Swapnil Sharma

Pharmacophore based virtual screening, molecular docking and biological evaluation to identify novel PDE5 inhibitors with vasodilatory activity

Prompted by the role of PDE5 and its closely associated cAMP and cGMP in hypertension, we have attempted to discover novel PDE5 inhibitors through ligand based virtual screening. Rigorously validated model comprising of one HBA, one HY and one RA was used as a query to search the NCI database leading to retrieval of many compounds which were screened on the basis of estimated activity, fit value and Lipinskis violation. Selected compounds were subjected to docking studies which resulted into visualization of potential interaction capabilities of NCI compounds in line to pharmacophoric features. Finally three compounds were subjected to in vitro evaluation using the isolated rat aortic model. The results showed that all three compounds are potent and novel PDE5 inhibitors with vasodilatory activity range from 10(-2) to 10(-5) M.

In silico and in vitro screening to identify structurally diverse non-azole CYP51 inhibitors as potent antifungal agent

The problem of resistance to azole class of antifungals is a serious cause of concern to the medical fraternity and thus there is an urgent need to identify non-azole scaffolds with high affinity for lanosterol 14α-demethylase (CYP51). In view of this we have attempted to identify novel non-azole CYP51 inhibitors through the application of pharmacophore based virtual screening and in vitro evaluation. A rigorously validated pharmacophore model comprising of 2 hydrogen bond acceptor and 2 hydrophobic features has been developed and used to mine NCI database. Out of 265 retrieved hits, NSC 1215 and 1520 have been chosen on the basis of Lipinskis rule of five, fit and estimated values. Both the hits were docked into the active site of CYP51. In view of high fit value and CDocker score, NSC 1215 and 1520 have been subjected to in vitro microbiological assay. The result reveals that NSC 1215 and 1520 are active against Candida albicans, Candida parapsilosis, Candida tropicalis, and Aspergillus niger. In addition to this the absorption characteristics of both the hits have also been determined using the rat sac technique and permeation in order of NSC 1520>NSC 1215 has been observed.

Discovery of a selective, safe and novel anti-malarial compound with activity against chloroquine resistant strain of Plasmodium falciparum.

In recent years the DNA minor groove has attracted much attention for the development of anti-malarial agents. In view of this we have attempted to discover novel DNA minor groove binders through in-silico and in-vitro workflow. A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database. This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski’s violation. Finally two compounds NSC639017 and NSC371488 were evaluated for their in-vitro anti-malarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains by SYBR green-I based fluorescence assay. The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation.

Synthetic and Biological Aspects of Thiadiazoles and their Condensed Derivatives: An Overview

The three heteroatoms containing five membered heterocycles such as thiadiazoles have been extensively studied due to their important pharmacological activities. The thiadiazole nucleus is an important class of compounds for new drug development. The chemical and biological behavior and synthesis of thiadiazole derivatives have gained much importance in last few decades. This review article provides up to date information about exploration of new methods, developments, synthetic strategies, and their diverse pharmaceutical activities.

Synthesis and Antimicrobial Evaluation of Some Novel Trisubstituted s-Triazine Derivatives Based on Isatinimino, Sulphonamido, and Azacarbazole

A study directed towards exploring the temperature-dependent reactivity of the chlorine atoms of 2,4,6-trichloro-s-triazine (TCT) in the nucleophilic displacement reaction, allowed a facile replacement of its chlorine atoms in succession with (i) N-amino methyl substituted isatin-3-hydrazones, (ii) N1-substituted-4-amino benzene sulphonamides, and (iii) 8-amino-4-oxo-N-benzyl-azacarbazole to produce the corresponding 2,4,6-trisubstituted-s-triazine, namely; 2-(N-amino methyl substituted isatin-3-hydrazinyl)-4-(N1-substituted-4′-amino benzenesulfonamidyl)-6-(8′-amino-4′-oxo-N-benzylazacarbazolyl)-1,3,5-triazine derivatives in acceptable yields. The compounds prepared were further evaluated for their antibacterial activity against E. coli and B. subtilis and antifungal activities against A. niger and A. flavus, and some of them showed promising activity profile.

Lipid-polymer hybrid nanoparticles: Development & statistical optimization of norfloxacin for topical drug delivery system

Poly lactic acid is a biodegradable, biocompatible, and non-toxic polymer, widely used in many pharmaceutical preparations such as controlled release formulations, parenteral preparations, surgical treatment applications, and tissue engineering. In this study, we prepared lipid-polymer hybrid nanoparticles for topical and site targeting delivery of Norfloxacin by emulsification solvent evaporation method (ESE). The design of experiment (DOE) was done by using software to optimize the result, and then a surface plot was generated to compare with the practical results. The surface morphology, particle size, zeta potential and composition of the lipid-polymer hybrid nanoparticles were characterized by SEM, TEM, AFM, and FTIR. The thermal behavior of the lipid-polymer hybrid nanoparticles was characterized by DSC and TGA. The prepared lipid-polymer hybrid nanoparticles of Norfloxacin exhibited an average particle size from 178.6 ± 3.7 nm to 220.8 ± 2.3 nm, and showed very narrow distribution with polydispersity index ranging from 0.206 ± 0.36 to 0.383 ± 0.66. The surface charge on the lipid-polymer hybrid nanoparticles were confirmed by zeta potential, showed the value from +23.4 ± 1.5 mV to +41.5 ± 3.4 mV. An Antimicrobial study was done against Staphylococcus aureus and Pseudomonas aeruginosa, and the lipid-polymer hybrid nanoparticles showed potential activity against these two. Lipid-polymer hybrid nanoparticles of Norfloxacin showed the %cumulative drug release of 89.72% in 24 h. A stability study of the optimized formulation showed the suitable condition for the storage of lipid-polymer hybrid nanoparticles was at 4 ± 2 °C/60 ± 5% RH. These results illustrated high potential of lipid-polymer hybrid nanoparticles Norfloxacin for usage as a topical antibiotic drug carriers.

Effect of In Vitro Transcorneal Approach of Aceclofenac Eye Drops through Excised Goat, Sheep, and Buffalo Corneas

The current study involves the evaluation of factors that influence the transcorneal permeation of aqueous drops of aceclofenac ophthalmic formulation through freshly excised goat, sheep, and buffalo corneas. Aceclofenac formulation with different concentrations 0.1–0.5% (w/v) and with different pH and different preservatives, was taken into account. The amount of drug permeated from different formulations was estimated using an Franz diffusion cell. A linear increase in drug permeation was observed with increase in pH (5.5 to 7.4). The apparent permeability coefficient was found to be maximum 15.01 ± 0.45 on goat cornea and maximum transport of aceclofenac was observed at physiological pH of tears (i.e., 7). The results advocate that aceclofenac 0.5% (w/v) ophthalmic solution (pH 7.0) containing BAK (0.01%) provides maximum in vitro ocular permeability through goat, sheep, and buffalo corneas.

Synthesis and evaluation of some novel precursors of oxazolidinone analogues of chloroquinoline for their antimicrobial and cytotoxic potential

AbstractSome 3-(3-(7-chloroquinolin-4-ylamino)propyl-2-imino-5-(4-chloro/nitro/methoxy benzylidene) oxazolidin-4-one 4(a–c) and 4-(3-(7-chloroquinolin-4-ylamino) propyl)-2(4-chloro/nitro/methoxy benzylidene)-1,6-diox-4,9 diazaspiro[4,4]nonane-3,8-dione 5(a–c) derivatives were synthesized using appropriate synthetic route. The newly prepared compounds 5a–c demonstrated inhibitory effects on the growth of a MCF7 (hormone-dependant breast carcinoma cell line), HT29 (colon carcinoma cell line on leukemia). The MCF7 cell line was found to be very susceptible towards compound 5a with IC50 values of 16 μg/ml. Similarly, the HT29 cell line was found to be moderately susceptible towards compounds 5a and 5c with IC 50 values of 32 and 49 μg/ml, respectively. Graphical AbstractA series of novel spiro oxazolidinone 5(a-c) was synthesized in multistep reactions. Newly synthesized compounds were characterized and screened for their in-vitro cytotoxic potential against MCF7 and HT29 cell lines.

Identification of novel antifungal lead compounds through pharmacophore modeling, virtual screening, molecular docking, antimicrobial evaluation, and gastrointestinal permeation studies

Identification of novel antifungal lead compounds through pharmacophore modeling, virtual screening, molecular docking, antimicrobial evaluation, and gastrointestinal permeation studies Aarti Singh, Sarvesh Paliwal*, Mukta Sharma, Anupama Mittal, Swapnil Sharma, Neetika Tripathi and Amita Tilak Department of Pharmacy, Banasthali University, Banasthali, Rajasthan 304022, India; Department of Pharmacy, GSVM Medical College, Swaroop Nagar, Kanpur, Uttar Pradesh 208002, India

Gastroprotective activity of reconstituted red fruit pulp concentrate of Citrullus lanatus in rats

Aim: This study was carried out to evaluate the gastroprotective potential of the aqueous fruit pulp concentrate of Citrullus lanatus citroides (CLC) on pyloric ligation and indomethacin-induced ulcer in Wistar albino rats. Materials and methods: In indomethacin-induced ulcer model, CLC was administered in the doses of 250 mg/kg, 500 mg/kg and 1000 mg/kg body weight orally, tds for 5 days. The antiulcer activity was determined via observing reduction in ulcer index whereas in the pyloric ligation model, the gastroprotective effect of CLC was assessed from the alteration in volume of gastric juice, pH, free and total acidity, protein concentration in gastric juice. Further lipid peroxide (LPO), and activities of enzymic antioxidants such as superoxide dismutase (SOD) and catalase (CAT) was also determined along with the levels of hexose, hexosamine, sialic acid, fucose in gastric mucosa. Results: In both models, treatment with CLC caused a significant reduction in lesion index when compared to vehicle treated group, providing evidence for antiulcer capacity. In pyloric ligation model, pretreatment with CLC resulted in significant increase in pH, enzymic antioxidants, that is, SOD, CAT, with a significant decrease in volume of gastric juice, free and total acidity, protein concentration, acid output, and LPO levels respectively. The presence of the flavonoids and polyphenols may be responsible for the gastroprotective effect of CLC. Conclusions: The aqueous fruit pulp concentrate of CLC showed significant gastroprotective potential against pyloric ligation and indomethacin-induced ulceration in rats.