Gurunadham Munagala

Metal-Free Approach for the Synthesis of N-Aryl Sulfoximines via Aryne Intermediate

A metal-free and operationally simple N-arylation of NH-sulfoximines with aryne precursors is reported. Transition metal-free reaction conditions and shorter reaction times are the highlights of the present method. The mild optimized condition was also found to be suitable with enantiopure substrates.

Metal-free, high yielding synthesis of unsymmetrical biaryl, bi(heteroaryl), aryl vinyl, aryl alkyl sulfones via coupling of aryne with sulfinic acid salts

Here, we report a metal-free, high yielding method for the synthesis of unsymmetrical biaryl sulfones via coupling of aryne with sulfinic acid salts. The optimized condition also works efficiently for bi(heteroaryl), aryl vinyl and aryl alkyl sulfones. The present method took comparatively shorter reaction times and has good functional group compatibility.

Nitrofuranyl Methyl Piperazines as New Anti-TB Agents: Identification, Validation, Medicinal Chemistry, and PK Studies.

Whole-cell screening of 20,000 drug-like small molecules led to the identification of nitrofuranyl methylpiperazines as potent anti-TB agents. In the present study, validation followed by medicinal chemistry has been used to explore the structure-activity relationship. Ten compounds demonstrated potent MIC in the range of 0.17-0.0072 μM against H37Rv Mycobacterium tuberculosis (MTB) and were further investigated against nonreplicating and resistant (Rif(R) and MDR) strains of MTB. These compounds were also tested for cytotoxicity. Among the 10 tested compounds, five showed submicromolar to nanomolar potency against nonreplicating and resistant (Rif(R) and MDR) strains of MTB along with a good safety index. Based on their overall in vitro profiles, the solubility and pharmacokinetic properties of five potent compounds were studied, and two analogues, 14f and 16g, were found to have comparatively better solubility than others tested and acceptable pharmacokinetic properties. This study presents the rediscovery of a nitrofuranyl class of compounds with improved aqueous solubility and acceptable oral PK properties, opening a new direction for further development.

Synthesis and Biological Evaluation of Polar Functionalities Containing Nitrodihydroimidazooxazoles as Anti-TB Agents

Novel polar functionalities containing 6-nitro-2,3-dihydroimidazooxazole (NHIO) analogues were synthesized to produce a compound with enhanced solubility. Polar functionalities including sulfonyl, uridyl, and thiouridyl-bearing NHIO analogues were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H37Rv. The aqueous solubility of compounds with MIC values ≤0.5 μg/mL were tested, and six compounds showed enhanced aqueous solubility. The best six compounds were further tested against resistant (Rif(R) and MDR) and dormant strains of MTB and tested for cytotoxicity in HepG2 cell line. Based on its overall in vitro characteristics and solubility profile, compound 6d was further shown to possess high microsomal stability, solubility under all tested biological conditions (PBS, SGF and SIF), and favorable oral in vivo pharmacokinetics and in vivo efficacy.

Synthesis and biological evaluation of substituted N-alkylphenyl-3,5-dinitrobenzamide analogs as anti-TB agents

Here, a medicinal chemistry study of an N-alkylphenyl-3,5-dinitrobenzamide (DNB) scaffold as a potent anti-TB agent is presented. A series of chemical modifications were performed and forty-three new molecules were synthesized to study the structure–activity relationship (SAR) by evaluating against a sensitive strain (H37Rv) of Mycobacterium tuberculosis (MTB). Potent DNB analogs 4b, 7a, 7c, 7d, 7j, 7r and 9a were further tested against resistant strains of MTB. Their intracellular as well as bactericidal potential was also evaluated. Cytotoxicity and in vivo pharmacokinetic studies suggested that DNB analogs have an acceptable safety index, in vivo stability and bio-availability. From the present work, two compounds 7a and 7d have shown nanomolar to sub micro-molar MIC in extracellular and intracellular assays.

Development and validation of a highly sensitive LC–MS/MS-ESI method for quantification of IIIM-019—A novel nitroimidazole derivative with promising action against Tuberculosis: Application to drug development

The study aims to illustrate an analytical validation of a rapid and sensitive liquid chromatography (LC) coupled to tandem mass spectrometry (MS-MS) and electrospray ionization (ESI) method for quantification of IIIM-019 (a novel nitroimidazole derivative with potential activity against Tuberculosis) in mice plasma. The extraction of the analyte and the internal standard (Tolbutamide) from the plasma samples involves protein precipitation using acetonitrile. The chromatographic separation was accomplished using a gradient mode and the mobile phase comprised of acetonitrile and 0.1% formic acid in water. The flow rate used was 0.7 ml/min on a C18e high performance Chromolith column. IIIM-019 and Tolbutamide (IS) were analyzed by combined reversed-phase LC/MS-MS with positive ion electrospray ionization. The MS-MS ion transitions used were 533>170.1, 533>198 for IIIM-019 and 271>74, 271>155 for internal standard (IS) respectively. The method was linear over a concentration range of 0.5-1000 ng/ml and the lower limit of quantification was 0.50 ng/ml. The entire study was validated for accuracy, precision, linearity, range, selectivity, lower limit of quantification (LLOQ), recovery, and matrix effect in accordance with the FDA guidelines of method validation. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The intra and inter-day precisions were in the range of 0.51-11.18% and 0.51-7.55%. The pharmacokinetics was performed on male Balb/c mice by oral (2.5mg/kg), intraperitoneal (2.5mg/kg) and intravenous (1mg/kg) routes. The oral bioavailability of IIIM-019 was 51.6%. The method was also applied successfully in determining microsomal stability wherein the compound was found to be very slightly metabolized by rat liver microsomes.