A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II.

Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN.

Insights into the Mechanism of Thiol-Triggered COS/H2S Release from N-Dithiasuccinoyl Amines.

The hydrolysis of carbonyl sulfide (COS) to form H2S by carbonic anhydrase has been demonstrated to be a viable strategy to deliver H2S in a biological system. Herein, we describe N-dithiasuccinoyl amines as thiol-triggered COS/H2S donors. Notably, thiol species especially GSH and homocysteine can trigger the release of both COS and H2S directly from several specific analogues via an unexpected mechanism. Importantly, two representative analogues Dts-1 and Dts-5 show intracellular H2S release, and Dts-1 imparts potent anti-inflammatory effects in LPS-challenged microglia cells. In conclusion, N-dithiasuccinoyl amine could serve as promising COS/H2S donors for either H2S biological studies or H2S-based therapeutics development.

Synthesis and evaluation of a novel quinoline-triazole analogs for antitubercular properties via molecular hybridization approach.

Towards a quest for establishing new antitubercular agents, we have designed new quinoline-triazole hybrid analogs in a six-step reaction sequence involving versatile reactions like Vilsmeier-Haack and click reaction protocol. The design is based on the structural modification of bedaquiline moiety and involves molecular hybridization approach. The structure of the synthesized product was elucidated by single crystal X-ray diffraction study. The synthesized target compounds were screened for their antitubercular activity against Mycobacterium bovis. Interestingly, two compounds of the series (8d and 8m) showed significant inhibition with MIC of 31.5 and 34.8 µM. Compounds bearing 3-fluoro phenyl and n-octyl groups on the 1,2,3-triazole ring emerged as the most potent leads among the compounds tested. Further these hit compounds were also screened for their cytotoxic effect on human embryonic kindey 293 (HEK293) cells and other cancer cell lines such as HeLa (Cervical), PC3 (Prostate), Panc-1 (Pancreatic) and SKOV3 (Ovarian) indicating to be safer with the minimal cytotoxicity.

New INH-pyrazole analogs: Design, synthesis and evaluation of antitubercular and antibacterial activity.

With the aim of developing promising antitubercular and antibacterial leads, we have designed and synthesized a new series of isonicotinohydrazide based pyrazole derivatives (5a-r). All new derivatives (4a-b and 5a-r) were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) strain. Four compounds 5j, 5k, 5l and 4b emerged as promising antitubercular agents with MIC of ⩽4.9 µM which is much lower than the MIC of the first line antitubercular drug, ethambutol. The 3-chlorophenyl substituent at position-3 of the pyrazole ring enhanced the antiTB activity of the molecules. Three derivatives 5b, 5k and 4b exhibited promising antibacterial activity against the tested bacterial strains. The active molecules were nontoxic to normal Vero cells and showed high selectivity index (>160). The structure and antitubercular activity relationship was further supported by in silico molecular docking study of the active compounds against enoyl acyl carrier protein reductase (InhA) enzyme of M. tuberculosis.

Design of new phenothiazine-thiadiazole hybrids via molecular hybridization approach for the development of potent antitubercular agents.

A new library of phenothiazine and 1,3,4-thiadiazole hybrid derivatives (5a-u) was designed based on the molecular hybridization approach and the molecules were synthesized in excellent yields using a facile single-step chloro-amine coupling reaction between 2-chloro-1-(10H-phenothiazin-10-yl)ethanones and 2-amino-5-subsituted-1,3,4-thiadiazoles. The compounds were evaluated for their in vitro inhibition activity against Mycobacterium tuberculosis H37Rv (MTB). Compounds 5 g and 5 n were emerged as the most active compounds of the series with MIC of 0.8 µg/mL (∼ 1.9 µM). Also, compounds 5a, 5b, 5c, 5e, 5l and 5m (MIC = 1.6 µg/mL), and compounds 5j, 5k and 5o (MIC = 3.125 µg/mL) showed significant inhibition activity. The structure-activity relationship demonstrated that an alkyl (methyl/n-propyl) or substituted (4-methyl/4-Cl/4-F) phenyl groups on the 1,3,4-thiadiazole ring enhance the inhibition activity of the compounds. The cytotoxicity study revealed that none of the active molecules are toxic to a normal Vero cell line thus proving the lack of general cellular toxicity. Further, the active molecules were subjected to molecular docking studies with target enzymes InhA and CYP121.

One-pot synthesis of new triazole--Imidazo[2,1-b][1,3,4]thiadiazole hybrids via click chemistry and evaluation of their antitubercular activity.

A new series of triazole-imidazo[2,1-b][1,3,4]thiadiazole hybrids (6a-s, 7a) were designed by a molecular hybridisation approach and the target molecules were synthesized via one pot click chemistry protocol. All the intermediates and final molecules were characterised using spectral methods and one of the target compounds (6c) was analysed by the single crystal XRD study. The derivatives were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain. Two compounds, 6f and 6n, demonstrated significant growth inhibitory activity against the bacterial strain with a MIC of 3.125 µg/mL. The presence of chloro substituent on the imidazo[2,1-b][1,3,4]thiadiazole ring and ethyl, benzyl or cyanomethylene groups on the 1,2,3-triazole ring enhance the inhibition activity of the molecules. The active compounds are not toxic to a normal cell line which signifies the lack of general cellular toxicity of these compounds.

Synthesis and biological evaluation of new imidazo[2,1-b][1,3,4]thiadiazole-benzimidazole derivatives.

In this report, we describe the synthesis and biological evaluation of a new series of 2-(imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-1H-benzimidazole derivatives (5a-ac). The molecules were analyzed by (1)H NMR, (13)C NMR, mass spectral and elemental data. The structure of one of the pre-final compounds, 6-(4-methoxyphenyl)-2-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4d) and that of a target compound, 2-[2-methyl-6-(4-methyl phenyl) imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzimidazole (5aa) were confirmed by single crystal XRD studies. All the target compounds were screened for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Seven (5c, 5d, 5l, 5p, 5r, 5z and 5aa) out of twenty nine compounds showed potent anti-tubercular activity with a MIC of 3.125 µg/mL. A p-substituted phenyl group (p-tolyl or p-chlorophenyl) in the imidazo[2,1-b][1,3,4]thiadiazole ring and/or a chloro group in the benzimidazole ring enhance anti-tuberculosis activity whereas a nitro group in the benzimidazole ring reduces the activity. In the antibacterial screening, compounds 5i, 5w and 5ac showed promising activity against the tested bacterial strains. Further, antifungal and antioxidant activities of these molecules were also investigated. In the cytotoxicity study, the active antitubercular compounds exhibited very low toxicity against a normal cell line.