jayan joseph | University of Mysore (original) (raw)

Papers by jayan joseph

Research paper thumbnail of 3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential

Journal of Medicinal Chemistry, Mar 5, 2012

A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from ... more A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h).

Research paper thumbnail of Radical chemistry of glucosamine naphthalene acetic acid and naphthalene acetic acid: a pulse radiolysis study

Journal of Physical Organic Chemistry, 2014

ABSTRACT Free radical-induced oxidation reactions of glucosamine naphthalene acetic acid (GNaa) a... more ABSTRACT Free radical-induced oxidation reactions of glucosamine naphthalene acetic acid (GNaa) and naphthalene acetic acid (Naa) have been studied using pulse radiolysis. GNaa was synthesized by covalently attaching Naa on glucosamine. Hydroxyl adduct (from the reaction of hydroxyl radicals (●OH) at the naphthalene ring) was identified as themajor transient intermediate (suggesting that the ●OHreaction is on the naphthalene ring) and is characterized by its absorption maxima of 340 and 400 nm. Both GNaa and Naa undergo similar reaction pattern. The bimolecular rate constants determined for the reactions are 4.8 × 109 and 8.9 × 109dm3mol�1 s�1 forGNaa andNaa respectively. Themechanismof reactionof ●OHwithGNaawas further confirmed using steady-state method. Radical cation of GNaa was detected as an intermediate during the reaction of sulfate radical (SO4●�) withGNaa (k2=4.52×109dm3mol�1 s�1). This radical cation transforms to a ●OH adduct at higher pH. The radical cation of GNaa is comparatively long lived, and a cyclic transition state by neighboring group participation accounts for its stability. The oxy radical anion (O●�) reacts with GNaa (k2=1.12×109dm3mol�1 s�1) mainly by one-electron transfer mechanism. The reduction potential values of Naa and GNaa were determined using cyclic voltammetric technique, and these are 1.39V versus NHE for Naa and 1.60V versus NHE for GNaa.

Research paper thumbnail of Structure–Activity-Relationship Studies around the 2-Amino Group and Pyridine Core of Antimalarial 3,5-Diarylaminopyridines Lead to a Novel Series of Pyrazine Analogues with Oral in Vivo Activity

Journal of Medicinal Chemistry, 2013

Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identific... more Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of P. falciparum in the nanomolar IC 50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the P.berghei mouse model this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC 50 values of 8.4 and 10 nM against K1 and NF54 strains, respectively. When evaluated in P. berghei-infected mice compound 4 was completely curative at an oral dose of 4×10 mg/kg. Gregg for assistance in running the in vitro ADME studies.

Research paper thumbnail of 3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential

Journal of Medicinal Chemistry, 2012

A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from ... more A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h).

Research paper thumbnail of Structure–Activity Relationship Studies of Orally Active Antimalarial 3,5-Substituted 2-Aminopyridines

Journal of Medicinal Chemistry, 2012

In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner ... more In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.

Research paper thumbnail of ChemInform Abstract: Aryl/Heteroaryl Pentafluorobenzenesulfonates (ArOPFBs): New Electrophilic Coupling Partners for Room Temperature Suzuki-Miyaura Cross-Coupling Reactions

Research paper thumbnail of Aryl/heteroaryl pentafluorobenzenesulfonates (ArOPFBs): new electrophilic coupling partners for room temperature Suzuki–Miyaura cross-coupling reactions

Tetrahedron Letters, 2015

The first cross-coupling reaction between aryl/heteroaryl pentafluorobenzenesulfonates and aryl/h... more The first cross-coupling reaction between aryl/heteroaryl pentafluorobenzenesulfonates and aryl/heteroaryl boronic acids under mild conditions is described. The successful synthesis of highly ortho substituted biaryls and high chemoselectivity of these bench stable intermediates over tosylates, triflates, mesylates, and chlorides increases its scope as a valuable cross-coupling partner. The generality of this protocol was further extended to other boron containing nucleophiles (boronates, trifluoroborates) and alkyl boronic acids.

Research paper thumbnail of 3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential

Journal of Medicinal Chemistry, Mar 5, 2012

A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from ... more A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h).

Research paper thumbnail of Radical chemistry of glucosamine naphthalene acetic acid and naphthalene acetic acid: a pulse radiolysis study

Journal of Physical Organic Chemistry, 2014

ABSTRACT Free radical-induced oxidation reactions of glucosamine naphthalene acetic acid (GNaa) a... more ABSTRACT Free radical-induced oxidation reactions of glucosamine naphthalene acetic acid (GNaa) and naphthalene acetic acid (Naa) have been studied using pulse radiolysis. GNaa was synthesized by covalently attaching Naa on glucosamine. Hydroxyl adduct (from the reaction of hydroxyl radicals (●OH) at the naphthalene ring) was identified as themajor transient intermediate (suggesting that the ●OHreaction is on the naphthalene ring) and is characterized by its absorption maxima of 340 and 400 nm. Both GNaa and Naa undergo similar reaction pattern. The bimolecular rate constants determined for the reactions are 4.8 × 109 and 8.9 × 109dm3mol�1 s�1 forGNaa andNaa respectively. Themechanismof reactionof ●OHwithGNaawas further confirmed using steady-state method. Radical cation of GNaa was detected as an intermediate during the reaction of sulfate radical (SO4●�) withGNaa (k2=4.52×109dm3mol�1 s�1). This radical cation transforms to a ●OH adduct at higher pH. The radical cation of GNaa is comparatively long lived, and a cyclic transition state by neighboring group participation accounts for its stability. The oxy radical anion (O●�) reacts with GNaa (k2=1.12×109dm3mol�1 s�1) mainly by one-electron transfer mechanism. The reduction potential values of Naa and GNaa were determined using cyclic voltammetric technique, and these are 1.39V versus NHE for Naa and 1.60V versus NHE for GNaa.

Research paper thumbnail of Structure–Activity-Relationship Studies around the 2-Amino Group and Pyridine Core of Antimalarial 3,5-Diarylaminopyridines Lead to a Novel Series of Pyrazine Analogues with Oral in Vivo Activity

Journal of Medicinal Chemistry, 2013

Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identific... more Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of P. falciparum in the nanomolar IC 50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the P.berghei mouse model this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC 50 values of 8.4 and 10 nM against K1 and NF54 strains, respectively. When evaluated in P. berghei-infected mice compound 4 was completely curative at an oral dose of 4×10 mg/kg. Gregg for assistance in running the in vitro ADME studies.

Research paper thumbnail of 3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential

Journal of Medicinal Chemistry, 2012

A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from ... more A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h).

Research paper thumbnail of Structure–Activity Relationship Studies of Orally Active Antimalarial 3,5-Substituted 2-Aminopyridines

Journal of Medicinal Chemistry, 2012

In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner ... more In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.

Research paper thumbnail of ChemInform Abstract: Aryl/Heteroaryl Pentafluorobenzenesulfonates (ArOPFBs): New Electrophilic Coupling Partners for Room Temperature Suzuki-Miyaura Cross-Coupling Reactions

Research paper thumbnail of Aryl/heteroaryl pentafluorobenzenesulfonates (ArOPFBs): new electrophilic coupling partners for room temperature Suzuki–Miyaura cross-coupling reactions

Tetrahedron Letters, 2015

The first cross-coupling reaction between aryl/heteroaryl pentafluorobenzenesulfonates and aryl/h... more The first cross-coupling reaction between aryl/heteroaryl pentafluorobenzenesulfonates and aryl/heteroaryl boronic acids under mild conditions is described. The successful synthesis of highly ortho substituted biaryls and high chemoselectivity of these bench stable intermediates over tosylates, triflates, mesylates, and chlorides increases its scope as a valuable cross-coupling partner. The generality of this protocol was further extended to other boron containing nucleophiles (boronates, trifluoroborates) and alkyl boronic acids.