Synthesis and Biological Evaluation of Coumarin Carboxamides as Selective and Potent Inhibitors of Carbonic Anhydrases IX and XII.

BACKGROUND: Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the reversible hydration of carbon dioxide to bicarbonate and proton. Inhibition of isoforms IX and XII could aid in the amelioration of cancer. OBJECTIVE: A series of coumarin carboxamides (6a-j) were synthesized and were assayed against hCA isoforms I, II, IX, and XII. METHODS: Thin Layer Chromatography (TLC) analysis was done by utilizing Merck silica gel 60 F254 aluminum plates. Stuart Digital Melting Point Apparatus (SMP 30) was used in determining the melting points of the compounds, which are uncorrected. High Resolution Mass Spectra (HRMS) were determined by Agilent QTOF mass spectrometer 6540 series instrument and were performed using ESI techniques at 70eV. RESULTS: All the compounds selectively inhibited isoforms IX and XII as against hCAs I and II. Compounds 6a-e exhibited the best inhibitory profiles against hCA IX (Ki < 25 nM). The isoform hCA XII was effectively inhibited by all compounds showing the Ki values less than 65 nM. The Compounds 6a, 6b, 6g, 6h, and 6j exhibited Ki values less than 10 nM. The binding interactions of the most potent compounds, 6a and 6b, were investigated through docking studies with hCAs IX and XII. CONCLUSION: These compounds may be utilized as useful starting points for the design and development of selective and potent hCA IX and XII inhibitors.

Alzheimer's disease and sleep disorders: Insights into the possible disease connections and the potential therapeutic targets.

One of the comorbid conditions in an individual with Alzheimer's disease is a sleep disorder. Clinical features of sleep disorders involve various sleep disturbances such as Obstructive Sleep Apnea (OSAS), Excessive Daytime Sleepiness (EDS), Rapid Eye Movement (REM), Breathing Disorders, Periodic limb movements in sleep (PLMS), etc. The primary tools used for the identification of such disturbances are Polysomnography (PSG) and Wrist actigraphy. This review will highlight and explains the different approaches used in the treatment of sleep disorders. Non-pharmacological treatments include Peter Hauri rules, sleep education program, and light therapy which play a key role in the regulation of sleep-wake cycles. Pharmacological therapy described in this article may be useful in treating sleep destruction in patients with Alzheimer's disease. Along with the Non-pharmacological and pharmacological treatment, here we discuss five commonly recognized plant-based nutraceuticals with hypothesized impact on sleep disorders: caffeine, chamomile, cherries, L-tryptophan, and valerian by the proper emphasis on the known mechanism of their action.

Synthesis and Biological Evaluation of Coumarin-Linked 4-Anilinomethyl-1,2,3-Triazoles as Potent Inhibitors of Carbonic Anhydrases IX and XIII Involved in Tumorigenesis.

A series of coumarin-linked 4-anilinomethyl-1,2,3-triazoles (6a-t) was synthesized via a molecular hybridization approach, through carbon C-6 of the coumarin moiety. The synthesized compounds were evaluated for their inhibition of carbonic anhydrase (CA) isoforms I, II, IX and XIII. CAs IX and XIII were selectively inhibited over the off-target isoforms I and II. The best inhibitory profiles against CA IX were shown by compounds 6a, 6e and 6f (Ki < 50 nM), with compound 6e displaying the best inhibition with a Ki value of 36.3 nM. Compounds 6a, 6b, 6j, 6o and 6q exhibited the best inhibitory profiles against CA XIII (Ki < 100 nM). These compounds can be further explored for the discovery of potent and effective CA IX and CA XIII inhibitors.

Design, synthesis and biological evaluation of coumarin linked 1,2,4-oxadiazoles as selective carbonic anhydrase IX and XII inhibitors.

A series of coumarin linked 1,2,4-oxadiazoles were synthesized and the synthesized compounds were subjected for evaluation against the four physiologically and pharmacologically relevant hCA isoforms, hCA I, II, IX and XII. Upon evaluation of the results, it was inferred that the coumarin linked 1,2,4-oxadiazoles showed selective hCA IX and XII inhibition (low to medium nanomolar range) over hCA I and II (>10000 nM). The inhibition constants ranged from low nanomolar to moderately nanomolar. Compounds 6o, 6a, 6q and 6c elicited hCA XII inhibition, with Ki values lower than that of the standard, Acetazolamide (AAZ) with compound 6o exhibiting a Ki value of 1 nM., against hCA IX, the compound 6c exhibited the most potent inhibition with a Ki value of 23.6 nM. Hence, compound 6o can be taken as an effective lead compound for the development of hCA XII inhibitors and compound 6c can be taken as a lead compound for the development of dual hCA IX and XII inhibitors. To understand the molecular interactions, the two most potent compounds 6a and 6o were docked within the hCA XII catalytic cleft in order to study their binding modes with that isoform.