6-Aminocoumarin oxime-ether/sulfonamides as selective hCA IX and XII inhibitors: Synthesis, evaluation, and molecular dynamics studies.

Carbonic anhydrase isoforms IX and XII are overexpressed in hypoxic tumor cells regulating various physiological processes such as cell proliferation, invasion, and metastasis, resulting in the onset and spread of cancer. Selective inhibition of these enzymes is a promising strategy for anticancer therapy. Coumarin derivatives were identified as selective and potent inhibitors of these isoforms. This study reports 6-aminocoumarin sulfonamide and oxime ether derivatives linked through a chloroacetyl moiety tethered to piperazine and piperidone, respectively, showing selective inhibition against human carbonic anhydrase (hCA) IX and XII with Ki ranging from 0.51 to 1.18 µM and 0.89-4.43 µM. While the sulfonamide derivative 8a exhibited submicromolar inhibition against hCA IX and XII with Ki 0.89 and 0.51 µM, the oxime ether derivatives showed lower activity than the sulfonamides, with the compound 5n inhibiting hCA IX and hCA XII with a Ki of 1.055 and 0.70 µM, respectively. The above results demonstrate the potential of these derivatives as selective, potent inhibitors of carbonic anhydrase IX and XII and provide a foundation for further optimization and development as effective anticancer agents. Further, the binding mode of the synthesized derivatives in the active site were examined using molecular docking and dynamic simulation studies.

Design, synthesis, and structure-activity studies of new rhodanine derivatives as carbonic anhydrase II, IX inhibitors.

Rhodanine and its derivatives are an important class of heterocycles with diverse biological properties, including anticancer, antibacterial, and anti-mycobacterial activities. In the present work, four series of new Rhodanine derivatives were synthesized and evaluated for their inhibitory activity against carbonic anhydrase I, II, IX, and XII isoforms. Interestingly, the tested compounds exhibited good inhibitory activity against the cytosolic isoform human carbonic anhydrase (hCA) II and tumor-associated hCA IX. While the Rhodanine-benzylidene derivatives (3a-l) and Rhodanine-hydrazine derivatives (6a-e) are found to be selective against hCA II, the Rhodanine-N-carboxylate derivatives (8a-d) are found to be highly selective toward hCA IX. The Rhodanine-linked isoxazole and 1,2,4-oxadiazole derivatives (8ba, 8da, and 8db) exhibited inhibitory activity against hCA II and hCA IX. Among the tested compounds, 3b, 3j, 6d, and 8db were found to inhibit hCA II with Ki values of 9.8, 46.4, 7.7, and 4.7 µM, respectively. Furthermore, their mechanism of action is supported by molecular docking studies. Notably, the synthesized Rhodanine derivatives belong to a nonsulfonamide class of carbonic anhydrase inhibitors.

Serendipitous identification of phenylhydrazine derivatives as potent inhibitors of carbapenem-resistant Acinetobacter baumannii.

Background: In the authors' previous study, 4-(2-((3-methyl-4-oxo-2-thioxo/dioxothiazolidin-5-ylidene) methyl) hydrazineyl) benzonitriles were found to demonstrate potent antibacterial activity against Acinetobacter baumannii. Interestingly, the aforementioned compounds contain a 4-cyanophenylhydrazine motif. Materials & methods: Intrigued by this observation, the authors focused on preparing a library of 4-cyanophenylhydrazine derivatives and studied their detailed antibacterial potential. Results: This study led to the identification of a 4-cyanophenylhydrazine with potent inhibitory activity against carbapenem-resistant A. baumannii BAA-1605, with minimum inhibitory concentration (MIC) of 0.25 µg/ml and highest selectivity index of 640. The compound also demonstrated potent inhibition against multidrug-resistant A. baumannii isolates (MIC: 0.25-1 µg/ml). Conclusion: The identified 4-cyanophenylhydrazine compound exhibited synergistic activity with amikacin, tobramycin and polymyxin B against carbapenem-resistant A. baumannii BAA-1605.

Luliconazole Topical Dermal Drug Delivery for Superficial Fungal Infections: Penetration Hurdles and Role of Functional Nanomaterials.

Luliconazole is the first and only anti-fungal agent approved for the short-term treatment of superficial fungal infections. However, commercially available conventional topical dermal drug delivery cargo of luliconazole is associated with certain limitations, like lower skin permeation and shorter skin retention of drug. Therefore, the present review is an attempt to unravel the penetration hurdles in luliconazole topical dermal drug delivery. Moreover, we have also summarized the activity of functional nanomaterials-based drug delivery systems employed by the scientific fraternity to improve luliconazole efficacy in superficial fungal infections on a case-to-case basis. In addition, efforts have also been made to unveil the critically acclaimed mechanism of action of luliconazole against fungal cells. Under the framework of future prospects, we have analyzed the combination of luliconazole with isoquercetin using the in-silico docking technique for offering synergistic antifungal activity. Isoquercetin exhibited a good affinity for superoxide dismutase (SOD), a fungal target, owing to the formation of hydrogen bonds with Glu132, Glu133, and Arg143, in addition to a few hydrophobic interactions. On the other hand, luliconazole inhibited lanosterol-14α-demethylase, and consequently blocked ergosterol. In addition, nanotechnology and artificial neural network (ANN) derived integrated drug delivery systems may also be explored for augmenting the luliconazole therapeutic efficacy in topical fungal infections. Synergy of ANN models along with topical nanoscaled drug delivery may help to achieve critical quality attributes (CQA), leading to commercial success of luliconazole.

A comprehensive review on potential therapeutic inhibitors of nosocomial Acinetobacter baumannii superbugs.

Acinetobacter baumannii, a Gram-negative, glucose non-fermentative coccobacilli are responsible for causing a wide range of opportunistic nosocomial infections, thus listed as a WHO "critical priority pathogen", for which identification and development of new antibacterial agents are an urgent unmet medical need. The current review attempts to present an overview of various mechanisms (enzymatic and non-enzymatic), virulence factors responsible for A. baumannii resistance. Furthermore, inhibitors of A. baumannii are categorized into different classes highlighting their MDR inhibition properties. In addition, novel adjuvants that potentiate existing antibiotics, as well as natural and synthetic compounds that limit biofilm formation in A. baumannii infections are discussed.

FabI (enoyl acyl carrier protein reductase) - A potential broad spectrum therapeutic target and its inhibitors.

Development of new anti-bacterial agents acting upon underexploited targets and thus evading known mechanisms of resistance is the need of the hour. The highly conserved and distinct bacterial fatty acid biosynthesis pathway (FAS-II), presents a validated and yet relatively underexploited target for drug discovery. FabI and its isoforms (FabL, FabK, FabV and InhA) are essential enoyl-ACP reductases present in several microorganisms. In addition, the components of the FAS-II pathway are distinct from the multi-enzyme FAS-I complex found in mammals. Thus, inhibition of FabI and its isoforms is anticipated to result in broad-spectrum antibacterial activity. Several research groups from industry and academic laboratories have devoted significant efforts to develop effective FabI-targeting antibiotics, which are currently in various stages of clinical development for the treatment of multi-drug resistant bacterial infections. This review summarizes all the natural as well as synthetic inhibitors of gram-positive and gram-negative enoyl ACP reductases (FabI). The knowledge of the reported inhibitors can aid in the development of broad-spectrum antibacterials specifically targeting FabI enzymes from S. aureus, S. epidermidis, B. anthracis, B. cereus, E. coli, P. aeruginosa, P. falciparum and M. tuberculosis.

Facile synthesis of 1,2,3-triazole-fused indolo- and pyrrolo[1,4]diazepines, DNA-binding and evaluation of their anticancer activity.

A facile synthetic strategy has been developed for the generation of structurally diverse N-fused heterocycles. The formation of fused 1,2,3-triazole indolo and pyrrolodiazepines proceeds through an initial Knoevenagel condensation followed by intramolecular azide-alkyne cycloaddition reaction at room temperature without recourse to the traditional Cu(I)-catalyzed azide-alkyne cycloadditions. The synthesized compounds were evaluated for their in vitro anti-cancer activity against the NCI 60 cell line panel. Among the tested compounds, 3a and 3h were found to exhibit potent inhibitory activity against many of the cell lines. Cell cycle analysis indicated that the compounds inhibit the cell cycle at sub G1 phase. The DNA- nano drop method, viscosity experiment and docking studies suggested these compounds possess DNA binding affinity.