver and Blood Stage Malarial Infection.

Curr Top Med Chem 2019 ;18(23):2008-2021

Department of Chemistry, Miranda House, University of Delhi, Delhi-110007, India.

Malaria is a lethal disease causing devastating global impact by killing more than 8,00,000 individuals yearly. A noticeable decline in malaria related deaths can be attributed to the most reliable treatment, ACTs against P. falciparum. However, the cumulative resistance of the malaria parasite against ACTs is a global threat to control the disease and, therefore the new effective therapeutics are urgently needed, including new treatment approaches. Majority of the antimalarial drugs target BS malarial infection. Currently, scientists are eager to explore the drugs with potency against not only BS but other life stages such as sexual and asexual stages of the malaria parasite. Liver Stage is considered as one of the important drug targets as it always leads to BS and the infection can be cured at this stage before it enters into the Blood Stage. However, a limited number of compounds are reported effective against LS malaria infection probably due to scarcity of in vitro LS culture methods and clinical possibilities. This mini review covers a range of chemical compounds showing efficacy against BS and LS of the malaria parasite's life cycle collectively (i.e. dual stage activity). These scaffolds targeting dual stages are essential for the eradication of malaria and to evade resistance.
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http://dx.doi.org/10.2174/1568026619666181129143623DOI Listing
January 2019

Antiplasmodial activity of hydroxyethylamine analogs: Synthesis, biological activity and structure activity relationship of plasmepsin inhibitors.

Bioorg Med Chem 2018 07 28;26(13):3837-3844. Epub 2018 Jun 28.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi 110007, India; South Ural State University, Laboratory of Computational Modeling of Drugs, 454080, Russia. Electronic address:

Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (K, 1.93 ± 0.29 µM for Plm II; K, 1.99 ± 0.05 µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (K, 0.84 ± 0.08 µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC, 2.27 ± 0.95 µM for 10f; IC, 3.11 ± 0.65 µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC value of 1.35 ± 0.85 µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.
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http://dx.doi.org/10.1016/j.bmc.2018.06.037DOI Listing
July 2018

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication.

Med Res Rev 2018 09 26;38(5):1511-1535. Epub 2018 Jan 26.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College University Enclave, University of Delhi, Delhi, India.

Over time, several exciting advances have been made in the treatment and prevention of malaria; however, this devastating disease continues to be a major global health problem and affects millions of people every year. Notably, the paucity of new efficient drug molecules and the inevitable drug resistance of the malaria parasite, Plasmodium falciparum, against frontline therapeutics are the foremost struggles facing malaria eradication initiatives. According to the malaria eradication agenda, the discovery of new chemical entities that can destroy the parasite at the liver stage, the asexual blood stage, the gametocyte stage, and the insect ookinete stage of the parasite life cycle (i.e., compounds exhibiting multistage activity) are in high demand, preferably with novel and multiple modes of action. Phenotypic screening of chemical libraries against the malaria parasite is certainly a crucial step toward overcoming these crises. In the last few years, various research groups, including industrial research laboratories, have performed large-scale phenotypic screenings that have identified a wealth of chemical entities active against multiple life stages of the malaria parasite. Vital scientific and technological developments have led to the discovery of multistage inhibitors of the malaria parasite; these compounds, considered highly valuable starting points for subsequent drug discovery and eradication of malaria, are reviewed.
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http://dx.doi.org/10.1002/med.21486DOI Listing
September 2018

Biochemical characterization of unusual cysteine protease of P. falciparum, metacaspase-2 (MCA-2).

Mol Biochem Parasitol 2018 03 6;220:28-41. Epub 2018 Jan 6.

National Institute for Research in Environmental Health, Bhopal 462001, India. Electronic address:

Earlier studies on Plasmodium apoptosis revealed the presence of proteases with caspases like- activity, which are known as "metacaspases". Although this family of cysteine proteases is structurally similar to caspases with Cys-His dyad but their evolutionary significance and functional relevance remains largely unknown. These proteases are considered to be an important target against malaria due to their absence in humans. In this report, we have biochemically characterized metacaspase-2 (PfMCA-2) of P.falciparum. Enzymatic assay showed that PfMCA-2 efficiently cleaved arginine/lysine specific peptide, but not caspase-specific substrate. Consistently, PfMCA-2 activity was sensitive to effector caspases inhibitor, Z-FA-FMK, and mildly inhibited by aprotinin and E-64. However, general caspase inhibitors such as Z-VAD-FMK and Z-DEVD-FMK had no effect on PfMCA-2 activity. Z-FA-FMK inhibits parasite growth with an IC value of 2.7 μM along with the notable morphological changes. PfMCA-2 specifically expressed in schizonts and gametocyte stages and there was a notable depletion of PfMCA-2 expression in Z-FA-FMK treated schizonts and gametocytes stages of parasite. Notably, PfMCA-2 cleaves a phylogenetically conserved protein, TSN (Tudor staphylococcal nuclease) and the proteolysis of PfTSN did not occur after treatment with the Z-FA-FMK. The production of large amount of reactive oxygen species in presence of Z-FA-FMK caused oxidative stress which in turn leads to loss of cell viability. The oxidative stress further generates positive feedback for the occurrence of cell death in term of phosphatidylserine externalization and DNA fragmentation in vitro.
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http://dx.doi.org/10.1016/j.molbiopara.2018.01.001DOI Listing
March 2018

Synergistic blending of high-valued heterocycles inhibits growth of Plasmodium falciparum in culture and P. berghei infection in mouse model.

Sci Rep 2017 07 27;7(1):6724. Epub 2017 Jul 27.

Department of Chemistry, Hansraj College University Enclave, University of Delhi, Delhi, 110007, India.

A series of phthalimide analogues, novelized with high-valued bioactive scaffolds was synthesized by means of click-chemistry under non-conventional microwave heating and evaluated as noteworthy growth inhibitors of Plasmodium falciparum (3D7 and W2) in culture. Analogues 6a, 6h and 6 u showed highest activity to inhibit the growth of the parasite with IC values in submicromolar range. Structure-activity correlation indicated the necessity of unsubstituted triazoles and leucine linker to obtain maximal growth inhibition of the parasite. Notably, phthalimide 6a and 6u selectively inhibited the ring-stage growth and parasite maturation. On other hand, phthalimide 6h displayed selective schizonticidal activity. Besides, they displayed synergistic interactions with chloroquine and dihydroartemisinin against parasite. Additional in vivo experiments using P. berghei infected mice showed that administration of 6h and 6u alone, as well as in combination with dihydroartemisinin, substantially reduced the parasite load. The high antimalarial activity of 6h and 6u, coupled with low toxicity advocate their potential role as novel antimalarial agents, either as standalone or combination therapies.
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http://dx.doi.org/10.1038/s41598-017-06097-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532363PMC
July 2017

An Overview of Currently Available Antimalarials.

Curr Top Med Chem 2017 ;17(19):2143-2157

Hansraj College, University of Delhi, Delhi-110007, India.

Background: Despite the substantial progress over the time, malaria remains a major public health concern and causing hundreds of thousands of deaths. Resistance to the available antimalarial therapy increases threat to the global public health.

Objective: Overview of currently available antimalarials.

Method: Literary survey.

Results: The summarized data about different types of antimalarial therapies and their efficiency and modes of action.

Conclusion: Despite the seemingly large number of the drugs currently available for malaria treatment, this arsenal is limited due to the narrow variation of their mechanism of action.
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http://dx.doi.org/10.2174/1568026617666170130123520DOI Listing
August 2017