Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug
Summary: The search for new anti-tubercular agents is vital for the fight against Mycobacterium tuberculosis, particularly given the rise of drug-resistant strains. DRILS-1398, a pyrazolo[4,3-d]pyrimidine derivative, was discovered as a potent inhibitor of M.tb chorismate mutase (M.tb-CM) with an IC...
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Elsevier
2025-06-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225007989 |
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| author | Deepesh Biswas Rebecca Kristina Edwin K. Shiva Kumar Anwar Alam Dhiraj Kumar Sandipan Chakraborty Gopalakrishnan Bulusu Farhan Jalees Ahmad Gautham G. Shenoy Lakshyaveer Singh Mansi Agarwal Fouzia Siraj Srinivas Oruganti Parimal Misra Nasreen Zafar Ehtesham Manojit Pal Seyed Ehtesham Hasnain |
| author_facet | Deepesh Biswas Rebecca Kristina Edwin K. Shiva Kumar Anwar Alam Dhiraj Kumar Sandipan Chakraborty Gopalakrishnan Bulusu Farhan Jalees Ahmad Gautham G. Shenoy Lakshyaveer Singh Mansi Agarwal Fouzia Siraj Srinivas Oruganti Parimal Misra Nasreen Zafar Ehtesham Manojit Pal Seyed Ehtesham Hasnain |
| author_sort | Deepesh Biswas |
| collection | DOAJ |
| description | Summary: The search for new anti-tubercular agents is vital for the fight against Mycobacterium tuberculosis, particularly given the rise of drug-resistant strains. DRILS-1398, a pyrazolo[4,3-d]pyrimidine derivative, was discovered as a potent inhibitor of M.tb chorismate mutase (M.tb-CM) with an IC50 = 3.0 ± 0.2 μM (n = 3) and IC90 = 10 μM. The compound demonstrated efficacy against multi-drug resistant M.tb strains (MIC = 4 μg/mL, ∼10.0 μM) and effective inhibition of intracellular M.tb in THP-1 macrophages. With favorable pharmacokinetics, moderate stability in vitro, and a promising safety profile, DRILS-1398 showed no toxicity at doses up to 500 mg/kg b.w./day when dosed orally daily once for 7 consecutive days in mice. Both DRILS-1398 and its formulation DRILS-1398(F) were successful in clearing M.tb infection from the lungs and spleen in murine models. These findings suggest DRILS-1398 as a promising lead candidate for developing a first-in-class anti-tubercular drug. |
| format | Article |
| id | doaj-art-965d1268ded34ebcb97af4ad01af87d8 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-965d1268ded34ebcb97af4ad01af87d82025-08-20T03:09:42ZengElsevieriScience2589-00422025-06-0128611253710.1016/j.isci.2025.112537Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drugDeepesh Biswas0Rebecca Kristina Edwin1K. Shiva Kumar2Anwar Alam3Dhiraj Kumar4Sandipan Chakraborty5Gopalakrishnan Bulusu6Farhan Jalees Ahmad7Gautham G. Shenoy8Lakshyaveer Singh9Mansi Agarwal10Fouzia Siraj11Srinivas Oruganti12Parimal Misra13Nasreen Zafar Ehtesham14Manojit Pal15Seyed Ehtesham Hasnain16Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India; Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal 576104, IndiaDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, IndiaDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, IndiaDepartment of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, IndiaCellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, IndiaDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, IndiaDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, IndiaDepartment of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, IndiaManipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal 576104, IndiaTuberculosis Aerosol Challenge Facility, International Centre of Genetic Engineering and Biotechnology, New Delhi 110067, IndiaIndian Council of Medical Research-Centre for Cancer Pathology, Safdarjung Hospital Campus, New Delhi 110029, IndiaIndian Council of Medical Research-Centre for Cancer Pathology, Safdarjung Hospital Campus, New Delhi 110029, IndiaDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, IndiaDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, IndiaDepartment of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, IndiaDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India; Corresponding authorDepartment of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; Department of Biochemical Engineering and Technology, Indian Institute of Technology, Hauz Khas, New Delhi 110016, India; Corresponding authorSummary: The search for new anti-tubercular agents is vital for the fight against Mycobacterium tuberculosis, particularly given the rise of drug-resistant strains. DRILS-1398, a pyrazolo[4,3-d]pyrimidine derivative, was discovered as a potent inhibitor of M.tb chorismate mutase (M.tb-CM) with an IC50 = 3.0 ± 0.2 μM (n = 3) and IC90 = 10 μM. The compound demonstrated efficacy against multi-drug resistant M.tb strains (MIC = 4 μg/mL, ∼10.0 μM) and effective inhibition of intracellular M.tb in THP-1 macrophages. With favorable pharmacokinetics, moderate stability in vitro, and a promising safety profile, DRILS-1398 showed no toxicity at doses up to 500 mg/kg b.w./day when dosed orally daily once for 7 consecutive days in mice. Both DRILS-1398 and its formulation DRILS-1398(F) were successful in clearing M.tb infection from the lungs and spleen in murine models. These findings suggest DRILS-1398 as a promising lead candidate for developing a first-in-class anti-tubercular drug.http://www.sciencedirect.com/science/article/pii/S2589004225007989Biological sciencesMedical MicrobiologyMicrobiologyNatural sciencesPharmacology |
| spellingShingle | Deepesh Biswas Rebecca Kristina Edwin K. Shiva Kumar Anwar Alam Dhiraj Kumar Sandipan Chakraborty Gopalakrishnan Bulusu Farhan Jalees Ahmad Gautham G. Shenoy Lakshyaveer Singh Mansi Agarwal Fouzia Siraj Srinivas Oruganti Parimal Misra Nasreen Zafar Ehtesham Manojit Pal Seyed Ehtesham Hasnain Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug iScience Biological sciences Medical Microbiology Microbiology Natural sciences Pharmacology |
| title | Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug |
| title_full | Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug |
| title_fullStr | Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug |
| title_full_unstemmed | Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug |
| title_short | Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug |
| title_sort | early preclinical development of mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor drils 1398 as a potential anti tb drug |
| topic | Biological sciences Medical Microbiology Microbiology Natural sciences Pharmacology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225007989 |
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