Browsing by Author "Yadav, Jagat Pal"

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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, Pradeep
Cancer 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.
Cucumis melo Var. agrestis Naudin as a potent antidiabetic: Investigation via experimental methods
(Elsevier B.V., 2022-09-06T00:00:00) Yadav, Jagat Pal; Singh, Ankit Kumar; Grishina, Maria; Pathak, Prateek; Patel, Dinesh Kumar
Background: The present study reveals that the ethanolic extract of Cucumis melo var. agrestis (CMVA), can influence the activity of blood glucose level, insulin level, oxidative stress, and lipid profile in Alloxan monohydrate induced diabetic rats. Methods: Wistar albino rats were randomly divided into five groups (n=6), viz. Normal control (non-diabetic), diabetic control (alloxan induced), diabetic treated group (infused with doses 250 and 500 mg/kg b.w) of CMVA ethanolic extract, and standard treated diabetes (infused with pioglitazone 1 mg/kg b.w). Diabetes was induced by administration of alloxan monohydrate (150 mg/kg i.p). The ethanolic extract of CMVA was supplemented orally in different doses for 45 days. Biochemical investigations as well as histopathological examination were carried out accordingly. Results: The diabetic rats supplemented with CMVA significantly decreased blood glucose levels in a dose dependent manner (#p < 0.001). The plasma insulin level was found significantly increased in rats treated with CMVA. However, in CMVA treated group, the oxidative stress parameters (such as SOD, CAT, GSHpx and GSH) and lipid parameters were restored up to normal level (#p < 0.001). Histopathological studies showed that the microscopic architecture of pancreatic cells were improved in CMVA treated groups. Conclusion: The research illustrated that CMVA has potent antidiabetic as well as antioxidant activity along with hypolipidemic effect. Therefore, active phyto-compounds of the selected plants can be isolated and further formulation can be develop in near future. � 2022
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, Pradeep
The �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.
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, Pradeep
Cancer 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.