Thiazolidine-4-carboxylic acid derivatives were recognized recently for their potent antitubercular activity. A total of sixty four thiazolidine derivatives published in the recent times were collected and 3D QSAR models were developed, using CoMFA and COMSIA with high predictability. Later, we selected three new molecules, recently synthesized in our lab and evaluated them using the developed QSAR models. The in vitro antitubercular activity (MIC) obtained for these new molecules is in agreement with the predicted values (pMIC).
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http://dx.doi.org/10.2174/1573409910666141121100515 | DOI Listing |
( ) is the world's most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi-(MDR) and extensively-(XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for long-term survival Here, we report the development of antitubercular small molecules that inhibit the cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule that can bind to the heme cofactor of both enzymes.
View Article and Find Full Text PDFBioorg Chem
December 2024
Medicinal Chemistry Research Laboratory, School of Pharmaceutical Sciences, Siksha O Anusandhan Deemed to be University, Bhubaneswar, Odisha 751003, India. Electronic address:
Tuberculosis is a highly infectious disease and it is a global threat in particular affecting people from developing countries. It is thought that nearly one-third of the global population lives with this causative bacterium in its dominant form. The spread of HIV and the development of resistance to both multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) aggravates the spread of the disease and needs novel drugs which combat this disease effectively.
View Article and Find Full Text PDFBrief Bioinform
November 2024
Institute of Medical Information, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing 100020, China.
Drug resistance in Mycobacterium tuberculosis (Mtb) is a significant challenge in the control and treatment of tuberculosis, making efforts to combat the spread of this global health burden more difficult. To accelerate anti-tuberculosis drug discovery, repurposing clinically approved or investigational drugs for the treatment of tuberculosis by computational methods has become an attractive strategy. In this study, we developed a virtual screening workflow that combines multiple machine learning and deep learning models, and 11 576 compounds extracted from the DrugBank database were screened against Mtb.
View Article and Find Full Text PDFArch Pharm (Weinheim)
January 2025
Fluoro & Agro Chemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India.
This report explores the potential of novel 6-aryloxy-2-aminopyrimidine-benzonitrile scaffolds as promising anti-infective agents in the face of the increasing threat of infectious diseases. Starting from 2-amino-4,6-dichloropyrimidine, a series of 24 compounds inspired from the antiviral drugs dapivirine, etravirine, and rilpivirine were designed and synthesized via a two-step reaction sequence in good yields. Biological testing of synthetic analogs revealed potent inhibition against both viral and tuberculosis targets.
View Article and Find Full Text PDFFuture Med Chem
January 2025
Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Aim: This research aimed to develop novel indole-2-carboxamides as potential antitubercular agents using rational drug design. It also focused on identifying the critical interactions required for these compounds to exhibit effective antitubercular activity.
Materials And Methods: Novel indole-2-carboxamides targeting MmpL3 were designed based on SAR, synthesized, and tested for their antitubercular and induction properties.
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