R.P. Tripathi

Synthesis and bioevaluation of glycosyl ureas as α-glucosidase inhibitors and their effect on mycobacterium

Glycosyl amino esters (2-13) on reaction with different isocyanates resulted in quantitative conversion to glycosyl ureas (14--32). Few of the selected ureas (15-20, 22-28, 30 and 32) on cyclative amidation with DBU/TBAB/4 A MS gave respective dihydropyrimidinones in fair to good yields (33-47). The compounds were screened for alpha-glucosidase inhibitory activity and two (19 and 23) of them showed strong inhibition against rat intestinal alpha-glucosidase. The compounds were also screened against Mycobacterium aurum, however, only one (19) of them exhibited marginal antitubercular activity.

Synthesis of glycosylated β-amino acids as new class of antitubercular agents

Abstract A series of glycosylated β-amino acids was prepared and evaluated against Mycobacterium tuberculosis, M. avium, M. fortuitum and M. smegmatis. The compounds were designed to mimic the enzyme d -alanine racemase and glycosyl transferase involved in the biosynthesis of essential cell wall peptidoglycan and arabinogalactan. Though most of the compounds exhibited little activity, however, one showed significant activity against all the strains in cell culture and activity was confirmed by B actec method.

Design and synthesis of 2-(2,6-dibromophenyl)-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents.

A series of 2-(2,6-dibromophenyl)-3-heteroaryl-1,3-thiazolidin-4-ones were designed, synthesized and evaluated as selective human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) enzyme inhibitors. The results of the HIV-1 RT kit and in vitro cell based assay showed that eight compounds effectively inhibited HIV-1 replication at 20-320 nM concentrations with minimal cytotoxicity in MT-4 as well as in CEM cells.

One pot efficient diversity oriented synthesis of polyfunctional styryl thiazolopyrimidines and their bio-evaluation as antimalarial and anti-HIV agents.

An efficient one pot synthesis of a series of pluripotent (E)-1-(3-methyl-5-aryl-7-styryl-5H-thiazolo[3,2-a]pyrimidin-6-yl)-3-arylprop-2-en-1-ones is reported. It involves reaction of 5-acetyl-6-methyl-4-aryl-dihydropyrimidine-2-thiones, propargyl bromide and aromatic aldehydes in presence of ethanolic KOH. The newly synthesized compounds were evaluated for antimalarial activity against Plasmodium falciparum and as HIV-RT inhibitors. Most of the compound displayed potent antimalarial activity with IC(50)<2 μg/mL. Compounds 6, 11 and 20 showed better activity against P. falciparum K1 strains in comparison to standard drug chloroquine. Compounds 6, 11, and 16 exhibited 73.44, 66.92, and 70.81% HIV-RT inhibition at 100 μg/mL.

Lead optimization at C-2 and N-3 positions of thiazolidin-4-ones as HIV-1 non-nucleoside reverse transcriptase inhibitors.

Based on rational drug design approach, a series of novel thiazolidin-4-ones bearing different aryl/heteroaryl moieties at position C-2 and N-3 are synthesized and evaluated as potent inhibitors for human immunodeficiency virus type-1 reverse transcriptase enzyme (HIV-1 RT). An in vitro HIV-1 RT assay showed that the compounds 4, 5, 6, 8, 12, 13, 14 and 17 have shown high inhibition of reverse transcriptase (75.41, 95.50, 98.07, 91.24, 85.27, 77.59, 84.11 & 76.49% inhibition) enzyme activity. Further, cell based assay showed that compounds 4, 5, 8 &12 are identified as the best compounds of the series (EC(50) ranged from 0.09 to 0.8 μg/ml and 0.12 to 1.06 μg/ml) against HIV-1 III(B) and HIV-1 ADA5 strains, respectively. Moreover, the compounds which were active against HIV-1 III(B) and HIV-1 ADA5 were also found to be active against primary isolates (EC(50) ranged from 0.10 to 1.55 μg/ml against HIV-1 UG070 and 0.07 to 1.1 μg/ml against HIV-1 VB59), respectively. Structure-activity relationship (SAR) studies demonstrated the importance of the lipophilic bulky substituent pattern on compact heteroaryl ring at N-3, replacement of C4 at C-2 phenyl by trivalent bioisosteric nitrogen and dihalo groups at C-2 aryl/heteroaryl of thiazolidin-4-ones is crucial for anti-HIV-1 activity. Molecular modeling of compounds 4, 5, 8 and 12 in complex with HIV-1 RT demonstrate that there is good correlation of results obtained from SAR studies. Therefore the compounds 4, 5, 8 and 12 may be considered as good candidates for further optimization of anti-HIV-1 activity.

Synthesis and antifilarial evaluation of N1,Nn- xylofuranosylated diaminoalkanes.

A series of N(1),N(n)-xylofuranosylated diaminoalkanes (3-9 and 11-18) has been synthesized either by reductive amination of deoxy xylouloses (2a, 2b) with amines followed by one pot reduction with NaBH(4) or NaCNBH(3); or by 1,4-conjugate addition of amines to glycosyl olefinic esters (10a, 10b). The compounds were screened for their interference with filarial worms glutathione metabolism, a potential target for chemotherapeutic attack. Interestingly, these compounds affected intracellular glutathione, gamma-glutamyl cysteine synthetase, glutathione reductase and glutathione-S-transferase(s) of bovine filarial worms to varying degrees. Some of the compounds though effected the motility and MTT reduction potential of filarial worms Brugia malayi, however, little microfilaricidal and macrofilaricidal were noted with compounds at 50mg/kg oral dose. Compounds 6, 16 and 17 were evaluated also for in vivo activity.

2‐(2,6‐Dihalo‐phenyl)‐3‐heteroaryl‐2‐ylmethyl‐1, 3‐thiazolidin‐4‐ones: Anti‐HIV agents

A diversity of novel 2‐aryl‐3‐heteroaryl‐2‐ylmethyl‐1,3‐thiazolidin‐4‐ones were designed and synthesized by reacting heteroaryl‐2‐ylmethyl amine with various 2,6‐dihalosubstituted benzaldehydes and mercaptoacetic acid. The title compounds were evaluated for human immunodeficiency virus type‐1 (HIV‐1) reverse transcriptase (RT) inhibitory activity. The results of in vitro assays showed that some of the compounds were effective inhibitors of HIV‐1 reverse transcriptase enzyme at micromolar concentrations with less cytotoxicity in both MT‐4 cells as well as acutely infected human T‐lymphoid CEM cells. Compounds 4h and 4k emerged as moderately more potent with EC50 are at 0.20 and 0.21u2003μm as compared to reference parent compound thiazolobenzimidazoles EC50 0.35u2003μm in MT‐4 cells.

DBU-Assisted Cyclorelease Elimination: Combinatorial Synthesis and γ- Glutamyl Cysteine Synthetase and Glutathione-S-Transeferase Modulatory Effect of C-Nucleoside Analogs

A combinatorial library of 60C- nucleoside analogs was synthesized by sequential coupling of building blocks followed by cyclative cleavage with DBU in an efficient manner. Only DMSO soluble compounds were tested for their modulatory effect against filarial gamma-glutamyl cysteine synthetase (gamma-GCase) and glutathione-S-transeferases (GSTs). Several compounds were found to be weak inhibitors of filarial gamma-GCase, whereas, most of them stimulated filarial GSTs.

Dithiocarbamate-thiourea hybrids useful as vaginal microbicides also show reverse transcriptase inhibition: design, synthesis, docking and pharmacokinetic studies.

Prophylactic prevention is considered as the most promising strategy to tackle STI/HIV. Twenty-five dithiocarbamate-thiourea hybrids (14-38) were synthesized as woman controlled topical vaginal microbicides to counter Trichomonas vaginalis and sperm along with RT inhibition potential. The four promising compounds (18, 26, 28 and 33) were tested for safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. Docking study of most promising vaginal microbicide (33) revealed that it docked in a position and orientation similar to known reverse transcriptase inhibitor Nevirapine. The preliminary in vivo pharmacokinetics of compound 33 was performed in NZ-rabbits to evaluate systemic toxicity in comparison to Nonoxynol-9.

Rational design and synthesis of novel thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors.

A series of novel thiazolidin-4-one analogues, characterized by different substitution patterns at positions C-2 and N-3 of the thiazolidin-4-one scaffold for anti-HIV-1 activity has been investigated. Most of the compounds showed anti-HIV-1 activity at micromolar concentrations when tested in TZM-bl cells in vitro. Among the thirty-three compounds tested, compound 16 was the most potent inhibitor of HIV-1 replication against HIV-1IIIB, HIV-1ADA5, HIV-1UG070 and HIV-1VB59 (EC50=0.02, 0.08, 0.08 and 0.08 μM, respectively) with selectivity index (SI=6940, 1735, 1692 and 1692) against tested viral strains, respectively. The results of the present study suggested that the substitution of the nitro group at 6 position of the C-2 phenyl ring and 4,6-dimethylpyridin-2-yl at the N-3 position of thiazolidin-4-one had a major impact on the anti-HIV-1 activity and was found to lower cytotoxicity. The substitution of the heteroaryl ring with bromo group and bicyclic heteroaryl ring at N-3 thiazolidin-4-one was found to lower anti-HIV-1 activity and increase cytotoxicity. The undertaken docking studies thus facilitated the identification of crucial interactions between the HIV-1 RT enzyme and thiazolidin-4-one inhibitors, which can be used to design new potential inhibitors.