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A new class of potent PI3Kα inhibitors is identified based on aryl substituted morpholino-triazine scaffold. The identified compounds showed not only a high level of enzymatic and cellular potency in nanomolar range but also high oral bioavailability. The three lead molecules (based on their in vitro potency) when evaluated further for in vitro metabolic stability as well as pharmacokinetic profile led to the identification of 26, as a candidate for further development. The IC50 and EC50 value of 26 is 60 and 500 nM, respectively, for PI3Kα enzyme inhibitory activity and ovarian cancer (A2780) cell line. The identified lead also showed a high level of microsomal stability and minimal inhibition activity for CYP3A4, CYP2C19, and CYP2D6 at 10 μM concentrations. The lead compound 26, demonstrated excellent oral bioavailability with an AUC of 5.2 μM at a dose of 3 mpk in mice and found to be well tolerated in mice when dosed at 30 mpk BID for 5 days.

Tuberculosis (TB) is a global health concern, and this situation has further worsened due to the emergence of drug-resistant strains and the failure of BCG vaccine to impart protection. There is an imperative need to develop highly sensitive, specific diagnostic tools, novel therapeutics, and vaccines for the eradication of TB. In the present study, a chemical screen of a pharmacologically active compound library was performed to identify antimycobacterial compounds. The phenotypic screen identified a few novel small-molecule inhibitors, including NU-6027, a known CDK-2 inhibitor. We demonstrate that NU-6027 inhibits Mycobacterium bovis BCG growth in vitro and also displayed cross-reactivity with Mycobacterium tuberculosis protein kinase D (PknD) and protein kinase G (PknG). Comparative structural and sequence analysis along with docking simulation suggest that the unique binding site stereochemistry of PknG and PknD accommodates NU-6027 more favorably than other M. tuberculosis Ser/Thr protein kinases. Further, we also show that NU-6027 treatment induces the expression of proapoptotic genes in macrophages. Finally, we demonstrate that NU-6027 inhibits M. tuberculosis growth in both macrophage and mouse tissues. Taken together, these results indicate that NU-6027 can be optimized further for the development of antimycobacterial agents.

The efficacy of drugs widely varies in individuals, and the gut microbiota plays an important role in this variability. The commensal microbiota living in the human gut encodes several enzymes that chemically modify systemic and orally administered drugs, and such modifications can lead to activation, inactivation, toxification, altered stability, poor bioavailability, and rapid excretion. Our knowledge of the role of the human gut microbiome in therapeutic outcomes continues to evolve. Recent studies suggest the existence of complex interactions between microbial functions and therapeutic drugs across the human body. Therapeutic drugs or xenobiotics can influence the composition of the gut microbiome and the microbial encoded functions. Both these deviations can alter the chemical transformations of the drugs and hence treatment outcomes. In this review, we provide an overview of (i) the genetic ecology of microbially encoded functions linked with xenobiotic degradation; (ii) the effect of drugs on the composition and function of the gut microbiome; and (iii) the importance of the gut microbiota in drug metabolism.

Abstract-Protonated chiral prolinamide organocatalysts have been shown to catalyze an enantioselective direct aldol process in water to provide the aldol product in high yield and good enantioselectivity. The two diastereomeric catalysts (S,R)-4b and (S,S)-4c show different reactivity. Ó 2005 Elsevier Ltd. All rights reserved.Organocatalysis is the acceleration of chemical reactions with a substoichiometric amount of an organic compound, which does not contain a metal atom.1 There are very few reports of organocatalyzed synthesis in aqueous media.2 Aqueous media predominate in biological systems and it must have been the solvent used by ÔNatureÕ in prebiotic formation of simple to complex molecules.3 A fundamental and interesting area of research is how homochirality originated in biomolecules in water during molecular evolution. 4 So in order to develop enzyme mimics 5 and in an attempt to understand the mechanism of the chemistry of life, catalysts having catalytic properties in water need to be developed.We have been interested in developing an organocatalyzed enantioselective aldol reaction in water 6 involving pyrrolidine-based chiral molecules. In order to achieve this objective, it is important to minimize the involvement of general base catalysis by the pyrrolidine and to enhance nucleophilic catalysis through the formation of an iminium ion. Spencer and co-workers have observed that iminium ion catalysis becomes more effective as the base strength of the amine catalysts is decreased.7 Also, it has been reported that Brönsted acids enhance the catalytic ability of pyrrolidine-based organocatalysts. 8 We envisaged that such a chiral catalyst, when protonated and dissolved in water, would exist in equilibrium with the free chiral amine (Eq. 1). This would lower the effective base strength of the catalyst thus favouring iminium ion catalysis, as observed by Spencer.So we prepared protonated chiral prolinamides to check our hypothesis. To our surprise, we found these molecules act as effective organocatalysts for direct cross aldol reaction of acetone with p-nitrobenzaldehyde in water. In this communication, we illustrate this concept through enantioselective catalysis using phenethylamine prolinamide hydrobromide salt.Initial investigations on the aldol reaction of acetone 1 and p-nitrobenzaldehyde 2 in water using catalyst 4a (20 mol %) provided aldol adduct 3 in 92% yield and 33% ee (Table 1, entry 1).9 Using proline as the catalyst, under similar conditions gave racemic 3 in 78% yield. 10Encouraged by this result, we prepared enantiomerically pure (S,R)-4b and (S,S)-4c and performed the aldol reaction using them as catalysts in water and obtained 3 in 45% and 39% ee, respectively (Table 1, entries 2 and 9). The variations in the amount of water suggest that a lower concentration of water slightly improves the enantioselectivity (entries 2, 3 and 4). Lower catalyst loading does not have any effect on the enantioselectivity but it results in a longer reaction time. Performing the reaction at a lower temp...