Browsing by Author "Jadhav, Hemant R."

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Antioxidant properties of Indian medicinal plants
(Wiley, 2002-11) Jadhav, Hemant R.
The antioxidant properties of methanol extracts of 12 Indian medicinal plants, traditionally used in disease areas that probably involve free radical mechanisms, were evaluated by two methods, namely the DPPH (1,1-diphenyl-2-picryl hydrazyl) test and the lipid peroxidation assay. In the latter assay, seven of these extracts showed 90% or more activity compared with the standard, vitamin E and hence were studied in detail after the removal of interfering pigments. The selective pigment removal from the extracts led to an increase in free radical scavenging activity and a decrease in inhibition of lipid
Bioactivity predictions and virtual screening using machine learning predictive model
(Taylor & Francis, 2024-01) Jadhav, Hemant R.
Recently, there has been significant attention on machine learning algorithms for predictive modeling. Prediction models for enzyme inhibitors are limited, and it is essential to account for chemical biases while developing them. The lack of repeatability in available models and chemical bias issues constrain drug discovery and development. A new prediction model for enzyme inhibitors has been developed, and the model efficacy was checked using Dipeptidyl peptidase 4 (DPP-4) inhibitors. A Python script was prepared and can be provided for personal use upon request. Among various machine learning algorithms, it was found that Random Forest offers the best accuracy. Two models were compared, one with diverse training and test data and the other with a random split. It was concluded that machine learning predictive models based on the Murcko scaffold can address chemical bias concerns. In-silico screening of the Drug Bank database identified two molecules against DPP-4, which are previously proven hit molecules. The approach was further validated through molecular docking studies and molecular dynamics simulations, demonstrating the credibility and relevance of the developed model for future investigations and potential translation into clinical applications.
Bitterness Score and its Correlation to Drug Concentration: An Approach for Estimating Bitterness Suppression in a Marketed Product of Ofloxacin
(Bentham Science, 2015) Jadhav, Hemant R.
In vitro approaches for assessing taste characteristics of taste masked drug and drug products are useful in reducing reliance on human panel tests. In this study, taste panel studies were used to determine bitterness threshold and bitterness score of various solutions of ofloxacin followed by correlation and the application of this approach in estimating bitterness suppression. Bitterness scores for different solutions of ofloxacin were estimated by trained human volunteers of a taste panel. Bitterness scores were correlated to ofloxacin concentration followed by determination of bitterness scores for various dissolution samples obtained from in vitro drug release study of ofloxacin taste masked drug product. Concentration of 80 µg/ml and below was perceived bitterless by all the volunteers of taste panel. A third order polynomial equation (y=13.51x3-91.08x2+206.7x-156.6; R2 = 0.973) was derived as a relationship between bitterness score (y) and log ofloxacin concentration (x). Marketed taste masked product achieved concentrations below bitterness threshold in in vitro drug release studies performed in pharmacopoeial apparatus at initial time points (0-5 min). Bitterness threshold and bitterness scores are helpful in estimating bitterness of ofloxacin solutions provided suitable correlation has been found between them. The suggested approach, which is applicable to any bitter or objectionable tasting drug, has potential to be used as analytical tool in formulation development and quality control.
Butadiene Sulfone-catalyzed Monobromination of Arenes with NBS as the Bromination Source
(Bentham Science, 2023-10) Jadhav, Hemant R.
In literature, dimethyl sulfoxide (DMSO) catalyzed bromination of arenes and heteroarenes is reported. In this study, simple, mild, and chemoselective N-bromosuccinimide (NBS) mediated monobromination of arenes and heteroarenes using butadiene sulfone as a catalyst is reported. Butadiene sulfone is a good substitute for DMSO as it is volatile, easy to recover and recycle, and environment- friendly. The method has been demonstrated to give high-yield brominated products for an extensive range of activated and deactivated arenes.
Butadiene sulfone-catalyzed monobromination of arenes with nbs as the bromination source: a simple, mild, efficient, and chemoselective protocol
(Bentham Science, 2024-02) Jadhav, Hemant R.
In literature, dimethyl sulfoxide (DMSO) catalyzed bromination of arenes and heteroarenes is reported. In this study, simple, mild, and chemoselective N-bromosuccinimide (NBS) mediated monobromination of arenes and heteroarenes using butadiene sulfone as a catalyst is reported.Butadiene sulfone is a good substitute for DMSO as it is volatile, easy to recover and recycle, and environment- friendly. The method has been demonstrated to give high-yield brominated products for an extensive range of activated and deactivated arenes.
A Comprehensive Review of Systemic Targeted Therapies in Cancer Treatment
(Bentham Science, 2023-10) Jadhav, Hemant R.
Cancer is one of the significant healthcare challenges in today’s world, even after advancements in modern science, including oncology. The complex nature of the disease, which involves multiple proteins and pathways, poses a substantial challenge in drug discovery. Several therapeutic options have emerged in the last decade. Systemic cancer therapies began with the advent of chemotherapy and were revolutionized with the development of targeted therapies. The present review is a definite overview of the advances in various therapeutic options for cancer, with a particular emphasis on targeted therapy using small molecules and biologicals
Computational Analysis of Phase I Metabolism in Clinically Studied Flavoalkaloids: Molecular Docking, MMGBSA Binding Energy Calculations, and Molecular Dynamics Simulations
(Wiley, 2024-09) Jadhav, Hemant R.
Flavoalkaloids, a potent class of cyclin-dependent kinase inhibitors, have undergone extensive clinical trials across various cancer types. Among them, flavopiridol, riviciclib, and voruciclib are the most advanced candidates. These molecules are lipophilic and possess functional groups conducive to both phase I and phase II metabolism in the liver. This study employs in-silico methods to identify the potential cytochrome P450-mediated sites of phase I metabolism (SOM) in these compounds. According to two web-server-based predictions, the N-methyl group was identified as the primary SOM in these compounds, showing the highest probability score for involvement of CYP3A4. Docking studies conducted using both Glide and the induced-fit method further confirmed N-demethylation as a significant metabolic pathway predominantly catalyzed by CYP3A4. The distance between the N-methyl group of the docked ligands and the iron atom of the heme ranged from 3 to 7 Å, with flavopiridol's N-methyl group positioned closest to the heme iron at 3.16 Å. The 100 ns molecular dynamic simulations additionally validated the stability of the interaction between flavoalkaloids and the heme Fe. Similarly, the docking-based SOM predictions matched the experimental SOM for other approved drugs. Thus, employing docking-based SOM predictions holds potential for enhancing lead optimization efforts in future medicinal chemistry research
Corrigendum to: Design and development of chromene-3-carboxylate derivatives as antidiabetic agents: Exploring the antidiabetic potential via dual inhibition of angiotensin II type 1 receptor and neprilysin enzyme
(Elsevier, 2025-10) Gaikwad, Anil Bhanudas; Jadhav, Hemant R.
Diabetes mellitus, particularly type II diabetes mellitus, is a metabolic condition that has a substantial impact on the health of individuals. The implication of diabetes with increased risk of cardiovascular diseases (CVD) and, consequently, myocardial infarction is well established. However, developing new antidiabetic drugs with an established efficacy on cardiovascular health is an underdeveloped area of research. To address this, in the present study, a new series of chromene-3-carboxylate derivatives (1B1–1B22) as dual inhibitors of Angiotensin II Type 1 Receptor (AT1R) and Neprilysin (NEP), which are recognized targets in diabetes with CVD, is reported. The compounds were rationally designed and synthesized, considering the pharmacophoric features of these two targets. The evaluation was performed via glucose uptake, α-amylase, AT1R, and NEP inhibition assay. The derivatives were found to increase glucose uptake and inhibit all three targets, of which compound 1B15 was the most active. The most active compound, 1B15, reduced the oxidative stress and restored the mitochondrial membrane potential. The biological findings were further corroborated by in silico studies, which included molecular modelling and dynamics. It was deduced that 1B15 remains unionized in acidic to weak basic pH and may be passively absorbed. Further, the molecule was found to undergo hydroxylation as a means of Phase I metabolism and glucuronic conjugation in Phase II. The wet lab experiments on 1B15 further validated the insilico absorption and metabolism prediction. The compounds, particularly 1B15, could be explored further as a lead for its utility as an antidiabetic with profound implications on cardiovascular health.
Cosmetic potential of herbal extracts
(NISCAIR, 2005-08) Jadhav, Hemant R.
Cosmetology, the science of alteration of appearance, has been practiced since primordial times. In India, the concept of using herbs for beautification finds its origin in traditional medicine literature like Ayurveda. The cosmetic preparations were used for the purpose of worship and sensual enjoyment. Moreover, since centuries, the herbal extracts, as a whole or part thereof, have been used for various ailments of the skin, hair and for overall appearance. The market research shows upward trend in the herbal trade with the herbal cosmetic industry playing a major role in fuelling this worldwide demand for herbals. The recent interest of consumers in herbal cosmetics has been stimulated by the decline of faith in modern cosmetics, the belief that plant remedies were natural and thereby superior to man-made synthetic cosmetics, and the reference to successful historical use by different cultures. These reasons have contributed to the increased acceptance as well as manufacture of herbal cosmetics. Many herbs have been scientifically evaluated for their cosmetic potential. Some traditional plants like Trigonella foenum-graecum Linn., Azadirachta indica A. Juss., Mimosa tenuiflora Benth., Aloe vera Linn., etc. need special mention. The great void remains though for a systematic, thorough review of scientific data that provides a basis for the use of specific herbs and their efficacy as cosmetics. Similarly, there is a lack of scientific review of phytochemicals that are used in cosmetic preparations. This review attempts to fill-up this gap and emphasizes the need for safety evaluation of herbal cosmetics.
Design, Synthesis and Evaluation of 2,4,6-substituted Pyrimidine Derivatives as BACE-1 Inhibitor: Plausible Lead for Alzheimer’s Disease
(Bentham Science, 2021) Jadhav, Hemant R.
Alzheimer’s disease is one of the most common neurodegenerative disorder afflicting a large mass of population. BACE-1 (β-secretase) is an aspartyl protease of the amyloidogenic pathway considered responsible for Alzheimer’s disease (AD). Since it catalyzes the rate-limiting step of Aβ-42 production from amyloid precursor protein (APP), its inhibition is considered a viable therapeutic strategy. We have reported the design of small molecular weight compounds supposed to be blood brain permeable as BACE-1 inhibitors. The clue for the design of this series is drawn from the previously designed series from our research group.
Design, synthesis and evaluation of acridin-9-yl hydrazide derivatives as BACE-1 inhibitors
(Springer, 2016-04) Jadhav, Hemant R.
BACE-1, an aspartyl protease is implicated in Alzheimer’s disease. In this paper, we report BACE-1 inhibitory potential of acridin-9-yl hydrazide derivatives, known to inhibit other aspartyl proteases. The derivatives were designed based on the docking study, synthesized and assessed for BACE-1 inhibition in vitro. Docking simulation predicted the binding of prototype acridin-9-yl hydrazide at BACE-1 active site. The enzyme–inhibitor complex was primarily stabilized by hydrogen bonds between the hydrazide part of the inhibitor and side chain of Gly11, which is important amino acid of 10s loop. The acridinyl moiety showed π–π stacking with Tyr71 while the phenyl ring was buried in S1 cavity. Enzyme inhibition experiments showed that the synthesized compounds had moderate activity with compound AA-13 having 54.54 % inhibition at 10 µM concentration.
Design, synthesis and evaluation of new methyl piperazine derivatives as anticancer agents
(Springer, 2024-07) Jadhav, Hemant R.
To overcome the problem of side effects and toxicity, development of new anticancer agents is needed. Recently, piperidine salicylanilide derivatives with nanomolar epidermal growth factor receptor (EGFR) inhibitory and cytotoxicity activity have been reported. In the present study effect of replacing piperidine in reported piperidine salicylanilide with N-methyl piperazine and changing substituent’s of phenyl ring at other end on anticancer activity have been explored. A series of sixteen methyl piperazine incorporated phenyl benzamide and phenyl methanone derivatives have been synthesized and tested in a panel of three cancer cell lines (adenocarcinomic human alveolar basal epithelial cells (A-549), human colon carcinoma (HCT-116) and human pancreatic carcinoma (MIAPaCa-2)), using gefitinib as standard. Further, to study the probable mechanism, due to their structural similarity with EGFR inhibitors, docking interactions with EGFR active site were observed using Schrodinger suite.
Design, Synthesis and In Vitro Evaluation of 2-Oxo-N-substituted Phenyl-2H-chromene-3-carboxamide Derivatives as HIV Integrase Strand Transfer Inhibitors
(Bentham Science, 2020) Jadhav, Hemant R.
A series of eighteen 2-Oxo-N-substituted phenyl- 2H-chromene-3- carboxamide analogues has been evaluated for HIV-1 integrase (IN) inhibition.
Design, Synthesis and In Vitro Evaluation of 4-Oxo-6-Substituted Phenyl- 2-Thioxo1,2,3,4-Tetrahydropyrimidine-5-Carbonitrile Derivatives as HIV Integrase Strand Transfer Inhibitors
(Bentham Science, 2021-11) Jadhav, Hemant R.
To design, synthesis and in vitro evaluation of 4-oxo-6-substituted phenyl-2- thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives as HIV integrase strand transfer inhibitors
Design, Synthesis and In Vitro Evaluation of Piperazine Incorporated Novel Anticancer Agents
(Bentham Science, 2018) Jadhav, Hemant R.
Novel 4-(3-(4-ethylpiperazin-1-yl)propoxy)-N-phenylbenzamide derivatives (C-1 to C-10) and (4-(3-(4-ethylpiperazin-1-yl)propoxy)phenyl)(4-(2-methoxyphenyl)piperazin-1- yl)ethanone derivatives (C-11 to C-16) were designed and synthesized by pharmacophore approach.
Design, synthesis and in vitro evaluation studies of sulfonyl-amino-acetamides as small molecule BACE-1 inhibitors
(Elsevier, 2016-06) Jadhav, Hemant R.
The identification of a series of sulfonyl-amino-acetamides as BACE-1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease is reported. The derivatives were designed based on the docking simulation study, synthesized and assessed for BACE-1 inhibition in vitro. The designed ligands revealed desired binding interactions with the catalytic aspartate dyad and occupance of S1 and S2′ active site regions. These in silico results correlated well with in vitro activity. Out of 33 compounds synthesized, 12 compounds showed significant inhibition at 10 μM concentration. The most active compound 2.17S had IC50 of 7.90 μM against BACE-1, which was concomitant with results of in silico docking study.
Design, Synthesis, and Pharmacological Evaluation of Embelin–Aryl/alkyl Amine Hybrids as Orally Bioavailable Blood–Brain Barrier Permeable Multitargeted Agents with Therapeutic Potential in Alzheimer’s Disease: Discovery of SB-1448
(ACS, 2023-02) Jadhav, Hemant R.
The complex and multifaceted nature of Alzheimer’s disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Embelia ribes Burm f., one of the oldest herbs in Indian traditional medicine. It is a micromolar inhibitor of cholinesterases (ChEs) and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we synthesize a series of embelin–aryl/alkyl amine hybrids to improve its physicochemical properties and therapeutic potency against targeted enzymes. The most active derivative, 9j (SB-1448), inhibits human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE), and human BACE-1 (hBACE-1) with IC50 values of 0.15, 1.6, and 0.6 μM, respectively. It inhibits both ChEs noncompetitively with ki values of 0.21 and 1.3 μM, respectively. It is orally bioavailable, crosses blood–brain barrier (BBB), inhibits Aβ self-aggregation, possesses good ADME properties, and protects neuronal cells from scopolamine-induced cell death. The oral administration of 9j at 30 mg/kg attenuates the scopolamine-induced cognitive impairments in C57BL/6J mice.
Design, synthesis, in silico, and in vitro evaluation of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide derivatives as AChE/BACE 1 dual inhibitors
(RSC, 2024-08) Jadhav, Hemant R.
Alzheimer's disease (AD) manifests as a progressive decline in cognitive function and mental behavior. Targeting two crucial enzymes associated with AD, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), in combination, holds promise for therapeutic breakthroughs. In this study, 40 derivatives of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide were designed based on prior research. These derivatives underwent synthesis and assessment for their inhibitory potential against AChE and BACE 1. ADME predictions indicated favorable physicochemical properties for these compounds. The findings offer novel avenues for exploring the dual inhibition of AChE and BACE 1 as a promising therapeutic strategy for AD.
Discovery of blood-brain barrier permeable and orally bioavailable caffeine-based amide derivatives as acetylcholinesterase inhibitors
(Elsevier, 2023-10) Jadhav, Hemant R.
Caffeine is one of the privileged natural products that shows numerous effects on the central nervous system. Herein, thirty-one caffeine-based amide derivatives were synthesized and evaluated in vitro for their anticholinesterase activity. The introduction of the amide group to the caffeine core augmented its anticholinesterase activity from an IC50 value of 128 to 1.32 µM (derivative, 6i). The SAR study revealed that N7 substitution on caffeine core is favorable over N1, and the presence of amide 'carbonyl' as a part of the linker contributes to the biological activity. The caffeine core of 6i exhibits interactions with the peripheral anionic site, whereas the N-benzyl ring fits nicely inside the catalytic anionic site. Analog 6i inhibits AChE in a mixed-type mode (Ki 4.58 µM) and crosses the BBB in an in-vitro PAMPA assay. Compound 6i has a descent metabolic stability in MLM (>70% remaining after 30 min) and favorable oral pharmacokinetics in Swiss albino mice.
Emerging in diabetic cardiomyopathy: molecular pathways and targets for therapeutic intervention
(Wiley, 2025) Jadhav, Hemant R.
Amongst various complications presented by diabetes, diabetic cardiomyopathy (DCM) is one of the most prominent and vexing complications. Due to the absence of consensus on prevention and treatment strategies, along with limitations in current therapies, a fresh perspective is essential and a requirement of the time. The succeeding review explores research that provides insights into novel molecular targets that could possibly evolve as breakthroughs in restraining the pathological hallmarks of DCM, such as inhibition of cardiomyocyte fibrosis or modulation of various inflammatory pathways, apoptotic pathways such as PANoptosis, cuproptosis, and ferroptosis, and mitochondrial dysfunction. This review shall also explore various RNA-targeting therapeutic areas that can combat the consecution of DCM. Therapeutic intervention targeting Phosphodiesterase 4D (PDE4D), LGR6 (G-protein-coupled receptor containing leucine-rich repeats 6), Interferon gamma inducible protein 16 (IFI16), Growth differentiation factor 11(GDF11), Transcription factor EB(TFEB), Secreted frizzled-related protein 1 (SFRP1), Fibroblast growth factor -21 (FGF21), Takeda G protein-coupled receptor-5 (TGR5), Nuclear receptor of the subfamily 4 (NR4A3), Enhancer of zeste homolog 2 (EZH2), and RNA-based therapeutics such as piR112710 and TUG1 are reviewed. Moreover, how these molecular targets intersect with DCM pathology, and how they can be further explored in a drug discovery paradigm for DCM management, is discussed.