Browsing by Author "Singh, Harshwardhan"
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Item Applications of dihydropyrimidinone derivatives on blood cancer and colon cancer(Elsevier, 2023-08-25T00:00:00) Singh, Ankit Kumar; Singh, Harshwardhan; Sonawane, Pankaj; Kumar, Adarsh; Verma, Amita; Kumar, PradeepDihydropyrimidinones (DHPMs) are characterized by their multifunctionalized scaffold with a pyrimidine moiety that exhibits diverse biological activities, especially anticancer activity. Malignant clonal expansion of blood-forming cells is referred to as blood cancer. Colorectal cancer (CRC) appears within the colon or another bodily area. There were 9,958,133 fatalities and 19,292,789 new cases of 36 cancers globally in 2020. In this, 1,148,515 cases and 576,858 deaths belong to colon cancer, whereas 474,519 cases and 311,594 deaths belong to leukemia. Different blood cancer cell lines, such as MOLT-4, HL-60, CCRF-CEMT, K-562, U937, MOLT-4, RPMI-8226, THP-1, and SR, as well as colon cancer/CRC cell lines, HCT-116, HCT-15, Colo205, HCC-2998, HCT-116, HT-29, KM-12, and SW-620, have been used to evaluate in vitro anticancer activity of DHPM derivatives. DHPM derivatives demonstrated notable effectiveness against blood and colon/colorectal cancers and may prove important building blocks in the development of novel anticancer agents. � 2023 Elsevier Inc. All rights reserved.Item Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022(American Chemical Society, 2023-07-26T00:00:00) Singh, Ankit Kumar; Sonawane, Pankaj; Kumar, Adarsh; Singh, Harshwardhan; Naumovich, Vladislav; Pathak, Prateek; Grishina, Maria; Khalilullah, Habibullah; Jaremko, Mariusz; Emwas, Abdul-Hamid; Verma, Amita; Kumar, PradeepSerine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and ?C-IN/OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants. � 2023 The Authors. Published by American Chemical Society.Item Concept of Hybrid Drugs and Recent Advancements in Anticancer Hybrids(MDPI, 2022-08-30T00:00:00) Singh, Ankit Kumar; Kumar, Adarsh; Singh, Harshwardhan; Sonawane, Pankaj; Paliwal, Harshali; Thareja, Suresh; Pathak, Prateek; Grishina, Maria; Jaremko, Mariusz; Emwas, Abdul-Hamid; Yadav, Jagat Pal; Verma, Amita; Khalilullah, Habibullah; Kumar, PradeepCancer is a complex disease, and its treatment is a big challenge, with variable efficacy of conventional anticancer drugs. A two-drug cocktail hybrid approach is a potential strategy in recent drug discovery that involves the combination of two drug pharmacophores into a single molecule. The hybrid molecule acts through distinct modes of action on several targets at a given time with more efficacy and less susceptibility to resistance. Thus, there is a huge scope for using hybrid compounds to tackle the present difficulties in cancer medicine. Recent work has applied this technique to uncover some interesting molecules with substantial anticancer properties. In this study, we report data on numerous promising hybrid anti-proliferative/anti-tumor agents developed over the previous 10 years (2011�2021). It includes quinazoline, indole, carbazole, pyrimidine, quinoline, quinone, imidazole, selenium, platinum, hydroxamic acid, ferrocene, curcumin, triazole, benzimidazole, isatin, pyrrolo benzodiazepine (PBD), chalcone, coumarin, nitrogen mustard, pyrazole, and pyridine-based anticancer hybrids produced via molecular hybridization techniques. Overall, this review offers a clear indication of the potential benefits of merging pharmacophoric subunits from multiple different known chemical prototypes to produce more potent and precise hybrid compounds. This provides valuable knowledge for researchers working on complex diseases such as cancer. � 2022 by the authors.Item Design, one-pot synthesis, computational and biological evaluation of diaryl benzimidazole derivatives as MEK inhibitors(Taylor and Francis Ltd., 2023-10-09T00:00:00) Ram, Teja; Singh, Ankit Kumar; Pathak, Prateek; Kumar, Adarsh; Singh, Harshwardhan; Grishina, Maria; Novak, Jurica; Kumar, PradeepMEK mutations are more common in various human malignancies, such as pancreatic cancer (70�90%), mock melanoma (50%), liver cancer (20�40%), colorectal cancer (25�35%), melanoma (15�20%), non-small cell lung cancer (10�20%) and basal breast cancer (1�5%). Considering the significance of MEK mutations in diverse cancer types, the rational design of the proposed compounds relies on the structural resemblance to FDA-approved MEK inhibitors like selumetinib and binimetinib. The compound under design features distinct substitutions at the benzimidazole moiety, specifically at positions 2 and 3, akin to the FDA-approved drugs, albeit differing in positions 5 and 6. Subsequent structural refinement was guided by key elements including the DFG motif, hydrophobic pocket and catalytic loop of the MEK protein. A set of 15 diverse diaryl benzimidazole derivatives (S1�S15) were synthesized via a one-pot approach and characterized through spectroscopic techniques, including MASS, IR, 1H NMR and 13C NMR. In vitro anticancer activities of all the synthesized compounds were evaluated against four cancer cell lines, A375, HT ?29, A431 and HFF, along with the standard drug trametinib. Molecular docking was performed for all synthesized compounds (S1�15), followed by 950 ns molecular dynamics simulation studies for the promising compounds S1, S5 and S15. The stability of these complexes was assessed by calculating the root-mean-square deviation, solvent accessible surface area and gyration radius relative to their parent structures. Additionally, free energy of binding calculations were performed. Based on the biological and computational results, S15 was the most potent compound and S1 and S5 are comparable to the standard drug trametinib. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Dihydropyrimidinone scaffold and potential therapeutic targets(Elsevier, 2023-08-25T00:00:00) Kumar, Adarsh; Singh, Ankit Kumar; Vijayan, Veena; Singh, Harshwardhan; Verma, Amita; Kumar, PradeepDihydropyrimidine is the most important heterocyclic ring system involved in the synthesis of RNA and DNA. Dihydropyrimidines were produced synthetically by multicomponent reactions such as the Biginelli reaction. Because of their remarkable biological characteristics, dihydropyrimidinones (DHPMs) have drawn considerable attention in recent years. In this chapter, we have described the synthetic and pharmacological properties of DHPMs employing multicomponent synthesis. It emphasizes also widespread pharmaceutical applications of DHPMs, including antitubercular, antifilarial, antihypertensive, antiinflammatory, anticancer, antifungal, antibacterial, anti-HIV, antihyperglycemic, anti-SARS, analgesic, antioxidant, anticonvulsant, anti-Alzheimer�s and antihepatitis properties. This chapter will be of immense importance for the scientists working in this area. � 2023 Elsevier Inc. All rights reserved.Item Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAFV600E inhibitors(Royal Society of Chemistry, 2022-10-21T00:00:00) Singh, Ankit Kumar; Novak, Jurica; Kumar, Adarsh; Singh, Harshwardhan; Thareja, Suresh; Pathak, Prateek; Grishina, Maria; Verma, Amita; Yadav, Jagat Pal; Khalilullah, Habibullah; Pathania, Vikas; Nandanwar, Hemraj; Jaremko, Mariusz; Emwas, Abdul-Hamid; Kumar, PradeepThe �RAS-RAF-MEK-ERK� pathway is an important signaling pathway in melanoma. BRAFV600E (70-90%) is the most common mutation in this pathway. BRAF inhibitors have four types of conformers: type I (?C-IN/DFG-IN), type II (?C-IN/DFG-OUT), type I1/2 (?C-OUT/DFG-IN), and type I/II (?C-OUT/DFG-OUT). First- and second-generation BRAF inhibitors show resistance to BRAFV600E and are ineffective against malignancies induced by dimer BRAF mutants causing �paradoxical� activation. In the present study, we performed molecular modeling of pyrimidine-sulfonamide hybrids inhibitors using 3D-QSAR, molecular docking, and molecular dynamics simulations. Previous reports reveal the importance of pyrimidine and sulfonamide moieties in the development of BRAFV600E inhibitors. Analysis of 3D-QSAR models provided novel pyrimidine sulfonamide hybrid BRAFV600E inhibitors. The designed compounds share similarities with several structural moieties present in first- and second-generation BRAF inhibitors. A total library of 88 designed compounds was generated and molecular docking studies were performed with them. Four molecules (T109, T183, T160, and T126) were identified as hits and selected for detailed studies. Molecular dynamics simulations were performed at 900 ns and binding was calculated. Based on molecular docking and simulation studies, it was found that the designed compounds have better interactions with the core active site [the nucleotide (ADP or ATP) binding site, DFG motif, and the phospho-acceptor site (activation segment) of BRAFV600E protein than previous inhibitors. Similar to the FDA-approved BRAFV600E inhibitors the developed compounds have [?C-OUT/DFG-IN] conformation. Compounds T126, T160 and T183 interacted with DIF (Leu505), making them potentially useful against BRAFV600E resistance and malignancies induced by dimer BRAF mutants. The synthesis and biological evaluation of the designed molecules is in progress, which may lead to some potent BRAFV600E selective inhibitors. � 2022 The Royal Society of Chemistry.Item In Silico Studies of Indole Derivatives as Antibacterial Agents(Korean Pharmacopuncture Institute, 2023-06-30T00:00:00) Shah, Mridul; Kumar, Adarsh; Singh, Ankit Kumar; Singh, Harshwardhan; Narasimhan, Balasubramanian; Kumar, PradeepObjectives: Molecular docking and QSAR studies of indole derivatives as antibacterial agents. Methods: In this study, we used a multiple linear regressions (MLR) approach to construct a 2D quantitative structure activity relationship of 14 reported indole derivatives. It was performed on the reported antibacterial activity data of 14 compounds based on theoretical chemical descriptors to construct statistical models that link structural properties of indole derivatives to antibacterial activity. We have also performed molecular docking studies of same compounds by using Maestro module of Schrodinger. A set the molecular descriptors like hydrophobic, geometric, electronic and topological characters were calculated to represent the structural features of compounds. The conventional antibiotics sultamicillin and ampicillin were not used in the model development since their structures are different from those of the created compounds. Biological activity data was first translated into pMIC values (i.e. -log MIC) and used as a dependent variable in QSAR investigation. Results: Compounds with high electronic energy and dipole moment were effective antibacterial agents against S. aureus, indole derivatives with lower ?2 values were excellent antibacterial agents against MRSA standard strain, and compounds with lower R value and a high 2?v value were effective antibacterial agents against MRSA isolate. Conclusion: Compounds 12 and 2 showed better binding score against penicillin binding protein 2 and penicillin binding protein 2a respectively. Copyright � Korean Pharmacopuncture InstituteItem Medicinal Chemistry Aspects of Isoxazole Analogues as Anti-tubercular Agents(Bentham Science Publishers, 2023-10-11T00:00:00) Singh, Harshwardhan; Anila, Kumari V. S.; Singh, Ankit Kumar; Kumar, Adarsh; Kumar, PradeepTuberculosis (TB) is the major cause of mortality around the world and one of the most common diseases linked to AIDS. Due to the emergence of multi-drug resistance, extensive drug resistance, and total drug resistance strains, TB has become a difficult disease to treat. Isoxazole scaffold shows a wide range of biological activities, including anticancer, antibacterial, anti-tubercular, antiviral, and anti-inflammatory activities etc. Several isoxazole derivatives have been produced and few of them have shown comparable anti-tubercular activity with standard drugs. In this review, we have focused on reported isoxazole derivatives having anti-tubercular activity and summarized their structure-activity relationship. � 2023 Bentham Science Publishers.Item Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents(Royal Society of Chemistry, 2023-03-03T00:00:00) Kumar, Adarsh; Bhagat, Kuber Kumar; Singh, Ankit Kumar; Singh, Harshwardhan; Angre, Tanuja; Verma, Amita; Khalilullah, Habibullah; Jaremko, Mariusz; Emwas, Abdul-Hamid; Kumar, PradeepCancer is a major cause of deaths across the globe due to chemoresistance and lack of selective chemotherapy. Pyrido[2,3-d]pyrimidine is an emerging scaffold in medicinal chemistry having a broad spectrum of activities, including antitumor, antibacterial, CNS depressive, anticonvulsant, and antipyretic activities. In this study, we have covered different cancer targets, including tyrosine kinase, extracellular regulated protein kinases - ABL kinase, phosphatidylinositol-3 kinase, mammalian target of rapamycin, p38 mitogen-activated protein kinases, BCR-ABL, dihydrofolate reductase, cyclin-dependent kinase, phosphodiesterase, KRAS and fibroblast growth factor receptors, their signaling pathways, mechanism of action and structure-activity relationship of pyrido[2,3-d]pyrimidine derivatives as inhibitors of the above-mentioned targets. This review will represent the complete medicinal and pharmacological profile of pyrido[2,3-d]pyrimidines as anticancer agents, and will help scientists to design new selective, effective and safe anticancer agents. � 2023 The Royal Society of Chemistry.Item MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives(Royal Society of Chemistry, 2023-08-10T00:00:00) Ram, Teja; Singh, Ankit Kumar; Kumar, Adarsh; Singh, Harshwardhan; Pathak, Prateek; Grishina, Maria; Khalilullah, Habibullah; Jaremko, Mariusz; Emwas, Abdul-Hamid; Verma, Amita; Kumar, PradeepMEK1/2 are critical components of the RAS-RAF-MEK-ERK or MAPK signalling pathway that regulates a variety of cellular functions including proliferation, survival, and differentiation. In 1997, a lung cancer cell line was first found to have a MEK mutation (encoding MEK2P298L). MEK is involved in various human cancers such as non-small cell lung cancer (NSCLC), spurious melanoma, and pancreatic, colorectal, basal, breast, and liver cancer. To date, 4 MEK inhibitors i.e., trametinib, cobimetinib, selumetinib, and binimetinib have been approved by the FDA and several are under clinical trials. In this review, we have highlighted structural insights into the MEK1/2 proteins, such as the ?C-helix, catalytic loop, P-loop, F-helix, hydrophobic pocket, and DFG motif. We have also discussed current issues with all FDA-approved MEK inhibitors or drugs under clinical trials and combination therapies to improve the efficacy of clinical drugs. Finally, this study addressed recent developments on synthetic MEK inhibitors (from their discovery in 1997 to 2022), their unique properties, and their relevance to MEK mutant inhibition. � The Royal Society of Chemistry 2023.Item Metal Complexes in Cancer Treatment: Journey So Far(John Wiley and Sons Inc, 2023-02-24T00:00:00) Kumar Singh, Ankit; Kumar, Adarsh; Singh, Harshwardhan; Sonawane, Pankaj; Pathak, Prateek; Grishina, Maria; Pal Yadav, Jagat; Verma, Amita; Kumar, PradeepMetal complexes in cancer therapy have attracted much interest mainly because metals exhibit unique characteristics, such as redox activity, metal-ligand interaction, structure and bonding, Lewis acid properties etc. In 1965, Barnett Rosenberg serendipitously discovered the metal-based compound cisplatin, an outstanding breakthrough in the history of metal-based anticancer complexes and led to a new area of anticancer drug discovery. Many metal-based compounds have been studied for their potential anticancer properties. Some of these compounds have FDA approval for clinical use, while others are now undergoing clinical trials for cancer therapy and detection. In the present study, we have highlighted the primary mode of action of metallic complexes and all FDA-approved/under clinical trial drugs with reference to cancer treatment. This review also focuses on recent progress on metal-based complexes such as platinum, ruthenium, iron, etc. with potential anticancer activities. � 2023 Wiley-VHCA AG, Zurich, Switzerland.Item Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective(MDPI, 2023-02-15T00:00:00) Kumar, Adarsh; Singh, Ankit Kumar; Singh, Harshwardhan; Vijayan, Veena; Kumar, Deepak; Naik, Jashwanth; Thareja, Suresh; Yadav, Jagat Pal; Pathak, Prateek; Grishina, Maria; Verma, Amita; Khalilullah, Habibullah; Jaremko, Mariusz; Emwas, Abdul-Hamid; Kumar, PradeepCancer is one of the major healthcare challenges across the globe. Several anticancer drugs are available on the market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there is a dire need to develop safer and target-specific anticancer drugs. More than 85% of all physiologically active pharmaceuticals are heterocycles or contain at least one heteroatom. Nitrogen heterocycles constituting the most common heterocyclic framework. In this study, we have compiled the FDA approved heterocyclic drugs with nitrogen atoms and their pharmacological properties. Moreover, we have reported nitrogen containing heterocycles, including pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, ?-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3-d]pyrimidines, which are used in the treatment of different types of cancer, concurrently covering the biochemical mechanisms of action and cellular targets. � 2023 by the authors.Item Phytochemical Profiling and Pharmacological Evaluation of Leaf Extracts of Ruellia tuberosa L.: An In Vitro and In Silico Approach(John Wiley and Sons Inc, 2023-08-04T00:00:00) Sharma, Akanksha; Kumar, Adarsh; Singh, Ankit Kumar; Singh, Harshwardhan; Kumar, K. Jayaram; Kumar, PradeepThe present study was designed to appraise the photoprotective, antioxidant, and antibacterial bioactivities of Ruellia tuberosa leaves extracts (RtPE, RtChl, RtEA, RtAc, RtMe, and RtHMe). The results showed that, RtHMe extracts of R. tuberosa was rich in total phenolic content, i. e., 1.60 mgGAE/g dry extract, while highest total flavonoid content was found in RtAc extract, i. e., 0.40 mgQE/g. RtMe showed effective antioxidant activity (%RSA: 58.16) at the concentration of 120 ?L. RtMe, RtEA and RtHMe exhibited effective in vitro antibacterial activity against Gram-negative bacteria (E. coli). In silico docking studies revealed that paucifloside (?11.743 kcal/mol), indole-3-carboxaldehyde (?7.519 kcal/mol), nuomioside (?7.275 kcal/mol), isocassifolioside (?6.992 kcal/mol) showed best docking score against PDB ID 2EX8 [penicillin binding protein 4 (dacB) from Escherichia coli, complexed with penicillin-G], PDB ID 6CQA (E. coli dihydrofolate reductase protein complexed with inhibitor AMPQD), PDB ID 2Y2I [Penicillin-binding protein 1B in complex with an alkyl boronate (ZA3)] and PDB ID 2OLV (from S. aureus), respectively. Docked phytochemicals also showed good drug likeness properties. � 2023 Wiley-VHCA AG, Zurich, Switzerland.Item Regulation of thymidylate synthase: an approach to overcome 5-FU resistance in colorectal cancer(Springer, 2022-10-29T00:00:00) Kumar, Adarsh; Singh, Ankit Kumar; Singh, Harshwardhan; Thareja, Suresh; Kumar, PradeepThymidylate synthase is the rate-limiting enzyme required for DNA synthesis and overexpression of this enzyme causes resistance to cancer cells. Long treatments with 5-FU cause resistance to Thymidylate synthase targeting drugs. We have also compiled different mechanisms of drug resistance including autophagy and apoptosis, drug detoxification and ABC transporters, drug efflux, signaling pathways (AKT/PI3K, RAS-MAPK, WNT/? catenin, mTOR, NFKB, and Notch1 and FOXM1) and different genes associated with resistance in colorectal cancer. We can overcome 5-FU resistance in cancer cells by regulating thymidylate synthase by natural products (Coptidis rhizoma), HDAC inhibitors, mTOR inhibitors, Folate antagonists, and several other drugs which have been used in combination with TS inhibitors. This review is a compilation of different approaches reported for the regulation of thymidylate synthase to overcome resistance in colorectal cancer cells. Graphical abstract: [Figure not available: see fulltext.] � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Synthetic Methodologies and SAR of Quinazoline Derivatives as PI3K Inhibitors(Bentham Science Publishers, 2023-01-19T00:00:00) Raj, Aditya; Kumar, Adarsh; Singh, Ankit Kumar; Singh, Harshwardhan; Thareja, Suresh; Kumar, PradeepPI3K is an important anticancer target as it controls cellular functions such as growth, transformation, pro-liferation, motility and differentiation. Plasma cell cancer (multiple myeloma) occurs more than 10% among all haema-tological malignancies and accounts for 2% of all cancer-related deaths each year, it is mainly regulated by PI3K/AKT signaling cascade. Quinazoline derivatives have been reported as promising PI3K inhibitors. Lapatinib, afatinib, ge-fitinib, erlotinib, idelalisib and copanlisib are quinazoline-based, FDA-approved PI3K inhibitors, while compounds like NVPBYL719, GDC-0032, AZD8186, AZD-6482, etc. are under different stages of clinical trials. In light of the above-mentioned facts, in the present study, we have reported different synthetic approaches, mechanisms of anticancer action, and structure-activity relationship analysis of reported quinazoline derivatives as PI3K inhibitors to help researchers working in the field in designing better and isoform-selective PI3K inhibitors. � 2023 Bentham Science Publishers.Item Virtual screening, structure based pharmacophore mapping, and molecular simulation studies of pyrido[2,3-d]pyrimidines as selective thymidylate synthase inhibitors(Taylor and Francis Ltd., 2023-05-08T00:00:00) Kumar, Adarsh; Novak, Jurica; Singh, Ankit Kumar; Singh, Harshwardhan; Thareja, Suresh; Pathak, Prateek; Grishina, Maria; Verma, Amita; Kumar, PradeepHuman thymidylate synthase is the rate-limiting enzyme in the de novo synthesis of 2'-deoxythymidine-5'-monophosphate. dUMP (pyrimidine) and folate binding site hTS inhibitors showed resistance in colorectal cancer (CRC). In the present study, we have performed virtual screening of the pyrido[2,3-d]pyrimidine database, followed by binding free energy calculations, and pharmacophore mapping to design novel pyrido[2,3-d]pyrimidine derivatives to stabilize inactive confirmation of hTS. A library of 42 molecules was designed. Based on the molecular docking studies, four ligands (T36, T39, T40, and T13) were identified to have better interactions and docking scores with the catalytic sites [dUMP (pyrimidine) and folate binding sites] of hTS protein than standard drug, raltitrexed. To validate efficacy of the designed molecules, we performed molecular dynamics simulation studies at 1000 ns with principal component analysis and binding free energy calculations on the hTS protein, also drug likeness properties of all hits were in acceptable range. Compounds T36, T39, T40, and T13 interacted with the catalytic amino acid (Cys195), an essential amino acid for anticancer activity. The designed molecules stabilized the inactive conformation of hTS, resulting in the inhibition of hTS. The designed compounds will undergo synthesis and biological evaluation, which may yield selective, less toxic, and highly potent hTS inhibitors. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.