FadD32, a fatty acyl-AMP ligase, plays an indispensable role in mycobacterial mycolic acid synthesis and is a validated target for tuberculosis (TB) drug development. The crystal structure of Mycobacterium tuberculosis (Mtb)FadD32 has laid the foundation of structure-based drug discovery against this crucial enzyme. Here, we screened the "isoxazole" scaffold containing molecules against MtbFadD32 and identified a compound 2,4-dibromo-6-[3-(trifluoromethyl)-1,2-oxazol-5-yl]phenol (M1) with specific inhibitory activity against Mtb. Kinetics experiments showed that M1 inhibits MtbFadD32 and MtbFadD28 activity. The transcriptomics response of Mtb disclosed M1-mediated regulation of mycobacterial decisive genes involved in cell wall synthesis, consequently creating unfavorable conditions for Mtb survival. Further, M1 curtails the Mtb survival in infected macrophages and reduces Mtb burden and tubercular granulomas in a chronic infection model of BALB/c mice. Our findings provide an effective chemical scaffold to inhibit MtbFadD32 with the potential to inhibit multiple MtbFadD family of enzymes for further development as a promising candidate for treating TB.

01 Jan 2025·European Journal of Medicinal Chemistry

Antibacterial and antifungal pyrazoles based on different construction strategies

Review

Author: Cao, Shuang ; Liu, Ziwei ; Rehman, Muneeb Ur ; Guo, Ju ; Long, Sihui ; Shu, Xi ; He, Fang

The growing prevalence of microbial infections, and antimicrobial resistance (AMR) stemming from the overuse and misuse of antibiotics, call for novel therapeutic agents, particularly ones targeting resistant microbial strains. Scientists are striving to develop innovative agents to tackle the rising microbial infections and abate the risk of AMR. Pyrazole, a five-membered heterocyclic compound belonging to the azole family, is a versatile scaffold and serves as a core structure in many drugs with antimicrobial and other therapeutic effects. In this review, we have updated pyrazole-based antibacterial and antifungal agents mainly developed between 2016 and 2024, by combining with diverse pharmacophores such as coumarin, thiazole, oxadiazole, isoxazole, indole, etc. Meanwhile, the various strategies (molecular hybridization, bioisosterism, scaffold hopping, multicomponent reactions, and catalyst-free synthesis) for integrating different functional groups with the pyrazole ring are discussed. Additionally, structure-activity relationships of these pyrazole derivatives, i.e., how structural modifications impact their selectivity and therapeutic potential against bacterial and fungal strains, are highlighted. This review provides insights into designing next-generation antimicrobials to combat AMR, and offers valuable perspectives to the scientists working on heterocyclic compounds with diverse bioactivities.

01 Dec 2024·European Journal of Medicinal Chemistry

Isoxazole compounds: Unveiling the synthetic strategy, in-silico SAR & toxicity studies and future perspective as PARP inhibitor in cancer therapy

Review

Author: Malik, Udita ; Pal, Dilipkumar

Latest developments in cancer treatment have shed a light on the crucial role of PARP inhibitors that enhance the treatment effectiveness by modifying abnormal repair pathways. PARP inhibitors, such as Olaparib, Rucaparib, Niraparib, and Talazoparib have been approved in a number of cancers including BRCA 1/BRCA2 associated malignancies although there are many difficulties as therapeutical resistance. Besides the conventional synthetic drugs, natural compounds such as flavones and flavonoids have been found to be PARP inhibitors but only in preclinical studies. Isoxazole is very important class of potential candidates for medicinal chemistry with anti-cancer and other pharmacological activities. At present, there are no approved PARP inhibitors of isoxazole origin but their ability to hit many pathways inside the cancer cells points out on its importance for future treatments design. In drug development, isoxazoles are helpful because of the molecular design flexibility that may be enhanced using various synthetic approaches. This review highlights the molecular mechanisms of PARP inhibition, importance of isoxazole compounds and present advances in their synthetic strategies that demonstrate promise for these agents as new anticancer drugs. It emphasizes that isoxazole-based PARP inhibitors compounds could be novel anti-cancer drugs. Through this review, we hope to grow a curiosity in additional explorations of isoxazole-based PARP inhibitors and their applications in the trends of novel insights towards precision cancer therapy.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	US	Ganial Immunotherapeutics, Inc.	-

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