Bioevaluation of quinoline-4-carbonyl derivatives of piperazinyl-benzothiazinones as promising antimycobacterial agents.

The quinoline moiety remains a privileged antitubercular (anti-TB) pharmacophore, whereas 8-nitrobenzothiazinones are emerging potent antimycobacterial agents with two investigational candidates in the clinical pipeline. Herein, we report the synthesis and bioevaluation of 30 piperazinyl-benzothiazinone-based quinoline hybrids as prospective anti-TB agents. Preliminary evaluation revealed 24/30 compounds exhibiting substantial activity (minimum inhibitory concentration [MIC] = 0.06-1 µg/ml) against Mycobacterium tuberculosis (Mtb) H37Rv. Cytotoxicity analysis against Vero cells found these to be devoid of any significant toxicity, with the majority displaying a selectivity index of >80. Furthermore, potent nontoxic compounds, when screened against clinical isolates of drug-resistant Mtb strains, demonstrated equipotent inhibition with MIC values of 0.03-0.25 µg/ml. A time-kill study identified a lead compound exhibiting concentration-dependent bactericidal activity, with 10× MIC completely eliminating Mtb bacilli within 7 days. Along with acceptable aqueous solubility and microsomal stability, the optimum active compounds of the series manifested all desirable traits of a promising antimycobacterial candidate.

Design and development of novel series of indole-3-sulfonamide ureido derivatives as selective carbonic anhydrase II inhibitors.

Indole is a privileged moiety with a wide range of bioactivities, making it a popular scaffold in drug design and development studies as well as in synthetic chemistry. Here, novel urea derivatives of indole, containing sulfonamide at position-3 of indole, were synthesized using a well-known tail approach, as carbonic anhydrases (CAs; EC 4.2.1.1) inhibitors. All the newly synthesized molecules were screened for their CA-inhibitory activity against four clinically relevant isoforms of human-origin carbonic anhydrase (hCA), that is, hCA I, hCA II, hCA IX, and hCA XII. These compounds were specifically active against hCA II, more than against hCA I, hCA IX, and hCA XII. Derivative 6l was found to be most active, with a Ki value of 7.7 µM against hCA II.

Synthesis of Ring-Locked Tetracyclic Dithienocyclopentapyrans and Dibenzocyclopentapyran via 1,5-Hydride Shift and Copper-Catalyzed C-O Bond Formation for Nonfullerene Acceptors.

We discovered a unique synthetic route to construct 2H-pyran-containing tetracyclic dithienocyclopentapyran (DTCP) and dibenzocyclopentapyran (DBCP) architectures. The synthesis involves an acid-induced dehydration cyclization followed by a [1,5] hydride-shift isomerization to form a cyclopentanone moiety which was converted to the pyran-embedded tetracyclic products by a CuI-catalyzed intramolecular C-O bond formation in good yield. DTCP was used as a building block to prepare an acceptor-donor-acceptor (A-D-A) type n-type material DTCP-BC leading to a solar cell efficiency of 9.32%.

Design, synthesis, in silico, and in vitro evaluation of 3-phenylpyrazole acetamide derivatives as antimycobacterial agents.

Mycobacterium tuberculosis (Mtb) is one of the most dangerous pathogens affecting immunocompetent and immunocompromised patients worldwide. Novel molecules, which are efficient and can reduce the duration of therapy against drug-resistant strains, are an urgent unmet need of the hour. In our current study, a series of new 2-(3-phenyl-1H-pyrazol-1-yl)acetamide and N'-benzylidene-2-(3-phenyl-1H-pyrazol-1-yl)acetohydrazide derivatives were designed, synthesized, and evaluated for their antimycobacterial potential. The biological evaluation revealed that 6b, 6m, 6l, 7a, and 7k exhibited selective and potent inhibitory activity against Mtb. Furthermore, compounds 6m and 7h were found to be nontoxic to Vero cells with CC50 of greater than 20 and 80 mg/ml, respectively, and exhibited promising selectivity indices (SI) of greater than 666 and 320, respectively. All derivatives exhibited excellent ADME (absorption, distribution, metabolism, and excretion) properties in silico. Also, all the derivatives were found compliant with Lipinski's rule of five, showing their druggability profile. Molecular docking insights of these derivatives have shown outstanding binding energies on the mycobacterial membrane protein large transporters. These results indicate that this scaffold may lead to a potential antimycobacterial drug candidate in the discovery of antitubercular agents.

Pd(II)-Catalyzed Direct Dehydrogenative Mono- and Diolefination of Selenophenes.

Pd(II)-catalyzed dehydrogenative Heck olefination of selenophenes with a broad olefinic substrate scope and high functional group tolerance is demonstrated. Carbonyl-substituted and phenyl-substituted olefins with electron-donating (D) and electron-accepting (A) groups can be regioselectively installed at C2 of the selenophene. The 2-olefinated selenophenes can subsequently undergo a second oxidative olefination to rapidly produce a new class of symmetrical D-π-D or unsymmetrical D-π-A 2,5-diolefinated selenophene materials.

Synthesis of unsymmetrical benzotrichalcogenophenes by N-heterocyclic carbene-palladium-catalyzed intramolecular direct C3-arylation of chalcogenophenes.

A series of new unsymmetrical benzotrichalcogenophenes (BTCs) were synthesized by the Pd-N-heterocyclic carbene catalyzed intramolecular C3-arylation of furan, thiophene, selenophene and tellurophene units. This is the first time that a C3-direct arylation of selenophene and tellurophene moieties has ever been demonstrated.

Copper mediated decarboxylative direct C-H arylation of heteroarenes with benzoic acids.

Decarboxylative coupling reactions to date require a stoichiometric oxidant (such as copper and silver salts) for decarboxylation purposes along with a metal catalyst (e.g. palladium) for cross-coupling. In this communication, an economic and sustainable approach by using a simple copper salt was developed in the presence of molecular oxygen as the sole oxidant. A wide range of 5-membered heteroarenes undergo aryl-heteroaryl cross-coupling with electron deficient aryl carboxylic acids.

Palladium(II)-Catalyzed meta-C-H Olefination: Constructing Multisubstituted Arenes through Homo-Diolefination and Sequential Hetero-Diolefination.

Divinylbenzene derivatives represent an important class of molecular building blocks in organic chemistry and materials science. Reported herein is the palladium-catalyzed synthesis of divinylbenzenes by meta-C-H olefination of sulfone-based arenes. Successful sequential olefinations in a position-selective manner provided a novel route for the synthesis of hetero-dialkenylated products, which are difficult to access using conventional methods. Additionally, 1,3,5-trialkenylated compounds can be generated upon successful removal of the directing group.

Stable Cu(I) complexes with thioamidoguanidine possessing halide-bridge structure.

Treatment of an aryl-sec-alkyl unsymmetrical thiourea (Tu) with Cu(II)X(2) (X = I, Br) transform the thiourea (Tu) into a thioamidoguanidino (Tag) moiety with concomitant reduction of Cu(II) to Cu(I), which forms a [Cu(2)(I)(µ(2)-X)(2)Tag(2)] (X = I (for A) and X = Br (for B)) complex. Meanwhile, the treatment of same unsymmetrical thiourea (Tu) with Cu(I)X (X = Br) forms a stable cluster with a [Cu(I)(3)(µ(2)-S)(4)Tu(4)X(3)] core (C). Single crystal X-ray diffraction revealed that compounds A and B exhibit 1D chain with a Cu(2)(µ(2)-X)(2) core, whereas compound C is a Cu(I)(3)S(4)Br(3) cluster. Compound A is centrosymmetric due to the trans orientation of two Tag units whereas compound B is ascentric due to the cis orientation of two Tag units. In compound A, the Cu(2)I(2) core is perfectly rhomboidal where the iodine atoms are trans oriented. However in compound B, the Cu(2)Br(2) core is not perfectly rhomboidal (bowl shaped) and the bromine atoms are cis oriented. It is interesting to note that although the Tag moiety in compounds A and B contain two morpholine-O atoms; only one of the morpholine-O atoms (O2) is involved in the generation of three-dimensional network. The Cu(I)(3)S(4)Br(3) cluster in compound C contains one tri- and two tetra-coordinated Cu(I) centers. The Cu(I) cluster in C contains a Cu(2)(µ(2)-S)(2) rhomboidal plane exhibiting a chair and a boat form containing the Cu(I)(3)S(3) unit. In compounds A and B, the two Cu(I) centers are µ(2)-X bridged and have a µ(1)-S linkage, whereas in compound C the linkages are opposite having four µ(2)-S bridges and three µ(1)-Br linkages.

Intra- and intermolecular C-S bond formation using a single catalytic system: first direct access to arylthiobenzothiazoles.

We have for the first time developed two ligand-assisted Cu(I)-catalyzed sequential intra- and intermolecular S-arylations leading to the direct synthesis of arylthiobenzothiazoles in one pot without an inert atmosphere. Low catalyst loading, inexpensive metal catalyst and ligand, lower reaction temperature, and shorter reaction times make this method superior to all reported methods for the synthesis of arylthiobenzothiazole.

Acyl-isothiocyanates as efficient thiocyanate transfer reagents.

An unprecedented transfer of a thiocyanate (-SCN) group from aroyl/acyl isothiocyanate to alkyl or benzylic bromide is observed in the presence of a tertiary amine. This process is most effective when the bromomethyl proton is less acidic, while the presence of a more acidic proton gives 1,3-oxathiol-2-ylidine and other related products.