Hemant R. Jadhav

Histamine H3 Receptor Function and Ligands: Recent Developments

Histamine H3 receptors are found mostly in central nervous system involved in the regulation of release of various neurotransmitters in brain. They have been implicated in diverse potential therapeutic applications such as sleep-wake disorders, attention-deficient hyperactivity disorder, epilepsy, cognitive impairment and obesity. This review is an attempt to elucidate the function of H3 receptors and their role in various CNS disorders. Also, it is aimed at collating the information on efforts of various medicinal chemists to synthesize the H3 receptor agonists and antagonists in single article.

Formulation, evaluation and 32 full factorial design-based optimization of ondansetron hydrochloride incorporated taste masked microspheres

Abstract Context: Masking the bitter taste of Ondansetron hydrochloride (ONS) may improve palatability, acceptance and compliance of ONS products. Objective: ONS-loaded, taste-masked microspheres were prepared with a polycationic pH-sensitive polymer and 32 full factorial design (FFD) was applied to optimize microsphere batches. Materials and methods: Solvent evaporation, in acetone--methanol/liquid paraffin system, was used to prepare taste-masked ONS microspheres. The effect of varying drug/polymer (D/P) ratios on microspheres characteristics were studied by 32 FFD. Desirability function was used to search the optimum formulation. Microspheres were evaluated by FTIR, XRD and DSC to examine interaction and effect of microencapsulation process. In vitro taste assessment approach based on bitterness threshold and drug release was used to assess bitterness scores. Results: Prepared ONS microspheres were spherical and surface was wrinkled. ONS was molecularly dispersed in microspheres without any incompatibility with EE100. In hydrochloric acid buffer pH 1.2, ONS released completely from microsphere in just 10 min. Contrary to this, ONS release at initial 5 min from taste-masked microspheres was less than the bitterness threshold. Conclusion: Full factorial design and in vitro taste assessment approach, coupled together, was successfully applied to develop and optimize batches of ONS incorporated taste-masked microspheres.

Quantitative structure activity relationship analysis of aminoimidazoles as BACE-I inhibitors

Abstractβ-Secretase (BACE-1) is an important and attractive target involved in the pathogenesis of Alzheimer’s disease (AD). The enzyme is involved in the cleavage of amyloid precursor protein (APP) which is the rate-limiting step for the production of Aβ-42. β-Secretase inhibitors inhibit the amyloidogenic cleavage of APP and hence prevent the synthesis of Aβ-42, the cause of AD. A data set of aminoimidazoles was used to study the two-dimensional quantitative structure activity relationships (2D-QSAR) to explore the structural requirements for BACE-1 inhibition. This series of molecules is known to possess BACE-1 inhibitory activity in vivo. 2D-QSAR models were developed using multiple linear regression analysis which were then validated using leave-one-out method. The selected QSAR model displayed significant relationship between descriptors and biological activity along with internal and external predictivity. The developed model was also validated using external data set of hydantoins. The study reveals that thermo-dynamic descriptors (molar refractivity, Log P, van der Waals energy, polar surface area) and steric descriptors (Harary index, Randic index) play important role in β-secretase inhibition. The information generated may be useful for the design of novel and potent β-secretase inhibitors.

Rational design, synthesis and in vitro evaluation of allylidene hydrazinecarboximidamide derivatives as BACE-1 inhibitors

BACE-1 (β-secretase) is considered to be one of the promising targets for treatment of Alzheimers disease as it catalyzes the rate limiting step of Aβ-42 production. Herein, we report a novel class of allylidene hydrazinecarboximidamide derivatives as moderately potent BACE-1 inhibitors, having aminoguanidine substitution on allyl linker with two aromatic groups on either side. A library of derivatives was designed based on the docking studies, synthesized and evaluated for BACE-1 inhibition in vitro. The designed ligands displayed interactions with the catalytic aspartate dyad through guanidinium functionality. Further, the aromatic rings placed on either side of the linker occupied S1 and S3 active site regions contributing to the activity. These ligands were also predicted to follow Lipinski rule and cross blood brain barrier. Compound 2.21, having high docking score, was found to be most active with IC50 of 6.423μM indicating good correlation with docking prediction.

Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors

Epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show excellent clinical efficacy for patients with non-small cell lung cancer (NSCLC) with EGFR mutations, including Exon 19 deletion and single-point substitution, and L858R of exon 21. The reason for the reduction in effectiveness of these EGFR TKIs is the T790M gatekeeper mutation in the ATP-binding pocket of Exon 20, which increases the affinity of EGFR for ATP. Newer EGFR TKIs, such as afatinib, osimertinib, rociletinib, EGF816 and ASP8273, selectively target T790M mutants, sparing wild-type EGFR. EGFR TKIs have fewer adverse effects than chemotherapy and also improve progression-free survival. Combination therapy of EGFR TKIs with anti-EGFR antibodies is recommended for overcoming the problem of resistance to some extent. This review could help medicinal chemists to design novel EGFR TKIs against NSCLC.

Formulation and evaluation of lipid based taste masked granules of ondansetron HCl

INTRODUCTION AND AIM Various taste masking approaches comprising the excipients which delay the reach of the drug to taste buds are reported. Lipidic substances can act as release retarding agent and provides a matrix base responsible for suppressing the bitter taste of drug. This work was aimed to study the influence of different proportions of a lipid carrier on the inhibition of bitterness of the drug vis-a-vis in vitro release of drug from the granules. METHODS The lipid-matrix granules of ondansetron HCl with Geleol pellets (glycerol monostearate) were obtained by manual hot melt fusion technique. The prepared granules were characterized by SEM, DSC and XRD. The taste assessment of prepared granules was done by in vitro method based on drug release. RESULTS Distribution of drug inside the lipid-matrix granules was not properly analyzed by DSC and XRD, moreover these studies revealed no interaction between the drug and lipid. The dissolution tests displayed the significant retardation of drug release from the granules compared to pure drug and additionally indicated the attainment of matrix system via appearance of unbroken granules during in vitro testing. Higuchi relationship for drug release was obtained by drug release kinetics, which also revealed the functioning drug release mechanism, as diffusion controlled but the addition of hydrophilic substance (Cab-o-sil) has changed the mechanism of drug release. CONCLUSION The proportions of Geleol and Cab-o-sil taken in granules had affected the dissolution profile. Higher amount of GE resulted in high taste masking ability.

QSAR and Docking Studies of N-hydroxy Urea Derivatives as Flap Endonuclease-1 Inhibitors

Flap endonuclease-I (FEN-1) is involved in DNA repair and considered to be a novel target for the development of anticancer agents. N-hydroxy urea derivatives have been reported as FEN-1 inhibitors. To derive in vitro and in silico correlation, we have performed 2D-quantitative structure activity relationship (QSAR) analysis and docking studies on these compounds. 2D-QSAR models were developed using multiple linear regression (MLR) analysis and cross-validation using leave one out (LOO) method. The best model displayed R(2) of 0.806 and Q(2) of 0.607. Docking study revealed key interactions with desired amino acids and compare well with the in vitro potency of the reported compounds. Both studies reveal a link between FEN-1 inhibition and physicochemical descriptors or interactions with amino acids in active site. The information generated is first of its kind and may be helpful in the design of novel FEN-1 inhibitors.

Dynamin Functions and Ligands: Classical Mechanisms Behind

Dynamin is a GTPase that plays a vital role in clathrin-dependent endocytosis and other vesicular trafficking processes by acting as a pair of molecular scissors for newly formed vesicles originating from the plasma membrane. Dynamins and related proteins are important components for the cleavage of clathrin-coated vesicles, phagosomes, and mitochondria. These proteins help in organelle division, viral resistance, and mitochondrial fusion/fission. Dysfunction and mutations in dynamin have been implicated in the pathophysiology of various disorders, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Charcot-Marie-Tooth disease, heart failure, schizophrenia, epilepsy, cancer, dominant optic atrophy, osteoporosis, and Down’s syndrome. This review is an attempt to illustrate the dynamin-related mechanisms involved in the above-mentioned disorders and to help medicinal chemists to design novel dynamin ligands, which could be useful in the treatment of dynamin-related disorders.

Formulation and characterization of taste masked ondansetron–magnesium aluminum silicate adsorption systems

Abstract Context: Taste masking greatly influences the acceptability of bitter tasting formulation; moreover, it governs the commercial and therapeutic success of drug products. Objective: This work is directed toward masking the bitter taste of ondansetron HCl (ONS) utilizing the excipient, which can delay the reach of drug to the taste buds. Material and methods: Magnesium aluminum silicate (Veegum F), a clay material having capability to adsorb the drugs onto it, was used. The adsorption systems of ONS with Veegum were obtained by dynamic adsorption technique and examined by scanning electron microscopy, differential scanning calorimetry, Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD) for morphology, thermal behavior, and interactions. The taste assessment of prepared systems was done by in vitro method based on drug release. Results: The molecular interaction between ONS and Veegum in the system was revealed by FTIR spectroscopy. A change in thermal behavior of the system was observed owing to interaction or replacement of the cationic groups of Veegum with that of ONS. XRD studies revealed that the prepared system was having lower crystallinity as compared to ONS. The in vitro drug release study showed that ONS release from the system was relatively slow in basic environment than the acidic one. Discussion: Adsorption of ONS on the surface of Veegum was mainly due to electrostatic interactions and hydrogen bonding. Conclusion: The experimental results reveal the successful intercalation of ONS into the space available between the layers of Veegum. Furthermore, this resulted in a control on drug release in salivary pH resulting in a concentration lower than bitterness threshold.

Small Molecular Inhibitors for the Treatment of Rheumatoid Arthritis: Progress so Far

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by persistent inflammation and joint damage. The main aim of RA treatment is to control the disease progress. Despite the success of biologicals like Adalimumab, Atlizumab, infliximab, etc. in treatment of RA, the high cost and associated immunological adverse effects have triggered discovery of small molecules targeting RA. This review describes the last 15 years of small molecular drug discovery in RA, focused mainly on preclinical and clinical studies.