Synthesis, antimalarial and antitubercular activities of meridianin derivatives

• Published in: European journal of medicinal chemistry 2015-06, Vol.98, p.160-169
• Main Authors: Yadav, Rammohan R., Khan, Shabana I., Singh, Samsher, Khan, Inshad A., Vishwakarma, Ram A., Bharate, Sandip B.
• Format: Article
• Language: English
• Subjects: Animals; Antimalarial; Antimalarials - pharmacology; Antitubercular; Antitubercular Agents - pharmacology; Cell Line, Tumor; Humans; Indoles - chemical synthesis; Indoles - pharmacology; Inhibitory Concentration 50; Meridianins; Mycobacterium tuberculosis; Plasmodium falciparum; Plasmodium falciparum - drug effects; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Quantitative Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.05.020

Meridianins are marine-derived indole alkaloids, known to possess kinase inhibitory and antimalarial activities. A series of N-aryl and heteroaryl sulfonamide derivatives of meridianins were prepared and screened for antimalarial activity against D6 and W2 strains of Plasmodium falciparum. 2-Nitro-4-trifluoromethyl sulfonamide derivative 14v displayed promising antiplasmodial activity against both strains with IC50 values of 2.56 and 3.41 μM, respectively. These compounds were not cytotoxic to mammalian cell lines including VERO (monkey kidney fibroblasts), LLC-PK1 (pig kidney epithelial cells) and four cancer cell lines; SK-MEL (human malignant, melanoma), KB (human epidermal carcinoma), BT-549 (ductal carcinoma), SK-OV-3 (human ovary carcinoma) up to 25 μg/ml. Furthermore, all sulfonamide derivatives along with acyl, alkyl and C-ring modified derivatives of meridianins were screened for antitubercular activity against a sensitive strain (H37Rv) of Mycobacterium tuberculosis (Mtb), wherein several compounds showed MIC values in the range of 5.2–304.8 μM. Meridianin C (3) and meridianin G (7) showed anti-tubercular activity with MIC values of 111.1 and 304.8 μM, respectively. The C-ring modified analog 12 exhibited potent anti-tubercular activity against H37Rv strain of Mtb with MIC of 5.2 μM. Furthermore, the most potent analogs 11b and 12 were screened against two clinical isolates of M. tuberculosis INHR and MDR and one laboratory generated mutant strain RifR. These two analogs 11b and 12 displayed promising activity against these resistant strains with MIC values in the range of 5.2–187.7 μM. This is the first report on the anti-tubercular activity of this scaffold. A meridianin sulfonamide derivative 14v showed promising antimalarial activity against D2 and W2 strains of Plasmodium falciparum, better than its parent natural product. The C-ring modified analog 12 exhibited potent anti-tubercular activity against sensitive as well as resistant Mtb strains with MIC of 2–8 μg/ml. [Display omitted] •Meridianin sulfonamide derivatives displayed promising antimalarial activity.•Sulfonamide 14v showed activity against D6 and W2 strains with IC50 of 2.5–3.4 μM.•Anti-tubercular activity of this scaffold is reported for first time.•Meridianins showed anti-TB activity against H37Rv with MIC of 32 and 64 μg/ml.•C-Ring modified analog showed potent activity against both sensitive as well as resistant Mtb strains.