First‐in‐class pyrido[2,3‐d]pyrimidine‐2,4(1H,3H)‐diones against leishmaniasis and tuberculosis: Rationale, in vitro, ex vivo studies and mechanistic insights

• Published in: Archiv der Pharmazie (Weinheim) Vol. 355; no. 4; pp. e2100440 - n/a
• Main Authors: Ramesh, Deepthi, Sarkar, Deblina, Joji, Annu, Singh, Monica, Mohanty, Amaresh K., G. Vijayakumar, Balaji, Chatterjee, Mitali, Sriram, Dharmarajan, Muthuvel, Suresh K., Kannan, Tharanikkarasu
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.04.2022
• Subjects: Animals; Antiprotozoal Agents - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; dihydrofolate reductase‐thymidylate synthase complex; Leishmania donovani; Leishmaniasis; Life Sciences & Biomedicine; Mice; Pharmacology & Pharmacy; Physical Sciences; pyrido[2,3‐d]pyrimidine‐2,4(1H,3H)‐dione; Pyrimidines - chemistry; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; thymidylate kinase; tuberculosis; Tuberculosis - drug therapy; MYCOBACTERIUM-TUBERCULOSIS; DRUG; DESIGN; tuberculosis; leishmaniasis; REDUCTASE-THYMIDYLATE SYNTHASE; PHYSICOCHEMICAL PROPERTIES; 3-d]pyrimidine-2; 4(1H; pyrido; DIHYDROFOLATE-REDUCTASE; PULMONARY TUBERCULOSIS; BIOLOGICAL EVALUATION; 3H)-dione; ANTILEISHMANIAL ACTIVITY; VISCERAL LEISHMANIASIS; dihydrofolate reductase-thymidylate synthase complex; thymidylate kinase; pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202100440

Pyrido[2,3‐d]pyrimidine‐2,4(1H,3H)‐diones were synthesized, for the first time, from indole chalcones and 6‐aminouracil, and their ability to inhibit leishmaniasis and tuberculosis (Tb) infections was evaluated. The in vitro antileishmanial activity against promastigotes of Leishmania donovani revealed exceptional activities of compounds 3, 12 and 13, with IC50 values ranging from 10.23 ± 1.50 to 15.58 ± 1.67 µg/ml, which is better than the IC50 value of the standard drug pentostam of 500 μg/ml. The selectivity of the compounds towards Leishmania parasites was evaluated via ex vivo studies in Swiss albino mice. The efficiency of these compounds against Tb infection was then evaluated using the in vitro anti‐Tb microplate Alamar Blue assay. Five compounds, 3, 7, 8, 9 and 12, showed MIC100 values against the Mycobacterium tuberculosis H37Rv strain at 25 µg/ml, and compound 20 yielded an MIC100 value of 50 µg/ml. Molecular modelling of these compounds highlighted interactions with binding sites of dihydrofolate reductase, pteridine reductase and thymidylate kinase, thus establishing the rationale of their pharmacological activity against both pathogens, which is consistent with the in vitro results. From the above results, it is clear that compounds 3 and 12 are promising lead candidates for Leishmania and Mycobacterium infections and may be promising for coinfections. Novel pyrido[2,3‐d]pyrimidine‐2,4(1H,3H)‐diones were synthesized to fight leishmaniasis and tuberculosis infections. Compounds 3, 12 and 13 inhibited Leishmania donovani promastigotes, with IC50 values ranging from 10.23 ± 1.50 to 15.58 ± 1.67 µg/ml. Compounds 3 and 12 yielded MIC100 values of 25 µg/ml against Mycobacterium tuberculosis. Compounds 3 and 12 are thus promising lead candidates for Leishmania and Mycobacterium infections.