Ram Kishore Agrawal

Recent developments and biological activities of thiazolidinone derivatives: A review

Thiazolidinone is considered as a biologically important active scaffold that possesses almost all types of biological activities. Successful introduction of ralitoline as a potent anti-convulsant, etozoline as a antihypertensive, pioglitazone as a hypoglycemic agent and thiazolidomycin activity against streptomyces species proved potential of thiazolidinone moiety. This diversity in the biological response profile has attracted the attention of many researchers to explore this skeleton to its multiple potential against several activities. This review is complementary to earlier reviews and aims to review the work reported on various biological activities of thiazolidinone derivatives from year 2000 to the beginning of 2011. Data are presented for active compounds, some of which have passed the preclinical testing stage.

1,3,4-Thiadiazole and its Derivatives: A Review on Recent Progress in Biological Activities

The 1,3,4‐thiadiazole nucleus is one of the most important and well‐known heterocyclic nuclei, which is a common and integral feature of a variety of natural products and medicinal agents. Thiadiazole nucleus is present as a core structural component in an array of drug categories such as antimicrobial, anti‐inflammatory, analgesic, antiepileptic, antiviral, antineoplastic, and antitubercular agents. The broad and potent activity of thiadiazole and their derivatives has established them as pharmacologically significant scaffolds. In this study, an attempt has been made with recent research findings on this nucleus, to review the structural modifications on different thiadiazole derivatives for various pharmacological activities.

Predicting anti-HIV activity of 1,3,4-thiazolidinone derivatives: 3D-QSAR approach.

HIV-1 (human immunodeficiency virus type-1) is the pathogenic retrovirus and causative agent of AIDS. HIV-1 RT is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as NNRTIs and NRTIs. NNRTIs bind to a region that is not associated with the active site of the enzyme. Within the NNRTIs category, there is a set of inhibitors commonly referred to as thiazolidinone derivatives. The present 3D-QSAR study attempts to explore the structural requirements of thiazolidinone derivatives for anti-HIV activity. Based on the structures and biodata of previous thiazolidinone analogs, 3D-QSAR studies have been performed with a training set consisting of 96 molecules, which resulted in two reliable computational models, CoMFA and CoMSIA with r(2) values of 0.931 and 0.972, standard error of estimation (SEE) of 0.173 and 0.089, and q(2) values of 0.663 and 0.784, respectively, with the number of partial least-squares (PLS) components being six. It is shown that the steric and electrostatic properties predicted by CoMFA contours and the hydrogen bond acceptor, hydrogen bond donor, and hydrophobic properties predicted by CoMSIA contours are related to anti-HIV activity. The predictive ability of the resultant model was evaluated using a test set comprising of 17 molecules and the predicted r(2) values of CoMFA and CoMSIA models were 0.861 and 0.958, respectively. These models are more significant guide to trace the features that really matter especially with respect to the design of novel compounds.

Metronidazole loaded pectin microspheres for colon targeting

A multiparticulate system having pH-sensitive property and specific enzyme biodegradability for colon-targeted delivery of metronidazole was developed. Pectin microspheres were prepared using emulsion-dehydration technique. These microspheres were coated with Eudragit(R) S-100 using oil-in-oil solvent evaporation method. The SEM was used to characterize the surface of these microspheres and a distinct coating over microspheres could be seen. The in vitro drug release studies exhibited no drug release at gastric pH, however continuous release of drug was observed from the formulation at colonic pH. Further, the release of drug from formulation was found to be higher in the presence of rat caecal contents, indicating the effect of colonic enzymes on the pectin microspheres. The in vivo studies were also performed by assessing the drug concentration in various parts of the GIT at different time intervals which exhibited the potentiality of formulation for colon targeting. Hence, it can be concluded that Eudragit coated pectin microspheres can be used for the colon specific delivery of drug.

QSAR analysis of caffeoyl naphthalene sulfonamide derivatives as HIV-1 integrase inhibitors

Human immunodeficiency virus type 1 (HIV-1) integrase is a potential target for anti-HIV therapy. It is an essential enzyme required for replication of the acquired immunodeficiency syndrome (AIDS) virus. Caffeoyl naphthalene sulfonamide derivatives act against HIV integrase and thus have the potential to become a part of an anti-HIV drug regimen. Although caffeoyl naphthalene sulfonamide derivatives have all the features required of good anti-HIV agents such as the presence of bis-catechol moieties, polyaromatic rings, and a central linker, they do not perform well as anti-HIV agents in cell-based assays, that is, they do not stop viral replication at nontoxic concentration. We carried out a quantitative structure–activity relationship (QSAR) study of caffeoyl naphthalene sulfonamide derivatives via the software WIN CAChe 6.1 and STATISTICA to improve its activity. QSAR reveals that if partition coefficient, connectivity index, and shape index of these molecules are altered, the activity is likely to increase. On the basis of the QSAR model, we designed a new series of compounds, calculated the activities, and found that they were more potent than the existing compounds.

Synthesis and antibacterial evaluation of 2-substituted-4,5-diphenyl-N-alkyl imidazole derivatives

Objective: To synthesis 2-substituted-4,5-diphenyl-N-alkyl imidazole derivatives, and evaluate their antibacterial activity. Methods: A mixture of benzil (10 mmol) and ammonium acetate (0.1 mol) (immediately fused) in glacial acetic acid (25 mL) was stirred at 80-100℃ for 1 h under nitrogen atmosphere (to prevent incorporation of any atmospheric impurities and moisture). Substituted aldehydes (10 mmol) in glacial acetic acid (5 mL) was added drop-wise over a period of 15-20 min at the same temperature and stirred for another 4 h, the progress of the reaction was monitored by TLC test using ethyl acetate as eluent. The newly synthesized compounds were characterized by IR, 1HNMR, 13CNMR and by mass spectroscopy. Results: All the synthesized compounds were confirmed by spectroscopical techniques and evaluated for antimicrobial activity against Staphylococcus aureus (S. aurius), Bacilus subtilus (B. subtilus), and Escheria coli (E. coli). These compounds showed antibacterial activity (zone of inhibition) against S. aurius ranged from 3 mm to 9 mmin diameter, B. subtilus, 4-8 mm, and E. coli 5-12 mm. Out of 2a-2e, only 2a and 2b showed some sort of activity but none of them had considerable activity compared with that of the standard. Conclusions: All the synthesized compounds show moderate activity against the tested bacteria S. aurius, B. subtilus, and E. coli. So, further structural modification is necessary to improve the antibacterial action of 2-substituted-4,5-diphenyl-N-alkyl imidazole derivatives.

QSAR study on some arylsulfonamides as anti-HIV agents

In pursuit of better anti-HIV drugs, quantitative structure-activity relationship (QSAR) studies were performed on a series of aryl sulfonamide HIV protease inhibitors using Win CAChe 6.1. Multiple linear regression analysis was performed to derive QSAR models, which were further evaluated for statistical significance and predictive power by internal and external validation. The QSAR model indicates that the thermodynamic descriptors (heat of formation, log P, and molar refractivity) and steric descriptor (solvent assessable surface area) play an important role for the anti-HIV activity. The results of the present study may be useful on the designing of more potent anti-HIV agents.

Design, synthesis, and evaluation of thiazolidinone derivatives as antimicrobial and anti-viral agents.

A series of 1,3‐thiazolidin‐4‐one derivatives were prepared by the reaction of respective aromatic amine, aromatic aldehyde, and thioglycolic acid in dry benzene/toluene. The newly synthesized compounds were characterized on the basis of elemental analysis, IR, 1HNMR, and mass spectra. The newly synthesized final compounds were evaluated for their in vitro antibacterial, antifungal, and anti‐viral activities. Preliminary results indicated that some of the compounds demonstrated antibacterial activity in the range of 7–13 μg/mL, antifungal activity in the range of 13–17 μg/mL, comparable with the standard drugs, ciprofloxacin and fluconazole. Structure–activity relationship studies revealed that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus had a significant impact on the in vitro antimicrobial and anti‐viral activity of these classes of agents.

Bioconjugation of polymers: a novel platform for targeted drug delivery.

Bioconjugation, a novel technique is usually exploited to improve the biopharmaceutical aspects of a bioactive as well as afford its spatial and temporal distribution. The strategy enlightens newer vistas for delivery of drugs, peptides, enzymes, and oligonucleotides. Site specific delivery may be obtained by tailoring the conjugates as an inactive prodrug and designing polymer drug linkages susceptible to cleavage by specific enzymes or pH. These prodrugs substantially change the mechanisms of cellular entry, pharmacokinetic disposition and ultimately target the drug. The conjugate vehicles are being exploited for targeting pharmacological agents to visceral tissues viz brain, colon etc. These biomaterials are bringing into play, novel drug delivery systems for selectively and specifically ferrying drugs to the desired organ. Noteworthy contributions reported with bioconjugated nanoparticles for biosensing and bioimaging incorporate cell staining, DNA detection, separation and recombination relevance in DNA protection. Only recently, these tailor-made polymers have also gained impetuous for enzyme therapy, gene therapy, insulin therapy, cancer therapy and management of AIDS with the interception of minimal side effects. The present review exhaustively provides an insight to the polymer bioconjugates and their implications for targeted delivery. The article also discusses the therapeutic aspects of these conjugates and that these may serve as fascinating tools for drug delivery.

Metabotropic Glutamate Receptors: A Review on Prospectives and Therapeutic Aspects

The metabotropic glutamate (mGluRs) receptors are a distinct class of G-protein-coupled receptors that act through activation of phospholipase C and/or inhibition of adenylate cyclase. They encompass seven-transmembrane domain proteins, comprehensively expressed in neuronal and glial cells within the brain, spinal cord and periphery and are involved in controlling pathophysiology of a number of diseases. These receptors may be sorted into three groups based on similarity of amino acid sequence, pharmacology and the transducer pathways they couple. The agonists and antagonists act at the N-terminal glutamate binding site and present a pharmacological strategy to modulate pathogenesis. A number of these compounds are positive or negative allosteric modulators that bind within the receptor transmembrane heptahelical domains. This imparts improved subtype selectivity, improved bioavailability and better drug like properties (e.g. CNS penetration). The mGluRs are presently the focal point of sizeable attention because of their potential as drug targets for the treatment of neurological and psychiatric disorders of the brain including Schizophrenia, Alzheimers disease, Parkinsons disease, addiction, anxiety, depression, epilepsy and pain. The present review focuses on signal transduction mechanisms implicated to control and functionally upregulate the glutamatergic transmission system. The article also hallmarks agonists and antagonists for mGluRs as pivotal agents to ameliorate an array of neurological and psychiatric disorders.