Sanjay Batra

An expedited synthesis of 2‐sulfonamido‐substituted 4 H ‐chromene derivatives via reaction between para ‐quinone methides and ynamides in the presence of triflic acid at room temperature is described. Most of the synthesized compounds displayed potent antiplasmodial activity against both the chloroquine‐sensitive and ‐resistant strains of Plasmodium falciparum with a good selectivity index.

Visceral leishmaniasis is a life-threatening neglected tropical disease that predominantly affects the liver and spleen. The widespread emergence of drug resistance, along with the continued absence of an effective vaccine, underscores the urgent need to explore novel chemical scaffolds with potent antileishmanial activity. In this context, we report the discovery of a new series of imidazo-fused β-carbolines synthesized via the Groebke-Blackburn-Bienaymé reaction of substituted 3-amino-β-carboline with aldehyde and isonitrile, which exhibited significant antileishmanial activity against Leishmania donovani in both in vitro and in vivo models. Among the synthesized compounds, 11ab and 11ad emerged as the most potent, displaying IC₅₀ values of 0.662 μM and 0.652 μM, respectively, against the amastigote stage, along with favorable safety indices. In the in vivo evaluation, both compounds achieved greater than 80% parasite suppression in the L. donovani-infected golden hamster model. Mechanistic investigations revealed that compound 11ad exerts its antileishmanial activity through the inhibition of histone deacetylase (Silent Information Regulator 2) activity. Furthermore, 11ad induces elevated intracellular levels of reactive oxygen species, leading to oxidative stress that triggers mitochondrial membrane depolarization and cytochrome-c release. These events ultimately result in phosphatidylserine-like membrane alteration and lead to apoptosis-like cell death. Compound 11ad also activates a host immune response by inducing Th1 cytokines and nitric oxide, which are crucial for killing the parasite. Thus, it was apparent that the compound potentially kills the parasite directly as well as by activating the host immune response.

Opioids are widely used for the management of chronic pain; however, their analgesic effects are primarily mediated through activation of the μ-opioid receptor (MOR), which is associated with serious adverse effects. It has been postulated that κ-opioid receptor (KOR) agonists biased toward G-protein signaling may provide effective analgesia while minimizing these side effects. Fused β-carbolines have recently emerged as promising biased KOR agonists with demonstrated antinociceptive potential. Herein, we report a modular synthetic strategy employing a Ugi multicomponent reaction between β-carboline-based aldehydes, aliphatic isonitriles, primary amines, and haloacetic acids to generate a new library of fused β-carboline derivatives. Biological evaluation of these compounds revealed that several members of the series exhibited potent and selective G-protein-biased KOR agonist activity. Notably, a clear positive correlation was observed between antinociceptive efficacy and the degree of G-protein bias. In contrast, compounds displaying reduced G-protein bias and a higher propensity for β-arrestin recruitment induced pronounced sedative effects and impaired neuromuscular coordination. Integrated analysis of G-protein bias, antinociceptive activity, and locomotor effects demonstrated that fused β-carbolines, compared with the unbiased KOR agonist U50488, achieved greater functional separation between therapeutic analgesia and motor-suppressant side effects.

Opioids are widely used for the management of chronic pain; however, their analgesic effects are primarily mediated through activation of the μ-opioid receptor (MOR), which is associated with serious adverse effects. It has been postulated that κ-opioid receptor (KOR) agonists biased toward G-protein signaling may provide effective analgesia while minimizing these side effects. Fused β-carbolines have recently emerged as promising biased KOR agonists with demonstrated antinociceptive potential. Herein, we report a modular synthetic strategy employing a Ugi multicomponent reaction between β-carboline-based aldehydes, aliphatic isonitriles, primary amines, and haloacetic acids to generate a new library of fused β-carboline derivatives. Biological evaluation of these compounds revealed that several members of the series exhibited potent and selective G-protein-biased KOR agonist activity. Notably, a clear positive correlation was observed between antinociceptive efficacy and the degree of G-protein bias. In contrast, compounds displaying reduced G-protein bias and a higher propensity for β-arrestin recruitment induced pronounced sedative effects and impaired neuromuscular coordination. Integrated analysis of G-protein bias, antinociceptive activity, and locomotor effects demonstrated that fused β-carbolines, compared with the unbiased KOR agonist U50488, achieved greater functional separation between therapeutic analgesia and motor-suppressant side effects.

The synthesis and bioevaluation of a new series of substituted 2,11-dihydroimidazo[1’,5’:1,2]pyrido-[3.4-b]indoles as antiplasmodial and antiproliferative agents are described. Several compounds (16aaf, 16abf, 16acf, 16adq, 16aeo, and 16afe ) exhibited significant...

Postmenopausal osteoporosis (PMO) is characterized by an imbalance in bone remodeling with increased osteoclast and decreased osteoblast activity, leading to bone loss and higher fracture risk. Current treatments, such as teriparatide, boost bone formation but also elevate resorption, limiting their long-term effectiveness. We discovered 3-butyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5cc), an orally active phosphodiesterase-1 (PDE1) inhibitor aimed at restoring this balance. 5cc enhances osteoblast differentiation assessed by increased alkaline phosphatase activity, Runx2 expression, and mineralized nodule formation. Additionally, it inhibited osteoclastogenesis by suppressing the RANKL/OPG ratio, modulating Eph-Ephrin signaling, and attenuating IL-1β-induced ROS and NF-κB activation in vitro. In ovariectomized mice, 5cc administration (5 mg/kg) improved the trabecular microarchitecture, bone mineral density, and strength, at levels comparable to teriparatide, while significantly reducing bone resorption markers. With 13.57% oral bioavailability and selectivity for PDE1A1 (32% inhibition at 500 nM), 5cc offers an innovative therapeutic candidate for PMO with a dual anabolic-antiresorptive profile and oral efficacy, warranting further clinical development.

The drastic increase in the emergence of methicillin and vancomycin resistant S. aureus has resulted in almost negligible treatment options available to tackle these drug‐resistant strains and therefore, search for newer antibiotics is essential. In this context, a new series of quaternized fused β‐carbolines was synthesized and evaluated for its anti‐bacterial potential. Several compounds from the series displayed potent anti‐bacterial activity against Gram‐positive bacteria including the drug‐resistant strains with minimal cytotoxicity and promising bactericidal action.

A Lewis acid-mediated modular synthesis of 3-substituted quinolines bearing electron-withdrawing groups from readily available 2-aminobenzyl alcohols and N , N ′-dimethylenamine(one)s is described.

Herein, we report the regioselective one‐pot synthesis of 1,4,5‐trisubstituted pyrazoles by reacting Morita‐Baylis‐Hillman (MBH) acetates derived from aryl aldehydes with alkyl or aryl hydrazines in the presence of iodine under aerobic conditions. The reaction proceeds through sequential S_N2′ nucleophilic substitution of substituted hydrazine onto the MBH acetate, I₂‐catalyzed oxidation of the allylic hydrazine to allylic hydrazone, heating‐induced intramolecular aza‐Michael reaction and cyclization, and oxidative aromatization. The key intermediate, thes‐transallyl hydrazones were isolated in good yields by performing the reactions at room temperature. However, the allyl hydrazones prepared from the MBH acetates of aliphatic aldehydes did not furnish the pyrazole owing to the absence of an activated methylene group in the substrate. The synthetic applications of the pyrazoles in Ugi reactions, decarboxylative halogenation, Pd‐catalyzed benzoylation of the N‐aryl ring, and metal‐free tetrazole synthesis has been demonstrated.