Varun Bhardwaj

Pyrrole: a resourceful small molecule in key medicinal hetero-aromatics

Pyrrole is widely known as a biologically active scaffold which possesses a diverse nature of activities. The combination of different pharmacophores in a pyrrole ring system has led to the formation of more active compounds. Pyrrole containing analogs are considered as a potential source of biologically active compounds that contains a significant set of advantageous properties and can be found in many natural products. The marketed drugs containing a pyrrole ring system are known to have many biological properties such as antipsychotic, β-adrenergic antagonist, anxiolytic, anticancer (leukemia, lymphoma and myelofibrosis etc.), antibacterial, antifungal, antiprotozoal, antimalarial and many more. Due to the diversity of these analogs in the therapeutic response profile, many researchers have been working to explore this skeleton to its maximum potential against several diseases or disorders. In this review, attempts have been made to disclose various tactical approaches to synthesize pyrrole and pyrrole containing analogs. The structure–activity relationship studies have been discussed along with their therapeutic applications which have been reported during last decade. Some molecules as the main components of the market and clinical trials have also been discussed.

Synthesis and in vitro antitumor activity of substituted quinazoline and quinoxaline derivatives: Search for anticancer agent

The synthesis of some 2-furano-4(3H)-quinazolinones, diamides (open ring quinazolines), quinoxalines and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Among the synthesize compounds, seventeen compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the selected compounds, 3-(2-chloro benzylideneamine)-2-(furan-2-yl) quinazoline-4(3h)-one 21 was found to be the most active candidate of the series at five dose level screening against Ovarian OVCAR-4 and Non-small cell lung cancer NCI-H522 with GI50 1.82 & 2.14 μM respectively. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for quinazoline, diamides and quinoxaline derivatives.

Tea: A native source of antimicrobial agents

Abstract Tea (Camellia sinensis) is one of the most popular nonalcoholic beverages, consumed by over two-thirds of the worlds population because of its refreshing, mild stimulant and medicinal properties. It is processed in different ways in different parts of the world to give green, black, oolong, and pu-erh tea. Among all tea polyphenols, epigallocatechin-3-gallate has been responsible for much of the health promoting abilities of tea including anti-inflammatory, antimicrobial, antitumour, anti-oxidative, protection from cardiovascular disease, anti-obesity, and anti-aging properties. In the present review, the antibacterial, antiviral, and antifungal activities of different types of tea and their polyphenols are reported, highlighting their mechanisms of action and structure–activity relationship. Moreover, considering that the changing patterns of infectious diseases and the emergence of microbial strains resistant to current antibiotics, there is an urgent need to find out new potent antimicrobial agents as adjuvants to antibiotic therapy. The synergistic effect of tea polyphenols in combination with conventional antimicrobial agents against clinical multidrug-resistant microorganisms has also been discussed in this review.

Design and synthesis of novel 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles as selective COX-2 inhibitors with potent anti-inflammatory activity

A novel series of 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles were designed and synthesized for selective COX-2 inhibition with potent anti-inflammatory activity. Among the compounds tested, 9g (2-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazole) was found to be the most potent inhibitor of COX-2 with IC50 of 0.31 μM showing promising degree of anti-inflammatory activity in the carrageenan-induced rat paw edema model with ED50 of 74.3 mg/kg. The lead compound 9g further showed suppression of acetic acid-induced writhes comparable to that of aspirin and gastro-sparing profile superior to the aspirin. Molecular docking analysis displayed higher binding affinity of ligands towards COX-2 than COX-1.

Quantitative structure-activity relationship (QSAR) studies as strategic approach in drug discovery

Drug design is a process which is driven by technological breakthroughs implying advanced experimental and computational methods. Nowadays, the techniques or the drug design methods are of paramount importance for prediction of biological profile, identification of hits, generation of leads, and moreover to accelerate the optimization of leads into drug candidates. Quantitative structure–activity relationship (QSAR) has served as a valuable predictive tool in the design of pharmaceuticals and agrochemicals. From decades to recent research, QSAR methods have been applied in the development of relationship between properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. Classical QSAR studies include ligands with their binding sites, inhibition constants, rate constants, and other biological end points, in addition molecular to properties such as lipophilicity, polarizability, electronic, and steric properties or with certain structural features. 3D-QSAR has emerged as a natural extension to the classical Hansch and Free–Wilson approaches, which exploit the three-dimensional properties of the ligands to predict their biological activities using robust chemometric techniques such as PLS, G/PLS, and ANN. This paper provides an overview of 1-6 dimension-based developed QSAR methods and their approaches. In particular, we present various dimensional QSAR approaches, such as comparative molecular field analysis (CoMFA), comparative molecular similarity analysis, Topomer CoMFA, self-organizing molecular field analysis, comparative molecule/pseudo receptor interaction analysis, comparative molecular active site analysis, and FLUFF-BALL, 4D-QSAR, and G-QSAR approaches.

A comparative QSAR analysis of quinazoline analogues as tyrosine kinase (erbB-2) inhibitors.

In this paper, an attempt was made to develop a Quantitative Structure Activity Relationship (QSAR) model on a series of quinazoline derivatives acting as Protein tyrosine kinases (erbB-2) inhibitors using Multiple Linear Regression, Principal Component Regression and Partial Least Squares Regression methods. Among these three methods, Multiple Linear Regression (MLR) method has come out with a very promising result as compared to other two methods. Various 2D descriptors were calculated and used in the present analysis. For model validation, the dataset was divided into training and test sets using spherical exclusion method. The developed MLR- QSAR model was found to be statistically significant with respect to training (r2 =0.956), cross-validation (q2 = 0.915), and external validation (pred_r2= 0.6170). The developed MLR model suggests that Estate Contribution descriptors SaaOE-Index (30.07%) and SsCIE-index (15.79%) are the most important descriptors in predicting Tyrosine kinase (erbB-2) inhibitory activity. Electron withdrawing group at 4th position of quinazoline enhances the activity as evident by positive value of SsClE-index (15.79). In addition, for quinazoline substituents, estate contribution descriptors SsCH3E -index has a large deactivating effect.

Drug–surfactant interaction: thermo-acoustic investigation of sodium dodecyl sulfate and antimicrobial drug (levofloxacin) for potential pharmaceutical application

In the present study, the advantages of surfactant micelles as drug delivery vehicles are taken into consideration, and the impact of the potential antimicrobial drug (levofloxacin) on the micellar system of anionic surfactant (SDS) has been studied. It would therefore be interesting to evaluate the region of micelle formation in order to design a system that could prove valuable in pharmaceutical formulations. In this context, conductance study, critical micelle concentration (CMC), and standard thermodynamic parameters of micellization, namely, ΔHom, ΔGom and ΔSom, have been evaluated at four different temperatures (298.15 to 313.15) K. Molar volume and compressibility measurements have also been carried out to evaluate the apparent molar volume and apparent molar adiabatic compression of drug–surfactant complex and discussed in terms of the solute–solute and solute–solvent interactions. In addition, spectroscopic analysis (FTIR and 1H-NMR) confirmed the presence of intermolecular interaction between levofloxacin–SDS moiety within the studied concentration. In conclusion, this study provides an indication to assess and develop surfactant immobilized levofloxacin for better biological activity.

Small hybrid heteroaromatics: resourceful biological tools in cancer research

Nowadays, hybrid drugs containing two or more covalently linked known potential pharmacophores are designed to simultaneously modulate multiple targets of multifactorial diseases to overcome the side effects associated with a single drug. In this review, an overview of the design strategies employed by various scientists over the past 20 years has been presented. The overview includes the synthesis of different chemical structure-based anticancer hybrids using molecular hybridization techniques. To tackle one of the worlds most devastating diseases such as cancer, researchers have exploited the molecular hybridization (MH) technique to synthesize different anticancer hybrids, which include hybrids based on azole, camptothecin, chalcone, pyrrolobenzodiazepine (PBD), coumarin, colchicine, platinum, and some miscellaneous structures. The selection of two or more moieties for generating the hybrid drug is generally aided by the observed (or anticipated) synergistic or additive pharmacological activities of each single moiety. This eventually leads to the identification of novel and better active chemical entities with a superior profile as compared to the parent moieties. In addition to the design strategies, this review also highlights the structure–activity relationship (SAR), mechanism of action, and key features of the synthesized anticancer hybrids.

Intermolecular interactions of CTAB and potential oxidation inhibitors: physico-chemical controlled approach for food/pharmaceutical function

We report the impact of lipophilic oxidation inhibitors i.e. butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on cationic surfactant, cetyltrimethylammonium bromide (CTAB) properties in short chain alcohols and their hydroalcoholic solutions. Considering the extensive employment of BHA and BHT in human products, controlled physicochemical approaches were taken into consideration. Principally, density (ρ), ultrasonic sound velocity (u) and viscosity (η) measurements were carried out at specific temperatures T = (298.15, 303.15 and 308.15) K. The physico-chemical parameters apparent molar volume (Vϕ) and apparent molar adiabatic compression (Kϕ,S) were calculated and revealed the existence of hydrophobic interactions whereas, viscosity measurements depicted the region of micellization. Additionally, 1H NMR spectroscopic study was employed to interpret the intermolecular interaction of antioxidants within the micellar structure. 1H NMR analysis suggested the intermolecular interaction especially in the hydrophilic head and interface region of the surfactant with regard to shifting obtained within spectrum.

A novel surfactant aided micellar system of oxidation inhibitors in clotrimazole bioadhesive gel: development, characterization, in vitro and in vivo antifungal evaluation against Candida clinical isolates

Clotrimazole (CLZ) is a widely used antifungal agent with poor aqueous solubility, which requires the development of new delivery systems to improve its therapeutic activity. However, butylatedhydroxy anisole (BHA) and butylatedhydroxy toluene (BHT) have been known as potential antioxidants with antimicrobial properties. In an attempt to develop a better formulation with an antifungal profile, a surfactant aided antioxidant micellar system was dispersed within a clotrimazole gel formulation. Initially, the gel library was prepared and subjected to in vitro evaluation. Based on in vitro release and kinetic profiles, the best three formulations were selected for further analysis. Moreover, in vitro antifungal activity (MIC) and fractional inhibitory concentration index (FICI) against different drug resistant and susceptible Candida isolates were carried out and directed to the best among the 27 formulations. The optimized best selected formulation was thereafter evaluated via morphology studies and in vivo antifungal evaluation. Morphology studies depicted the distribution of micellar structures within the polymeric gel network as well as the contact activity mechanism against Candida albicans. The physicochemical characterization showed that average micellar size was lower than ∼160 nm, low polydispersity index, negative zeta potential and gel pH 6.9. After 60 days, no significant change was observed within the formulation. Photostability studies revealed that antioxidants eminently inhibit the drug degradation under UV radiation with improved drug stability. In addition, in vivo antifungal activity was investigated on experimentally induced cutaneous infection in immunosuppressed Sprague Dawley (SD) rats. The in vivo study confirmed the maximum therapeutic efficacy, as the lowest number of cfu ml−1 was recorded. Conclusively, this study provide a good skin targeting effect and may be promising for stable and effective topical delivery of CLZ offering a maintained localized effect.