title: Synthesis, antimalarial and antitubercular activities of meridianin derivatives.
abstract: 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 INH(R) and MDR and one laboratory generated mutant strain Rif(R). 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.
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Rammohan R
authors.initials: RR
authors.lastname: Yadav
authors.affiliation: National Center for Natural Products Research (NCNPR) and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, MS 38677, USA; Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Clinical Microbiology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Samsher
authors.initials: S
authors.lastname: Singh
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Clinical Microbiology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Inshad A
authors.initials: IA
authors.lastname: Khan
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: sbharate@iiim.ac.in.
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D000995:Antitubercular Agents; D007211:Indoles; D011743:Pyrimidines; D013449:Sulfonamides
keywords: Antimalarial; Antitubercular; Meridianins; Mycobacterium tuberculosis; Plasmodium falciparum