HCl-mediated transamidation of unactivated formamides using aromatic amines in aqueous media

We report transamidation protocol to synthesize a range of secondary and tertiary amides from weakly nucleophilic aromatic and hetero-aryl amines with low reactive formamide derivatives, utilizing hydrochloric acid as catalyst. This current acid mediated strategy is beneficial because it eliminates the need for a metal catalyst, promoter or additives in the reaction, simplifies isolation and purification. Notably, this approach conventionally used to synthesize molecules on gram scales with excellent yields and a high tolerance for functional groups.</p

Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents

Series of styryl hydrazine thiazole hybrids inspired from dehydrozingerone (DZG) scaffold were designed and synthesized by molecular hybridization approach. <i>In vitro</i> antimycobacterial activity of synthesized compounds was evaluated against <i>Mycobacterium tuberculosis</i> H₃₇Rv strain. Among the series, compound <b>6o</b> exhibited significant activity (MIC = 1.5 μM; IC₅₀ = 0.48 μM) along with bactericidal (MBC = 12 μM) and intracellular antimycobacterial activities (IC₅₀ = <0.098 μM). Furthermore, <b>6o</b> displayed prominent antimycobacterial activity under hypoxic (MIC = 46 μM) and normal oxygen (MIC = 0.28 μM) conditions along with antimycobacterial efficiency against isoniazid (MIC = 3.2 μM for INH-R1; 1.5 μM for INH-R2) and rifampicin (MIC = 2.2 μM for RIF-R1; 6.3 μM for RIF-R2) resistant strains of Mtb. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for biological activity, suggesting the importance of molecular hybridization approach for the development of newer DZG clubbed hydrazine thiazole hybrids as potential antimycobacterial agents

Conglomeratin: a new antibacterial flavonol derivative from <i>Macaranga conglomerata</i> Brenan (Euphorbiaceae)

A new prenylated kaempferol, conglomeratin (1), alongside 7 known compounds including flavonoids (2 and 3), ellagic acid derivatives (4 and 5), triterpenoids (6 and 7), and a coumarin (8) were isolated from the leaves (1 − 5) and stem bark (6 − 8) of Macaranga conglomerata. Their structures were elucidated using spectroscopic and spectrometric techniques. The antibacterial assay was performed using disc diffusion method against Gram-positive and Gram-negative microorganisms. Compound 1 was significantly active against Pseudomonas aeruginosa ATCC 27853 (MIC = 7.8 µg/mL) and moderately active towards Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922 and Klebsiella pneumoniae ATCC 31488 (MIC = 62.5 µg/mL). Compound 2 showed potency against P. aeruginosa ATCC 27853 (MIC = 1.0 µg/mL) while 4 and 7 were selective towards K. pneumoniae ATCC 31488 (MIC = 7.8 and 1.0 µg/mL, respectively). These findings suggest that prenylation of flavonoids may contribute to improving their broad-spectrum antimicrobial activities.</p

Structural based investigation of novel pyrazole-thiazole Hybrids as dual CDK-1 and CDK-2 inhibitors for cancer chemotherapy

CDK-1 and CDK-2 are two promising targets for cancer treatment as they are vital in tumor development, proliferation, and apoptosis during the cell cycle process. In treating cancers, CDK inhibitors (small molecules) are used to prevent the overproliferation and overexpression of cancer cells. Consequently, inhibiting CDKs is a promising treatment strategy in oncology. The limitations imposed by current CDK-1 and CDK-2 inhibitors, including neurotoxicity and the development of resistance, have prompted our group to use the novel synthesized pyrazole-thiazole hybrid analogues to investigate their possible potency against CDK-1 and CDK-2. The research study employed detailed computational approaches including molecular docking, molecular dynamics (MD) simulations, post-MD analyses such as RMSD, RMSF, RoG, per-residue energy decomposition, hydrogen bond lifetime analysis, and drug-likeness studies like ADME properties prediction and cytotoxicity, to predict the properties and inhibitory potentials of synthesized pyrazole-thiazole hybrid analogues against CDK-1 and CDK-2. The in silico binding free energy and other analysis reported in the study revealed that four (7 g, 8a, 8b, and 8 h) of the tested molecules against CDK-1 demonstrated a higher binding affinity and structural influence on the target protein than the known inhibitor, Roscovitine (RVT). Similarly, in the case of CDK-2, four (7b, 8a, 8b, and 8f) of the tested compounds showed better results than (RVT). Furthermore, structural examination of the two proteins after binding to the inhibitors revealed that the compounds form stable complexes with the targets and significantly reduced the structural flexibility of the proteins. Therefore, this study suggests the novel pyrazole-thiazole hybrid analogues as potential CDK-1 and CDK-2 inhibitors and could be potential lead compounds for target-based anticancer drugs inhibiting the important proteins, CDK-1 and CDK-2.</p

Development of a DHA-Losartan hybrid as a potent inhibitor of multiple pathway-induced platelet aggregation

Despite the scientific progression in the prevention and treatment of cardiovascular diseases (CVDs) they remain the leading cause of mortality and disability worldwide. The classic treatment involves the simultaneous dosing of two antiplatelet drugs, aspirin and clopidogrel/prasugrel. However, besides drug resistance, severe side effects have been also manifested including acute bleeding and toxicity. Thus, new therapeutic agents with enhanced efficacy and diminished side effects are of importance. Towards this end, omega-3 (ω-3) fatty acids have demonstrated potent efficacy against CVDs through inhibiting platelet aggregation that bears a pivotal role in atherothrombosis. Another factor that displays a critical role in the pathogenesis of cardiovascular diseases is the renin-angiotensin system (RAS), and especially the AT1R blocker losartan that has been reported to exert antiplatelet activity mediated by this receptor. Along these lines, we envisaged developing a molecular hybrid consisted of docosahexaenoic acid (ω-3 fatty acid) and losartan, that could exert a notable antiplatelet effect against CVDs. The design and synthesis of the new DHA-losartan hybrid, designated DHA-L, bestowed with the additive properties of the parent compounds, is reported. In silico studies were first exploited to validate the potential of DHA-L to retain losartan’s ability to bind AT1R. The antiplatelet activity of DHA-L was evaluated against in vitro platelet aggregation induced by several platelet agonists. Notably, the hybrid illustrated a pleiotropic antiplatelet profile inhibiting platelet aggregation through multiple platelet activation pathways including P2Y12, PAR-1 (Protease-Activated Receptor-1), PAF (Platelet Activating Factor), COX-1 (cyclooxygenase-1) and collagen receptors. The stability of DHA-L in human plasma and in a wide range of pH values was also evaluated over time using an HPLC protocol. The hybridization approach described herein could pave the way for the development of novel potent multitargeted therapeutics with enhanced antiplatelet profile. Communicated by Ramaswamy H. Sarma</p

Isoflavonoid and Furanochromone Natural Products as Potential DNA Gyrase Inhibitors: Computational, Spectral, and Antimycobacterial Studies

In pursuit of new antitubercular agents, we here report the antimycobacterial (H37Rv) and DNA gyrase inhibitory potential of daidzein and khellin natural products (NPs). We procured a total of 16 NPs based on their pharmacophoric similarities with known antimycobacterial compounds. The H37Rv strain of M. tuberculosis was found to be susceptible to only two out of the 16 NPs procured; specifically, daidzein and khellin each exhibited an MIC of 25 μg/mL. Moreover, daidzein and khellin inhibited the DNA gyrase enzyme with IC50 values of 0.042 and 0.822 μg/mL, respectively, compared to ciprofloxacin with an IC50 value of 0.018 μg/mL. Daidzein and khellin were found to have lower toxicity toward the vero cell line, with IC50 values of 160.81 and 300.23 μg/mL, respectively. Further, molecular docking study and MD simulation of daidzein indicated that it remained stable inside the cavity of DNA GyrB domain for 100 ns