ABSTRACT
BACKGROUND: Chronic 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. METHODS: A 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. RESULTS: All 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 12(th) day by 9a and 20(th) day by 5b, 5c, 9e and 9f. The remaining compounds also exhibited normal glycemic levels by 25(th) day. CONCLUSION: The results from molecular modeling, in vitro and in vivo studies are suggesting them as safer and effective therapeutic agents against type2 diabetes. Graphical Abstract Development of PTPs inhibitors.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Phosphorus Compounds/pharmacology , Protein Tyrosine Phosphatases/antagonists & inhibitors , Animals , Antioxidants/pharmacology , Biomarkers/blood , Blood Glucose/drug effects , Blood Glucose/metabolism , Blood-Brain Barrier/metabolism , Caco-2 Cells , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Type 2/blood , Disease Models, Animal , Dogs , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/metabolism , Intestinal Absorption , Madin Darby Canine Kidney Cells , Male , Molecular Docking Simulation , Molecular Structure , Permeability , Phosphorus Compounds/chemical synthesis , Phosphorus Compounds/metabolism , Protein Binding , Protein Tyrosine Phosphatases/metabolism , Rats, Wistar , Skin Absorption , Structure-Activity Relationship , Time FactorsABSTRACT
Owing to the promising antiviral activity of amino acid ester-substituted phosphorylated nucleosides in the present study, a series of phosphorylated derivatives of emtricitabine and didanosine substituted with bioactive amino acid esters at P-atom were synthesized. Initially, molecular docking studies were screened to predict their molecular interactions with hemagglutinin-neuraminidase protein of Newcastle disease virus and E2 protein of human papillomavirus. The title compounds were screened for their antiviral ability against Newcastle disease virus (NDV) by their in ovo study in embryonated chicken eggs. Compounds 5g and 9c exposed well mode of interactions with HN protein and also exhibited potential growth of NDV inhibition. The remaining compounds exhibited better growth of NDV inhibition than their parent molecules, i.e., emtricitabine (FTC) and didanosine (ddI). In addition, the in vitro anticancer activity of all the title compounds were screenedagainst HeLa cell lines at 10 and 100 µg/mL concentrations. The compounds 5g and 9c showed an effective anticancer activity than that of the remaining title compounds with IC50 values of 40 and 60 µg/mL, respectively. The present in silico and in ovo antiviral and in vitro anticancer results of the title compounds are suggesting that the amino acid ester-substituted phosphorylated FTC and ddI derivatives, especially 5g and 9c, can be used as NDV inhibitors and anticancer agents for the control and management of viral diseases with cancerous condition.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Deoxycytidine/analogs & derivatives , Didanosine/analogs & derivatives , Animals , Binding Sites , Chick Embryo , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Didanosine/pharmacology , Drug Screening Assays, Antitumor , Emtricitabine , Esterification , HN Protein/drug effects , HeLa Cells , Humans , Microbial Sensitivity Tests , Newcastle disease virus/drug effects , Papillomaviridae/drug effects , Phosphorylation , Structure-Activity Relationship , Viral Proteins/drug effectsABSTRACT
A new class of biologically active 13-membered phosphorus-macroheterocycles (6a-l) were conveniently synthesized from 1,2-bis(salicylidene amino)-phenylene (1), by treating with phosporusoxychloride (3) and followed by reacting with various aromatic thiols and amines (5f-l) in one path, and in another path 1 was directly treated with various phosphorodichloridates (2a-e) in the presence of triethylamine at 0-10°C under N(2) atmosphere in THF. All the title compounds were confirmed by analytical and spectral data (IR, (1) H-, (13) C-, (31) P-NMR, and mass spectra) and screened for anti-oxidant activity. Among these compounds, 6k, 6e, and 6l containing nitro, fluoro, and chloro groups as substituents on the phenyl ring exhibited high anti-oxidant activity with effective inhibitory concentration (IC(50) ) values.
