Rohini Ramesh Joshi

Desymmetrization of meso-cyclopenten-cis-1,4-diol to 4-(R)-hydroxycyclopent-2-en-1-(S)-acetate by irreversible transesterification using Chirazyme®

Abstract The parameter optimization study for the desymmetrization of meso-cyclopenten-1,4-diol 1 through irreversible transesterification using an immobilized lipase from Mucor meihei, i.e., Lipozyme®/Chirazyme® is presented. The enzyme was studied for the transesterification of 1 in various organic solvents by varying reaction parameters such as the nature of acyl donor, temperature, enzyme quantity etc., to afford optically active 4-(R)-hydroxycyclopent-2-en-1-(S)-acetate 2 of >98% enantiomeric excess in >60% yield.

A practical and scalable process for 4-(R)-hydroxycyclopent-2-en-1-(S)-acetate by desymmetrization of meso-cyclopent-2-en-1,4-diacetate catalyzed by Trichosporon beigelii (NCIM 3326), a cheap biocatalyst

Abstract Various yeast and fungal cultures from NCIM, NCL, Pune, India were screened for the hydrolysis of meso -cyclopent-2-en-1,4-diacetate 2 to 4-( R )-hydroxycyclopen-2-en-1-( S )-acetate 1 to provide a cheaper and more effective alternative to PLE which is currently being used for the conversion. Yeast cultures of Trichosporon species were identified as having a pro- R preference in the hydrolysis of 2 ; but the enantioselectivity was poor. Hence detailed medium-engineering investigations were made for the hydrolysis of 2 to 1 using a culture of Trichosporon beigelii (NCIM 3326) as catalyst. Addition of 10% v/v ethanol was found to enhance the enantioselectivity of the enzyme, affording 1 of 85% optical purity (op) in 83% yield. Further exploration of inherent consecutive kinetic resolutions to the desymmetrization afforded 1 of >98% op in 74% chemical yield.

Regioselective and diastereoselective iodocyclization reaction of alkene-thioureas: an efficient approach to bicyclic β-lactams

Bicyclic β-lactams, i.e. 3-thia-1-dethiacephams, were synthesized via a highly regioselective and diastereoselective iodocyclization reaction of alkene-thioureas with molecular iodine. Furthermore, the structure of 3-thia-1-dethiacepham was confirmed by a chemical method, the dehydrohalogenation reaction using DBU.

Targeting dormant tuberculosis bacilli: results for molecules with a novel pyrimidone scaffold.

Our inability to completely control TB has been due in part to the presence of dormant mycobacteria. This also renders drug regimens ineffective and is the prime cause of the appearance of drug‐resistant strains. In continuation of our efforts to develop novel antitubercular agents that especially target dormant mycobacteria, a set of 55 new compounds belonging to the pyrimidone class were designed on the basis of CoMFA and CoMSIA studies, and these were synthesized and subsequently tested against both the dormant and virulent BCG strain of M. tuberculosis. Some novel compounds have been identified which selectively inhibit the dormant tuberculosis bacilli with significantly low IC50 values. This study reports the second molecule after TMC‐207, having the ability to inhibit tuberculosis bacilli exclusively in its dormant phase. The synthesis was accomplished by a modified multicomponent Biginelli reaction. A classification model was generated using the binary QSAR approach – recursive partitioning (RP) to identify structural characteristics related to the activity. Physicochemical, structural, topological, connectivity indices, and E‐state key descriptors were used for generation of the decision tree. The decision tree could provide insights into structure–activity relationships that will guide the design of more potent inhibitors.

Synthesis, Biological Evaluation and Molecular Docking studies of Novel 3-aryl-5-(alkyl-thio)-1H-1,2,4-triazoles Derivatives targeting Mycobacterium tuberculosis

A small library of new 3‐aryl‐5‐(alkyl‐thio)‐1H‐1,2,4‐triazoles was synthesized and screened for the antimycobacterial potency against Mycobacterium tuberculosis H37Ra strain and Mycobacterium bovis BCG both in active and dormant stage. Among the synthesized library, 25 compounds exhibited promising anti‐TB activity in the range of IC500.03–5.88 μg/ml for dormant stage and 20 compounds in the range of 0.03–6.96 μg/ml for active stage. Their lower toxicity (>100 μg/ml) and higher selectivity (SI = >10) against all cancer cell lines screened make them interesting compounds with potential antimycobacterial effects. Furthermore, to rationalize the observed biological activity data and to establish a structural basis for inhibition of M. tuberculosis, the molecular docking study was carried out against a potential target MTB CYP121 which revealed a significant correlation between the binding score and biological activity for these compounds. Cytotoxicity and in vivo pharmacokinetic studies suggested that 1,2,4‐triazole analogues have an acceptable safety index, in vivo stability and bio‐availability.

Continuous two step flow synthesis of m-amino acetophenone

Abstract The continuous flow nitration of acetophenone followed by reduction of the meta isomer has been demonstrated using simple tubular reactors. Because of ease of separation of the desired isomer from the first step, both steps are made continuous, but separately. The continuous flow nitration was carried out in a safe manner in a shorter reaction time than the conventional approach. The choice of micromixer was seen to affect the performance of the nitration reaction. The effect of different parameters on the yield of the desired product was studied. The reduction step with sodium sulfide was found to be economical and could be carried out efficiently at 70°C using sodium sulfide in ethanol, using a silicone tube. Both steps were demonstrated for several hours, yielding a sufficiently large quantity (∼100 g) of m-aminoacetophenone at lab scale in a single day using simple tubular reactors.

Continuous flow synthesis of β-amino α, β-unsaturated esters in aqueous medium

Abstract Continuous flow synthesis of many β-amino α, β-unsaturated esters has been demonstrated, through the reaction of a β-ketoester compound with ammonia and primary amines. Several combinations have been studied in detail in batch mode and a few have been taken for continuous flow synthesis based on their suitability. Upon studying the feasibility of continuous flow synthesis of different β-amino crotonates, the synthesis of methyl amino crotonate in the presence of a recyclable and reusable homogeneous acid catalyst has been studied in detail. Tubular reactors were seen to overcome the heat and mass transfer limitations, thereby providing a simple device for even a pilot scale production. A similar approach can be used for the synthesis of other β-amino crotonates. The continuous flow synthesis approach for producing methyl amino crotonate, in the absence of any external solvent, makes it a green process technology.

Synthesis and biological evaluation of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione as antimycobacterial agents

Resistance among dormant mycobacteria leading to multidrug‐resistant and extremely drug‐resistant tuberculosis is one of the major threats. Hence, a series of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione derivatives (4a–5c) have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). The triazolethiones 4b and 4v showed high antitubercular activity (both MIC and IC50) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity toward mycobacteria than other Gram‐negative and Gram‐positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100 μg/ml against THP‐1, A549, and PANC‐1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection.