Vikas Yadav - Academia.edu (original) (raw)

Papers by Vikas Yadav

Research paper thumbnail of Synthesis, Biological Activity and Molecular Modeling of 6-Benzylthioinosine Analogues as Subversive Substrates of Toxoplasma g ondii Adenosine Kinase

Journal of Medicinal Chemistry, 2004

Syntheses and biological activities of imidazo-, pyrimido-and diazepino[2,1-f]purinediones contai... more Syntheses and biological activities of imidazo-, pyrimido-and diazepino[2,1-f]purinediones containing N-alkyl substituents (with straight, branched or unsaturated chains) are described. Tricyclic derivatives were synthesized by the cyclization of 8-bromo-substituted 7-(2-bromoethyl)-, 7-(3chloropropyl)-or 7-(4-bromobutyl)-theophylline with primary amines under various conditions. Compound 22 with an ethenyl substituent was synthesized by dehydrohalogenation of 9-(2-bromoethyl)-1,3-dimethyltetrahydropyrimido[2,1-f] purinedione. The obtained derivatives (5-35) were initially evaluated for their affinity at rat A 1 and A 2A adenosine receptors (AR), showing moderate affinity for both adenosine receptor subtypes. The best ligands were diazepinopurinedione 28 (K i =0.28 μM) with fivefold A 2A selectivity and the nonselective A 1 /A 2A AR ligand pyrimidopurinedione 35 (K i A 1 = 0.28 μM and K i A 2A =0.30 μM). The compounds were also evaluated for their affinity at human A 1 , A 2A , A 2B and A 3 ARs. All of the obtained compounds were docked to the A 2A AR Xray structure in complex with the xanthine-based, potent adenosine receptor antagonist-XAC. The likely interactions of imidazo-, pyrimido-and diazepino[2,1-f]purinediones with the residues forming the A 2A binding pocket were discussed. Furthermore, the new compounds were tested in vivo as anticonvulsants in maximal electroshock, subcutaneous pentylenetetrazole (ScMet) and TOX tests in mice (i.p.). Pyrimidopurinediones showed anticonvulsant activity mainly in the ScMet test. The best derivative was compound 11, showing 100 % protection at a dose of 100 mg/kg without symptoms of neurotoxicity. Compounds 6, 7, 8 and 14 with short substituents showed neurotoxicity and caused death. In rat tests (p.o.), 9 was characterized by a high protection index (>13.3). AR affinity did not apparently correlate with the antiepileptic potency of the compounds.

Research paper thumbnail of 6-Benzylthioinosine analogues: Promising anti-toxoplasmic agents as inhibitors of the mammalian nucleoside transporter ENT1 ( es

Biochemical Pharmacology, 2005

b i o c h e m i c a l p h a r m a c o l o g y 7 1 ( 2 0 0 5 ) 6 9 -7 3 (M.H. el Kouni). a v a i l... more b i o c h e m i c a l p h a r m a c o l o g y 7 1 ( 2 0 0 5 ) 6 9 -7 3 (M.H. el Kouni). a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b i o c h e m p h a r m 0006-2952/$ -see front matter #

Research paper thumbnail of 6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: Activities and selective toxicities

Biochemical Pharmacology, 2005

Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in th... more Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Certain 6-substituted purine nucleosides act as subversive substrates of T. gondii, but not the human, adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not their host. Herein, we report the testing of newly synthesized 6-benzylthioinosine analogues with various substituents on the phenyl ring of their benzyl group as subversive substrates of T. gondii adenosine kinases. The binding affinity of these compounds to T. gondii adenosine kinase and their efficacy as antitoxoplasmic agents varied depending on the nature and position of the various substituents on the phenyl ring of their benzyl group. p-Cyano-6-benzylthioinosine and 2,4-dichloro-6-benzylthioinosine were the best ligands. In general, analogues with substitution at the para position of the phenyl ring were better ligands than those with the same substitutions at the meta or ortho position. The better binding of the para-substituted analogues is attributed to the combined effect of hydrophobic as well as van der Waals interactions. The 6-benzylthioinosine analogues were devoid of host-toxicity but all showed selective anti-toxoplasmic effect in cell culture and animal models. These results further confirm that toxoplasma adenosine kinase is an excellent target for chemotherapy and that 6-substituted purine nucleosides are potential selective antitoxoplasmic agents # Abbreviations: FBS, fetal bovine serum; HPMC, hydroxypropylmethylcellulose; MTT, microculture tetrazolium test; PBS, phosphate buffered saline * Corresponding author. Tel.: +1 205 934 1132; fax: +1 205 934 8240.

Research paper thumbnail of Sebacinaceae: Culturable Mycorrhiza-Like Endosymbiotic Fungi and Their Interaction with Non-Transformed and Transformed Roots

The term mycorrhiza refers to the association between fungi and roots of higher plants. This asso... more The term mycorrhiza refers to the association between fungi and roots of higher plants. This association is usually considered a mutualistic symbio-sis because of the highly beneficial relationships established between both partners, in which the host plants receive mineral nutrients via ...

Research paper thumbnail of Synthesis, Biological Activity and Molecular Modeling of 6-Benzylthioinosine Analogues as Subversive Substrates of Toxoplasma g ondii Adenosine Kinase

Journal of Medicinal Chemistry, 2004

Syntheses and biological activities of imidazo-, pyrimido-and diazepino[2,1-f]purinediones contai... more Syntheses and biological activities of imidazo-, pyrimido-and diazepino[2,1-f]purinediones containing N-alkyl substituents (with straight, branched or unsaturated chains) are described. Tricyclic derivatives were synthesized by the cyclization of 8-bromo-substituted 7-(2-bromoethyl)-, 7-(3chloropropyl)-or 7-(4-bromobutyl)-theophylline with primary amines under various conditions. Compound 22 with an ethenyl substituent was synthesized by dehydrohalogenation of 9-(2-bromoethyl)-1,3-dimethyltetrahydropyrimido[2,1-f] purinedione. The obtained derivatives (5-35) were initially evaluated for their affinity at rat A 1 and A 2A adenosine receptors (AR), showing moderate affinity for both adenosine receptor subtypes. The best ligands were diazepinopurinedione 28 (K i =0.28 μM) with fivefold A 2A selectivity and the nonselective A 1 /A 2A AR ligand pyrimidopurinedione 35 (K i A 1 = 0.28 μM and K i A 2A =0.30 μM). The compounds were also evaluated for their affinity at human A 1 , A 2A , A 2B and A 3 ARs. All of the obtained compounds were docked to the A 2A AR Xray structure in complex with the xanthine-based, potent adenosine receptor antagonist-XAC. The likely interactions of imidazo-, pyrimido-and diazepino[2,1-f]purinediones with the residues forming the A 2A binding pocket were discussed. Furthermore, the new compounds were tested in vivo as anticonvulsants in maximal electroshock, subcutaneous pentylenetetrazole (ScMet) and TOX tests in mice (i.p.). Pyrimidopurinediones showed anticonvulsant activity mainly in the ScMet test. The best derivative was compound 11, showing 100 % protection at a dose of 100 mg/kg without symptoms of neurotoxicity. Compounds 6, 7, 8 and 14 with short substituents showed neurotoxicity and caused death. In rat tests (p.o.), 9 was characterized by a high protection index (>13.3). AR affinity did not apparently correlate with the antiepileptic potency of the compounds.

Research paper thumbnail of 6-Benzylthioinosine analogues: Promising anti-toxoplasmic agents as inhibitors of the mammalian nucleoside transporter ENT1 ( es

Biochemical Pharmacology, 2005

b i o c h e m i c a l p h a r m a c o l o g y 7 1 ( 2 0 0 5 ) 6 9 -7 3 (M.H. el Kouni). a v a i l... more b i o c h e m i c a l p h a r m a c o l o g y 7 1 ( 2 0 0 5 ) 6 9 -7 3 (M.H. el Kouni). a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b i o c h e m p h a r m 0006-2952/$ -see front matter #

Research paper thumbnail of 6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: Activities and selective toxicities

Biochemical Pharmacology, 2005

Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in th... more Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Certain 6-substituted purine nucleosides act as subversive substrates of T. gondii, but not the human, adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not their host. Herein, we report the testing of newly synthesized 6-benzylthioinosine analogues with various substituents on the phenyl ring of their benzyl group as subversive substrates of T. gondii adenosine kinases. The binding affinity of these compounds to T. gondii adenosine kinase and their efficacy as antitoxoplasmic agents varied depending on the nature and position of the various substituents on the phenyl ring of their benzyl group. p-Cyano-6-benzylthioinosine and 2,4-dichloro-6-benzylthioinosine were the best ligands. In general, analogues with substitution at the para position of the phenyl ring were better ligands than those with the same substitutions at the meta or ortho position. The better binding of the para-substituted analogues is attributed to the combined effect of hydrophobic as well as van der Waals interactions. The 6-benzylthioinosine analogues were devoid of host-toxicity but all showed selective anti-toxoplasmic effect in cell culture and animal models. These results further confirm that toxoplasma adenosine kinase is an excellent target for chemotherapy and that 6-substituted purine nucleosides are potential selective antitoxoplasmic agents # Abbreviations: FBS, fetal bovine serum; HPMC, hydroxypropylmethylcellulose; MTT, microculture tetrazolium test; PBS, phosphate buffered saline * Corresponding author. Tel.: +1 205 934 1132; fax: +1 205 934 8240.

Research paper thumbnail of Sebacinaceae: Culturable Mycorrhiza-Like Endosymbiotic Fungi and Their Interaction with Non-Transformed and Transformed Roots

The term mycorrhiza refers to the association between fungi and roots of higher plants. This asso... more The term mycorrhiza refers to the association between fungi and roots of higher plants. This association is usually considered a mutualistic symbio-sis because of the highly beneficial relationships established between both partners, in which the host plants receive mineral nutrients via ...