Shrinivas D. Joshi

Controlled release of therapeutics using interpenetrating polymeric networks

Introduction: The ever-increasing developments in pharmaceutical formulations have led to the widespread use of biodegradable polymers in various forms and configurations. In particular, interpenetrating network (IPN) and semi-IPN polymer structures that are capable of releasing drugs in a controlled manner have gained much wider importance in recent years. Areas covered: Recently, IPNs and semi-IPNs have emerged as innovative materials of choice in controlled release (CR) of drugs as the release from these systems depends on pH of the media and temperature in addition to the nature of the system. These networks can be prepared as smart hydrogels following chemical or physical crosslinking methods to show remarkable drug release patterns compared to single polymer systems. Expert opinion: A large number of IPNs and semi-IPNs have been reported in the literature. The present review is focused on the preparation methods and their CR properties with reference to anticancer, anti-asthmatic, antibiotic, anti-inflammatory, anti-tuberculosis and antihypertensive drugs, as majority of these drugs have been reported to be the ideal choices for using IPNs and semi-IPNs.

Synthesis, characterization, biological activity, and 3D-QSAR studies on some novel class of pyrrole derivatives as antitubercular agents

A new series of pyrrole derivatives have been designed, synthesized, and their structures have been elucidated along with the evaluation of antitubercular activity against Mycobacterium tuberculosis H37Rv using the microplate alamar blue assay method and antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, and Escherichia coli by broth micro-dilution assay method. Structural activity relationships and 3D-QSAR analysis have been carried out by Topomer Comparative Molecular Field Analysis (CoMFA). Training set of 42 and test set of 8 active compounds were used to develop the method that showed cross-validated correlation coefficient (q2) of 0.815, standard error of prediction of 0.36, non-cross-validated correlation coefficient (r2) of 0.973, and standard error of estimate of 0.14 with six components.Graphical AbstractSynthesis; spectral and 3D-QSAR studies; and antibacterial, antitubercular, and cytotoxic activities of a novel series of pyrrole derivatives are described.

A click chemistry approach for the synthesis of mono and bis aryloxy linked coumarinyl triazoles as anti-tubercular agents.

A series of mono and bis-triazole coumarin hybrids 6a-u and 9a-f respectively have been synthesized using 4-(azidomethyl)-2H-chromen-2-ones 5a-i and aryl propargyl ethers 2a-c/8 employing Click chemistry modified protocol for Azide-Alkyne cycloadditions(CuAAC). Anti-tubercular screening showed moderate activity for mono aryloxy compounds 6a-u with MIC 50-100 μg/mL, whereas the bis compounds 9a-f were more effective with MICs between 0.2 and 12.5 μg/mL. Molecular modeling and 3D-QSAR measurements using CoMFA and Topomer CoMFA further supported the observed results. The bis compound 9b showed excellent activity with MIC value as low as 0.2 μg/mL.

Synthesis, antimycobacterial screening and ligand-based molecular docking studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties

We report here the synthesis, antibacterial and antitubercular evaluation of 61 novel pyrrolyl derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties. Molecular docking was carried out on enoyl ACP reductase from Mycobacterium tuberculsosis using Surflex-Dock, which is one of the key enzymes involved in type II fatty acid biosynthetic pathway of Mycobacterium tuberculosis, an attractive target for designing novel antitubercular agents. Docking analysis of the crystal structure of ENR performed using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of substituted pyrrolyl derivatives into hydrophobic pocket of InhA enzyme. Compounds 9b and 9d exhibited the highest antitubercular activity almost close to isoniazid (0.4 μg/mL) with a MIC value of 0.8 μg/mL. All other compounds showed the good activity with a MIC value of 6.25-100 μg/mL. The compounds were further tested for mammalian cell toxicity using human lung cancer cell-line (A549) and were nontoxic. Some compounds exhibited inhibition activities against InhA.

Multi-spectroscopic investigation of the binding interaction of fosfomycin with bovine serum albumin☆

The interaction between fosfomycin (FOS) and bovine serum albumin (BSA) has been investigated effectively by multi-spectroscopic techniques under physiological pH 7.4. FOS quenched the intrinsic fluorescence of BSA via static quenching. The number of binding sites n and observed binding constant KA were measured by the fluorescence quenching method. The thermodynamic parameters ΔG0, ΔH0 and ΔS0 were calculated at different temperatures according to the van’t Hoff equation. The site of binding of FOS in the protein was proposed to be Sudlow’s site I based on displacement experiments using site markers viz. warfarin, ibuprofen and digitoxin. The distance r between the donor (BSA) and acceptor (FOS) molecules was obtained according to the Förster theory. The effect of FOS on the conformation of BSA was analyzed using synchronous fluorescence spectra (SFS), circular dichroism (CD) and 3D fluorescence spectra. A molecular modeling study further confirmed the binding mode obtained by the experimental studies.

Two- and three-dimensional QSAR studies on a set of antimycobacterial pyrroles: CoMFA, Topomer CoMFA, and HQSAR

AbstractDesigning compounds having good anti-tubercular activity is gaining much importance in the area of tuberculosis research due to the reemergence of antibiotic resistance strains. In this study, quantitative structure activity relationship (QSAR) of a group of 55 anti-tubercular agents with varying structures and potencies, CoMFA, Topomer CoMFA, and HQSAR studies have been performed on a series of antimycobacterial pyrroles. A training set containing 46 compounds served to establish the model and CoMFA was assessed by r2 value of 0.852 and cross-validated the q2 value of 0.614. In the Topomer CoMFA, r2 was 0.805, whole cross-validated q2 was 0.535. The predictive ability of CoMFA and Topomer CoMFA models was determined using a test set of 9 compounds, which gave the predictive correlation coefficients (rpred2) of 0.623 and 0.458, respectively. HQSAR was also carried out as a complementary study, and the best HQSAR model was generated using atoms, bond, connectivity, and hydrogen atoms as fragment distinction, 7–10 as fragment size and three components showing the cross-validated q2 value of 0.710 and conventional r2 value of 0.795. CoMFA, Topomer CoMFA steric, electrostatic, and HQSAR atomic contribution maps were generated to analyze the structural features of the datasets on that govern their inhibitory potency.Graphical Abstract3D and 2D-QSAR studies (CoMFA, Topomer CoMFA, HQSAR) of antimycobacterial pyrroles are described.

Guar gum as platform for the oral controlled release of therapeutics

Introduction: The past decade of research has witnessed a huge advancement in research efforts on guar gum (GG)-based polymers as controlled release (CR) formulations for the delivery of therapeutics. Areas covered: The unique structure and beneficial properties of GG makes it an attractive biomaterial in CR applications. Current status on GG-based polymers has been addressed as a CR formulation in the form of microspheres, nanoparticles, hydrogels and matrix tablets for the delivery of various types of therapeutics having a wide range of physicochemical properties. Majority of literature on GG as a platform technology has dealt with oral route of drug administration as it is the most convenient, patient-compliant and preferred approach. Recent reports on GG-based polymers are summarized and critically discussed to narrate their usefulness as oral delivery systems. Expert opinion: The research on GG-based formulations has been focused on optimization of the therapy by designing CR dosage forms with a minimum number of excipients. In this context, GG-based polymers are quite attractive. The present review summarizes published reports on these systems and offers expert opinion relevant to oral delivery of therapeutics.

Design, synthesis, molecular docking and 3D-QSAR studies of potent inhibitors of enoyl-acyl carrier protein reductase as potential antimycobacterial agents.

In order to develop a lead antimycobacterium tuberculosis compound, a series of 52, novel pyrrole hydrazine derivatives have been synthesized and screened which target the essential enoyl-ACP reductase. The binding mode of the compounds at the active site of enoyl-ACP reductase was explored using surflex-docking method. The binding model suggests one or two hydrogen bonding interactions between pyrrole hydrazones and InhA enzyme. Highly active compound 5r (MIC 0.2 μg/mL) showed hydrogen bonding interactions with Tyr158 and NAD(+) in the same manner as those of ligands PT70 and triclosan. The CoMFA and CoMSIA models generated with database alignment were the best in terms of overall statistics. The predictive ability of the CoMFA and CoMSIA models was determined using a test set of 13 compounds, which gave predictive correlation coefficients (r(pred)(2)) of 0.896 and 0.930, respectively.

Enoyl ACP reductase as effective target for the synthesized novel antitubercular drugs: a-state-of-the-art.

The emergence of drug resistant strains of important human pathogens has created an urgent necessity to find new targets and novel antitubercular agents. According to the literature survey, we noticed that enoyl ACP reductase is one of the most promising targets. This enzyme is the most important catalyst for the FAS II synthesis of mycolic acid, which is the most essential component of the mycobacterial cell wall. This review summarizes the progress made in the design of enoyl ACP reductase inhibitors and the role played by 3D-structure of the enzyme in drug design process.

Synthesis and evaluation of antibacterial and antitubercular activities of some novel imidazo[2,1-b][1,3,4]thiadiazole derivatives

A series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazoles were synthesized, structures of the compounds were elucidated and evaluated for antitubercular activity against Mycobacterium tuberculosis H37Rv using microplate alamar blue assay (MABA) method, antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Vibrio cholera, and Escherichia coli by broth micro dilution assay method. Some compounds exhibited significant antibacterial and antitubercular activities. Compounds 10, 14, and 15 emerged as the most active molecules, showed significant antimicrobial activity and may serve as leads for further optimization.Graphical AbstractSynthesis, spectral studies, and antibacterial and antitubercular activities of a novel series of imidazo[2,1-b][1,3,4]thiadiazole derivatives are described.