Nirupam Das

Codrug: An efficient approach for drug optimization

Codrug or mutual prodrug is an approach where various effective drugs, which are associated with some drawbacks, can be modified by attaching with other drugs of same or different categories directly or via a linkage. More appropriately one can say combining two different pharmacophores with similar or different pharmacological activities elicit synergistic action or help to target the parent drug to specific site/organ/cells respectively. This approach is commonly used to improve physicochemical, biopharmaceutical and drug delivery properties of therapeutic agents.

Nanocrystal Technology in the Delivery of Poorly Soluble Drugs: An Overview

Extensive attempts to overcome problems related to solubility of drugs for maximizing bioavailability at targeted sites in the body have been made. The issue of drug solubility appears to attract the continued interest of pharmaceutical manufacturers. In this context, nanocrystallization has emerged as an important tool. In the present review, the authors discuss the advantages of nanocrystallized drugs and examine the products available in the market as well as drugs in the pipeline using nanocrystal-based formulations, which are being developed by pharmaceutical companies for drug delivery.

Design, synthesis, evaluation and molecular modelling studies of some novel 5,6-diphenyl-1,2,4-triazin-3(2H)-ones bearing five-member heterocyclic moieties as potential COX-2 inhibitors: A hybrid pharmacophore approach

A series of novel hybrids comprising of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole tethered to 5,6-diphenyl-1,2,4-triazin-3(2H)-one were designed, synthesised and evaluated as COX-2 inhibitors for the treatment of inflammation. The synthesised hybrids were characterised using FT-IR, 1H NMR, 13C NMR, elemental (C,H,N) analyses and assessed for their anti-inflammatory potential by in vitro albumin denaturation assay. Compounds exhibiting activity comparable to indomethacin and celecoxib were further evaluated for in vivo anti-inflammatory activity. Oral administration of promising compounds 3c-3e and 4c-4e did not evoke significant gastric, hepatic and renal toxicity in rats. These potential compounds exhibited reduced malondialdehyde (MDA) content on the gastric mucosa suggesting their protective effects by inhibition of lipid peroxidation. Based on the outcome of in vitro COX assay, compounds 3c-3e and 4c-4e (IC50 0.60-1.11μM) elicited an interesting profile as competitive selective COX-2 inhibitors. Further, selected compounds 3e and 4c were found devoid of cardiotoxicity post evaluation on myocardial infarcted rats. The in silico binding mode of the potential compounds into the COX-2 active site through docking and molecular dynamics exemplified their consensual interaction and subsequent COX-2 inhibition with significant implications for structure-based drug design.

Design, synthesis, preliminary pharmacological evaluation, and docking studies of pyrazoline derivatives

Ten derivatives of N1 substituted/unsubstituted 5-(4-chlorophenyl)-3-(2-thienyl) pyrazoline were synthesised from chalcone-like intermediate and substituted phenyl hydrazines, hydrazine hydrate, and semi/thiosemicarbazide. The chemical structure of compounds was confirmed by means of IR, 1H NMR, mass spectroscopy, and elemental analysis. The antidepressant and anticonvulsant activities were investigated by Porsolt’s behavioural despair test (forced swimming) and maximum electroshock seizure test, respectively. Rota-Rod test was performed to assess any probable changes in motor coordination induced by the test compounds. Four compounds (IId, IIg, IIi, and IIj) exhibited good activity profile against depression and docking studies confirmed their consensual interaction with monoamine oxidase A. In addition, compounds IIc and IIe showed protection against MES-induced seizures.

Antimalarial Drug Development: Past to Present Scenario

Malaria is a global health problem that needs attention of drug discovery scientists to investigate novel compounds with high drug efficacy, safety and low cost to counter the malaria parasites that are resistant to existing drug molecules. This is an overview of past to present status of antimalarial drugs including newly researched candidates and also the alternative approaches for the complete control of malaria.

Pharmacophoric Modeling and Atom-Based 3D-QSAR of Novel 1-Aryl-3-(1-acylpiperidin-4-yl) Urea as Human Soluble Epoxide Hydrolase Inhibitors (sEHIs)

Soluble Epoxide Hydrolase (sEH) is an important and promising new pharmacologic target for the treatment of acute systemic inflammation. Inhibition of sEH by a highly selective and potent sEH inhibitor (sEHI) elevates the epoxyeicosatrienoic acids (EETs) level in vivo leading to decreased inflammation. To explore the necessary structural requirement of 1, 3-disubstituted ureas as sEH inhibitors for anti-inflammatory activity, the molecular modeling studies have been pursued. A ligand-based pharmacophoric model and atom-based 3D-QSAR have been generated by Phase. Binding interaction as determined by the docking study revealed that these inhibitors interact at active site (ASP 335 & TYR 383) of sEH enzyme. The pharmacophore model was further used as a 3D query for virtual screening to retrieve potential inhibitors.

Design, Synthesis and Pharmacological Evaluation of N3 Aryl/ Heteroaryl Substituted 2-((Benzyloxy and Phenylthio) Methyl) 6,7- dimethoxyquinazolin-4(3H)-ones as Potential Anticonvulsant Agents

Novel N3 aryl/heteroaryl substituted 2-((benzyloxy and phenylthio) methyl) 6,7-dimethoxyquinazolin-4(3H)- ones (8a-8l) were synthesized and evaluated for their anticonvulsant activity using various models of epilepsy, such as maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and intracerebroventricular AMPA (α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in mice. The rotarod test has been used to determine the acute neurotoxicity. Further, the serum enzymatic activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were assessed along with histopathological examination of liver. Among all the derivatives, compound 8f displayed significant activity profile based on the overall magnitude of activity and minimum neurotoxicity.

Synthesis, Characterization, Biological Evaluation and Docking of Coumarin Coupled Thiazolidinedione Derivatives and its Bioisosteres as PPARγ Agonists

Thiazolidinedione (TZD) derivatives are the novel class of oral antidiabetic drugs which are selective agonist for the nuclear PPAR γ that enhances the transcription of several insulin responsive genes but TZDs are known to cause weight gain, hepatotoxicity and fluid retention. So a new series of coumarin coupled thiazolidinedione derivatives and its bioisosters (oxazolidinedione and imidazolidinedione) were synthesized by Knoevenagel condensation of 4-((7-hydroxy-2-oxo-2H-chromen-4-yl) methoxy) benzaldehyde with 2,4 thiazolidinedione and its bioisosteres. The structures of these compounds were established by means of FT IR, 1H-NMR, elemental analysis and mass spectroscopy. All the compounds were screened for antidiabetic activity in streptozotocin induced diabetic wistar male rats. Most of the compounds revealed significant antidiabetic activity when compared with the standard drug rosiglitazone. Compounds 5 & 6 containing oxazolidinedione ring system were found to be more active than compounds having thiazolidinedione and imidazolidinedione nucleus. Molecular docking was performed on 2 PRG protein by using the software Glide (Schrödinger, LLC, USA). The QikProp program was used to obtain the pharmacokinetic properties of analogues.

Benzoxazinones as human peroxisome proliferator activated receptor gamma (PPARγ) agonists: A docking study using glide

The purpose of the present study is to undertake a docking study of some benzoxazinone derivatives on human peroxisome proliferator activated receptor co-crystallized with an alpha-aryloxyphenylacetic acid agonist using Glide 4.5. The QikProp program was used to obtain the absorption, distribution, metabolism and excretion properties of the analogues. The intermolecular hydrogen bonding interaction of the best-fit ligands were found to be associated with Tyr473, Ser289, Hie 449, Hip 323, Ser 342 and Gly 284 amino acid residue at the receptor active site. Among all the observed interaction with similar binding pattern, the presence of methyl carboxypentyl side chain (Lig. No. 21) showed additional interaction with Ser 342 and the affinity was increased by carboxyl oxygen (as hydrogen bond acceptor) with a best Glide score of -14.54 as compared to the co-crystallized aryloxyphenyl acetic acid which achieved a glide score of -12.50.