Department Of Pharmaceutical Sciences and Natural Products
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Item A review on reported phytochemicals as druggable leads with antimalarial potential(Springer, 2023-07-04T00:00:00) Guchait, Avishek; Kumar, Asim; Singh, Roopam; Joshi, Gaurav; Dwivedi, Ashish RanjanThe science and practice of drug discovery and development is primarily benefitted from the natural sources. The chemistry of natural products has inspired medicinal chemists to develop and design various therapeutic molecules from the leads obtained from natural sources. This is evident from the growing number of publications on natural products derived from drug molecules. Some of the most successful bioactive natural product candidates so far are Taxol obtained from �Taxus Brevifolia,� Quinine obtained from the bark of the cinchona plant, morphine obtained from the dried latex of the poppy plant, Vincristine, and Vinblastine from �Vinca Rosea,� atropine from �Atropa Belladonna�, Digoxin and Digitoxin from �Digitalis Purpurea� and Artemisinin from �Artemisia Annua�. Parasitic pathogens are one of the significant menaces for the world as they lead to various diseases in hosts, and for many diseases, these parasite compromises the host�s immune system. Malaria is a parasitic disease especially endemic to tropical countries and is one of the leading causes of death worldwide. According to the latest data from WHO, millions of patients are suffering from malaria and its related complications on 30th March 2022. Natural products derived leads have brought a paradigm shift in the discovery of antimalarial drugs. The first antimalarial drug, quinine, was isolated from the Cinchona species (Family: Rubiaceae) in 1820 and is still used today. This was followed by another antimalarial drug a century later, chloroquine, discovered in the 1940s. After that, Artemisinin was founded in 1972 by Tu Youyou, co-recipient of the 2015 Nobel Prize in Medicine for her discovery. Unfortunately, the malarial parasite, mainly Plasmodium falciparum, develops resistance to these drugs, and thus there exists a need to explore other natural herbs for their role as antimalarials. The current review is therefore kept forth to congregate updated information on undergoing research in allied areas of natural product-based drug discovery, particularly for developing antimalarial agents. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities(American Chemical Society, 2023-02-22T00:00:00) Maity, Pritam; Chatterjee, Joydeep; Patil, Kiran T.; Arora, Sahil; Katiyar, Madhurendra K.; Kumar, Manvendra; Samarbakhsh, Amirreza; Joshi, Gaurav; Bhutani, Priyadeep; Chugh, Manoj; Gavande, Navnath S.; Kumar, RajEpidermal growth factor receptor (EGFR) is an oncogenic drug target and plays a critical role in several cellular functions including cancer cell growth, survival, proliferation, differentiation, and motility. Several small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) have been approved for targeting intracellular and extracellular domains of EGFR, respectively. However, cancer heterogeneity, mutations in the catalytic domain of EGFR, and persistent drug resistance limited their use. Different novel modalities are gaining a position in the limelight of anti-EGFR therapeutics to overcome such limitations. The current perspective reflects upon newer modalities, importantly the molecular degraders such as PROTACs, LYTACs, AUTECs, and ATTECs, etc., beginning with a snapshot of traditional and existing anti-EGFR therapies including small molecule inhibitors, mAbs, and antibody drug conjugates (ADCs). Further, a special emphasis has been made on the design, synthesis, successful applications, state-of-the-art, and emerging future opportunities of each discussed modality. � 2023 American Chemical Society.Item FDA approved fused pyrimidine-based drugs(Elsevier, 2022-10-14T00:00:00) Thakur, Shikha; Ansari, Arshad J.; Joshi, GauravThe present chapter is a compilation and analysis of USFDA approved small drug candidates about fused pyrimidine pharmacophore. Out of 63 drugs approved so far, nearly 38% of drugs are approved for chemotherapeutic treatment of cancer. Further, antiviral category shares 19% followed by drugs for cardiovascular disorders (14%), inflammatory diseases (9%), respiratory disorders (6%), neurological disorders (5%), benign prostatic hypertrophy (3%), erectile dysfunction (2%), diabetes (2%) and thrombocytopenia (2%). The chapter further focuses on key biological targets affected by the reported drug and their pharmacological mechanism of action. We have also focused on elucidating key chemical taxonomy utilized in fused pharmacophores of pyrimidine. The analysis suggested purine nucleosides (11 drugs) and xanthines/hypoxanthines (11 drugs) share the major chunk utilized in drug development out of fused pyrimidine nucleus. � 2023 Elsevier Ltd. All rights reserved.Item Pore-forming proteins and their role in cancer and inflammation: Mechanistic insights and plausible druggable targets(Elsevier Ireland Ltd, 2022-08-30T00:00:00) Sankar, Jishnu; Arora, Sahil; Joshi, Gaurav; Kumar, RajPerforin is a granular effector pore-forming protein formed in NK cells and Cytotoxic T lymphocytes. These cytotoxic proteins are part of the first-line immune defense in the human body. They ensure apoptosis of pathogen-infected cells or tumor cells in the human body. Activation of receptors on NK cell or T cell triggers secondary proteins in these cells. Further, it leads to Ca2+ dependent perforin egress towards the target cell, ensued by PI3K signaling pathway. Perforin undergoes oligomerization over the target cell membrane and forms transmembrane pores with the membrane-spanning domain-MACPF domain. Granzymes, proapoptotic serine proteases are released through these pores and initiate the target cell apoptotic pathway leading to the cell death. Although perforin is a savior for humans from tumor and viral infections, uncontrolled expression of the perforins leads to the autoimmune conditions, including Familial Hemophagocytic lymphohistiocytosis, insulin-dependent diabetes, and cerebral myocarditis. The present review is the concerted effort to highlight the mechanistic pathways concerning perforin secretion, NK cell and T cell-mediated cytotoxicity towards virus-infected and transformed cells. This is followed by the discussion on synthetic derivatives tested so far to inhibit the perforin in pre and clinical arena for certain unusual conditions. � 2022 Elsevier B.V.Item In Vivo Anticancer Evaluation of 6b, a Non-Covalent Imidazo[1,2-a]quinoxaline-Based Epidermal Growth Factor Receptor Inhibitor against Human Xenograft Tumor in Nude Mice(MDPI, 2022-08-30T00:00:00) Bhat, Zahid Rafiq; Kumar, Manvendra; Sharma, Nisha; Yadav, Umesh Prasad; Singh, Tashvinder; Joshi, Gaurav; Pujala, Brahmam; Raja, Mohd; Chatterjee, Joydeep; Tikoo, Kulbhushan; Singh, Sandeep; Kumar, RajTyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-a]quinoxaline-based EGFR inhibitor (6b), which showed promising inhibitory activity against the gefitinib-resistant H1975(L858R/T790M) lung cancer cell line. In the present study, we further explored the 6b compound in vivo by employing the A549-induced xenograft model in nude mice. The results indicate that the administration of the 6b compound significantly abolished the growth of the tumor in the A549 xenograft nude mice. Whereas the control mice bearing tumors displayed a declining trend in the survival curve, treatment with the 6b compound improved the survival profile of mice. Moreover, the histological examination showed the cancer cell cytotoxicity of the 6b compound was characterized by cytoplasmic destruction observed in the stained section of the tumor tissues of treated mice. The immunoblotting and qPCR results further signified that 6b inhibited EGFR in tissue samples and consequently altered the downstream pathways mediated by EGFR, leading to a reduction in cancer growth. Therefore, the in vivo findings were in corroboration with the in vitro results, suggesting that 6b possessed potential anticancer activity against EGFR-dependent lung cancer. 6b also exhibited good stability in human and mouse liver microsomes. � 2022 by the authors.Item Structural Diversity of D-Alanine: D-Alanine Ligase and Its Exploration in Development of Antibacterial Agents Against the Multi-Variant Bacterial Infections(John Wiley and Sons Inc, 2022-04-07T00:00:00) Mayank; Sidhu, Jagpreet Singh; Joshi, Gaurav; Sindhu, Jayant; Kaur, Navneet; Singh, NarinderD-alanine: D-alanine ligase (Rv2981c or Ddl) (EC 6.3.2.4) is a bacterial protein that performs critical functions for the proper growth and development of bacterial cells. Understanding the activity profile of Ddl within the various strains of the bacteria seems vital in broad-spectrum antimicrobial drug discovery. Therefore, to understand this heterologous nature, we focused on understanding the functional impact of the structural differences in the Ddl protein from Legionella pneumophila and E. coli bacteria. The structural features and dynamic behavior of Ddl, the interaction pattern, and the docking score of the Ddl-ATP/ADP are also found significantly different from each other. In-depth analysis viz molecular dynamics simulation and residue interaction network (RIN) studies provided us the detailed insight into the differences in the Ddl proteins from both the bacteria. In conclusion, understanding the inter-specific differences in the antibiotic targets Ddl in the case of diverse bacterial strains is vital for rationalizing the treatment of these infectious diseases. Therefore, the current work attempts to foresee the development of more efficacious antibacterial agents devoid of emerging resistance to bacterium strains. � 2022 Wiley-VCH GmbH.Item Exploring the COVID-19 vaccine candidates against SARS-CoV-2 and its variants: where do we stand and where do we go?(Taylor and Francis Ltd., 2021-12-03T00:00:00) Joshi, Gaurav; Borah, Pobitra; Thakur, Shweta; Sharma, Praveen; Mayank; Poduri, RamaraoAs of September 2021, 117 COVID-19 vaccines are in clinical development, and 194 are in preclinical development as per the World Health Organization (WHO) published draft landscape. Among the 117 vaccines undergoing clinical trials, the major platforms include protein subunit; RNA; inactivated virus; viral vector, among others. So far, USFDA recognized to approve the Pfizer-BioNTech (Comirnaty) COVID-19 vaccine for its full use in individuals of 16�years of age and older. Though the approved vaccines are being manufactured at a tremendous pace, the wealthiest countries have about 28% of total vaccines despite possessing only 10.8% of the total world population, suggesting an inequity of vaccine distribution. The review comprehensively summarizes the history of vaccines, mainly focusing on vaccines for SARS-CoV-2. The review also connects relevant topics, including measurement of vaccines efficacy against SARS-CoV-2 and its variants, associated challenges, and limitations, as hurdles in global vaccination are also kept forth. � 2021 Taylor & Francis Group, LLC.Item A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2(American Chemical Society, 2021-11-02T00:00:00) Arora, Sahil; Joshi, Gaurav; Chaturvedi, Anuhar; Heuser, Michael; Patil, Santoshkumar; Kumar, RajThe allosteric regulation of pyruvate kinase M2 (PKM2) affects the switching of the PKM2 protein between the high-activity and low-activity states that allow ATP and lactate production, respectively. PKM2, in its low catalytic state (dimeric form), is chiefly active in metabolically energetic cells, including cancer cells. More recently, PKM2 has emerged as an attractive target due to its role in metabolic dysfunction and other interrelated conditions. PKM2 (dimer) activity can be inhibited by modulating PKM2 dimer�tetramer dynamics using either PKM2 inhibitors that bind at the ATP binding active site of PKM2 (dimer) or PKM2 activators that bind at the allosteric site of PKM2, thus activating PKM2 from the dimer formation to the tetrameric formation. The present perspective focuses on medicinal chemistry approaches to design and discover PKM2 inhibitors and activators and further provides a scope for the future design of compounds targeting PKM2 with better efficacy and selectivity. � 2021 American Chemical SocietyItem Design, synthesis and anticancer activity of 2-arylimidazo[1,2-a]pyridinyl-3-amines(Academic Press Inc., 2021-11-01T00:00:00) Yadav, Umesh Prasad; Ansari, Arshad J.; Arora, Sahil; Joshi, Gaurav; Singh, Tashvinder; Kaur, Harsimrat; Dogra, Nilambra; Kumar, Raj; Kumar, Santosh; Sawant, Devesh M.; Singh, SandeepA series of imido-heterocycle compounds were designed, synthesized, characterized, and evaluated for the anticancer potential using breast (MCF-7 and MDA-MB-231), pancreatic (PANC-1), and colon (HCT-116 and HT-29) cancer cell lines and normal cells, while normal cells showed no toxicity. Among the screened compounds, 4h exhibited the best anticancer potential with IC50 values ranging from 1 to 5.5 ?M. Compound 4h caused G2/M phase arrest and apoptosis in all the cell lines except MDA-MB-231 mammosphere formation was inhibited. In-vitro enzyme assay showed selective topoisomerase II? inhibition by compound 4h, leading to DNA damage as observed by fluorescent staining. Cell signalling studies showed decreased expression of cell cycle promoting related proteins while apoptotic proteins were upregulated. Interestingly MDA-MB-231 cells showed only cytostatic effects upon treatment with compound 4h due to defective p53 status. Toxicity study using overexpression of dominant-negative mutant p53 in MCF-7 cells (which have wild type functional p53) showed that anticancer potential of compound 4h is positively correlated with p53 expression. � 2021 Elsevier Inc.Item Exploring insights of hydroxychloroquine, a controversial drug in Covid-19: An update(Elsevier Ltd, 2021-03-18T00:00:00) Joshi, Gaurav; Thakur, Shikha; Mayank; Poduri, RamaraoThe review summarizes chloroquine (CQ) and its safer derivative hydroxychloroquine (HCQ) and its utility in Covid-19. Recently this well-established drug made its way back to the headlines during the SARS-CoV-2 pandemic. This led to an upsurge in the scientific arena with multiple research and review articles along with expert opinions and commentaries. The HCQ has received mixed judgements so far about its efficacy to be used in Covid-19 patients in a limited trial conducted all across the Globe. The purpose of our article is to put forth the history, pharmacodynamics, and pharmacokinetics, along with the existing studies favouring and disapproving the role of HCQ in the treatment of Covid-19. We grouped HCQ use at three stages, this includes HCQ for i. prophylactic use by asymptomatic health workers or peoples at higher risk; ii. patients having mild symptoms; iii. patients with extreme symptoms. The review critically discusses the underlying plausible reasons and mechanisms exploring HCQ in prophylactic management or treatment of SARS-CoV-2. Furthermore, we have critically analysed the reported pharmacokinetic parameters and compiled the proponent, opponent, or neutral opinions on the use of HCQ in Covid-19. Authors discretion is to conduct more studies considering the optimal dosing regimen and pharmacokinetics assessment. � 2021 Elsevier Ltd