Naga Raju Chamarthi

A heterogeneous catalyst, SiO2-ZnBr2: An efficient neat access for α-aminophosphonates and antimicrobial activity evaluation

AbstractAn efficient, environmentally benign and green method was developed for the synthesis of α-aminophosphonates by one-pot three-component reaction (Kabachnik-Fields reaction) of amine (4-(4-chlorophenoxy)aniline), aldehydes and diethyl phosphite using catalyst, SiO2-ZnBr 2 under solvent-free conditions. The developed method under conventional conditions was further optimized in microwave and ultrasonication methods. A series of α-aminophosphonates, diethyl (4-(4-chlorophenoxy)phenylamino)(aryl/ heteroaryl)methylphosphonates was synthesized to check the generality. The catalyst, SiO2-ZnBr2 afforded good yields of products in all the methods in the range of 85–97% but variation was observed in reaction time. Microwave irradiation method took very less time (4–8 min) as compared with ultrasonication (35–52 min) and conventional (2–3 h) conditions. The major advantages are simple and mild conditions, short reaction times, high yield of the product with purity, use of cheap catalyst and reusability of the catalyst until to three times without significant loss of activity. Antibacterial and antifungal activities were evaluated for the title compounds (50 and 100 μg/mL) including minimum inhibitory concentrations. A few of the newly synthesized α-aminophosphonates exhibited promising antimicrobial activity at lower MIC values in the range of 15.0–25.0 μg/mL and closer to the standards (5–12 μg/mL). Graphical AbstractAn efficient, neat and green method was developed for α-aminophosphonates by Kabachnik-Fields reaction using catalyst, SiO2-ZnBr2. The developed method under conventional conditions was further optimized in microwave and ultrasonication methods. SiO2-ZnBr2 catalyst afforded good yields of the products (85-97%). Molecules were evaluated for antimicrobial activity including their MIC.

Molecular designing and in silico evaluation of darunavir derivatives as anticancer agents.

Darunavir is a synthetic nonpeptidic protease inhibitor which has been tested for anticancer properties. To deduce and enhance the anticancer activity of the Darunavir, we have modified its reactive moiety in an effective way. We designed 9 analogues in ChemBioOffice 2010 and minimized using the LigPrep tool of Schrödinger 2011. These analogues can obstruct the activity of other signalling pathways which are implicated in many tumors. Results of the QikProp showed that all the analogues lied in the specified range of all the pharmacokinetic (ADMET) properties required to become the successful drug. Docking study was performed to test its anticancer activity against the biomarkers of the five main types of cancers i.e. bone, brain, breast, colon and skin cancer. Grid was generated for each oncoproteins by specifying the active site amino acids. The binding model of best scoring analogue with each protein was assessed from their G-scores and disclosed by docking analysis using the XP visualizer tool. An analysis of the receptor-ligand interaction studies revealed that these nine Darunavir analogues are active against all cancer biomarkers and have the features to prove themselves as anticancer drugs, further to be synthesized and tested against the cell lines.

Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents.

BackgroundChronic and oral administration of benzylamine improves glucose tolerance. Picolylamine is a selective functional antagonist of the human adenosine A2B receptor. Phosphonic diamide derivatives enhance the cellular permeability and in turn their biological activities.MethodsA series of heteroaryl phosphonicdiamide derivatives were designed as therapeutics to control and manage type2 diabetes. Initially defined Lipinski parameters encouraged them as safer drugs. Molecular docking of these compounds against Protein tyrosine phosphatase (PTP), the potential therapeutic target of type 2 diabetes, revealed their potential binding ability explaining their anti-diabetic activity in terms of PTP inhibition. Human intestinal absorption, Caco-2 cell permeability, MDCK cell permeability, BBB penetration, skin permeability and plasma protein binding abilities of the title compounds were calculated by PreADMET server. A convenient method has been developed for the synthesis of title compounds through the formation of 1-ethoxy-N,N’-bis(4-fluorobenzyl/pyridin-3-ylmethyl)phosphinediamine by the reaction of 4-fluorobenzylamine/ 3-picolylamine with ethyldichlorophosphite, subsequently reacted with heteroaryl halides using lanthanum(III) chloride as a catalyst.ResultsAll the compounds exhibited significant in vitro anti-oxidant activity and in vivo evaluation in streptozotocin induced diabetic rat models revealed that the normal glycemic levels were observed on 12th day by 9a and 20th day by 5b, 5c, 9e and 9f. The remaining compounds also exhibited normal glycemic levels by 25th day.ConclusionThe results from molecular modeling, in vitro and in vivo studies are suggesting them as safer and effective therapeutic agents against type2 diabetes.Graphical AbstractDevelopment of PTPs inhibitors.

Design, synthesis, in silico and in vitro studies of novel 4-methylthiazole-5-carboxylic acid derivatives as potent anti-cancer agents

Since inhibitors of mucin onco proteins are potential targets for breast cancer therapy, a series of novel 4-methylthiazole-5-carboxylic acid (1) derivatives 3a-k were synthesized by the reaction of 1 with SOCl2 followed by different bases/alcohols in the presence of triethylamine. Once synthesized and characterized, their binding modes with MUC1 were studied by molecular docking analysis using Aruglab 4.0.1 and QSAR properties were determined using HyperChem. All synthesized compounds were screened for in vitro anti-breast cancer activity against MDA-MB-231 breast adenocarcinoma cell lines by Trypan-blue cell viability assay and MTT methods. Compounds 1, 3b, 3d, 3e, 3i and 3f showed good anti-breast cancer activity. Since 1 and 3d exhibited high potent activity against MDA-MB-231 cell lines, they show could be effective mucin onco protein inhibitors.

An efficient one-pot three-component synthesis of pyrimido[4,5- d ]pyrimidine derivatives in aqueous medium

A fast, efficient, and green synthesis of pyrimido[4,5-d]pyrimidine derivatives has been achieved via one-pot three-component reaction starting from 6-amino-N,N-dimethyluracil, phenylisothiocyanate or phenylisocyanate, and aromatic aldehydes in the presence of polyethylene glycol-bound sulfonic acid as a catalyst in water as solvent.

LaCl3.7H2O: An efficient catalyst for the synthesis of phosphinates (Michaelis-Arbuzov reaction) under neat conditions and their potential antimicrobial activity

AbstractAn expeditious neat procedure was developed for the synthesis of a series of new methyl phenyl heterocyclic phosphinates (3a–l) through Michaelis–Arbuzov reaction by the reaction of various heterocyclic halides (Cl or Br) (1a–l) with dimethyl phenylphosphonite (2) under N2 atmosphere using a heterogeneous catalyst, LaCl3.7H2O. The advantages of the developed procedure are good yields (80–89%) of the products, less reaction time (2–3 h), avoiding toxic catalysts and harmful solvents and easy work-up procedure. Further, antimicrobial activity of the synthesized compounds was evaluated at different concentrations 50, 100 and 150 μg/mL. Biological data revealed that compounds 3i, 3j and 3h, 3j exhibited potential antibacterial and antifungal activities, respectively, while the rest of the compounds showed moderate antimicrobial activity. ᅟAn expeditious neat procedure was developed for the synthesis of a series of new methyl phenyl heterocyclic phosphinates through Michaelis–Arbuzov reaction using a heterogeneous catalyst, LaCl3.7H2O.

New symmetrical acyclic and alicyclic bisurea derivatives of 4,4'-methylenebis(phenyl isocyanate): Synthesis, characterization, bioactivity and antioxidant activity evaluation and molecular docking studies

A family of bisurea derivatives of 4,4′-methylenebis(phenyl isocyanate) have been synthesized with simple, effective and efficient procedure in high yields. The new compounds showed moderate bioactivity (at 32.0 μg/μL concentration) against selected bacterial pathogens, viz., Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa; and two fungal species, Candida albicans and Cryptococcus neoformans var. grubii. Alternatively, their antioxidant activity was also evaluated by DPPH radical scavenging assay which revealed that the compounds, 10d, 10e, 10h and 10m exhibited moderate activity. However, the molecular docking studies of all the title compounds showed surprisingly higher binding energies with DNA gyrase A protein of E. coli when compared to the reference, streptomycin. Among the compounds 10e, 10f, 10g, 10k, 10l and 10m showed very good binding energies which implied that they could be promising next generation antimicrobials.