Development of Novel Indole-3-sulfonamide-heteroaryl Hybrids as Carbonic Anhydrase Inhibitors: Design, Synthesis and in-vitro Screening.

BACKGROUND: Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Inhibition of isoforms IX and XII has induced potent anticancer effects. OBJECTIVE: A series of indole-3-sulfonamide-heteroaryl hybrid (6a-y) was synthesized and screened for the inhibition of human (h) hCA isoforms I, II, IX, and XII. METHODS: The synthesis of target compounds (6a-y) was carried out in multistep starting from 5-nitro indole as starting material by using classical reported reaction conditions. The steps involved are N-Alkylation Chlorosulfonation, amination, reduction, and finally amidation reaction. RESULTS: Amongst all the compounds (6a-y) synthesized and screened, 6l was found to be active against all the screened hCA isoforms, with Ki ranging 8.03 µM, 4.15 µM, 7.09 µM, and 4.06 µM respectively. On the other hand, 6i, 6j, 6q, 6s, and 6t were highly selective against tumor-associated hCA IX, and 6u was selective against both hCA II and hCA IX with moderate inhibitory activities under the range of 100 µM. These compounds showed good activity against the tumor-associated hCA IX and might be developed as future drug leads for anticancer drug discovery. CONCLUSION: These compounds may be useful as starting points for the design and development of more selective and potent hCA IX and XII inhibitors.

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.

Synthesis and Biological Evaluation of Novel Heterocyclic Imines Linked Coumarin- Thiazole Hybrids as Anticancer Agents.

BACKGROUND: Human Galectin-1, a protein of lectin family showing affinity towards ß-galactosides has emerged as a critical regulator of tumor progression and metastasis, by modulating diverse biological events including homotypic cell aggregation, migration, apoptosis, angiogenesis and immune escape. Therefore, galectin-1 inhibitors might represent novel therapeutic agents for cancer. METHODS: A new series of heterocyclic imines linked coumarin-thiazole hybrids (6a-6r) was synthesized and evaluated for its cytotoxic potential against a panel of six human cancer cell lines namely, lung (A549), prostate (DU-145), breast (MCF-7 & MDA-MB-231), colon (HCT-15 & HT-29) using MTT assay. Characteristic apoptotic assays like DAPI staining, cell cycle, annexin V and Mitochondrial membrane potential studies were performed for the most active compound. Furthermore, Gal-1 inhibition was confirmed by ELISA and fluorescence spectroscopy. RESULTS: Among all, compound 6g {3-(2-(2-(pyridin-2-ylmethylene) hydrazineyl) thiazol-4-yl)-2H-chromen-2- one} exhibited promising growth inhibition against HCT-15 colorectal cancer cells with an IC50 value of 1.28 ± 0.14 µM. The characteristic apoptotic morphological features like chromatin condensation, membrane blebbing and apoptotic body formation were clearly observed with compound 6g on HCT-15 cells using DAPI staining studies. Further, annexin V-FITC/PI assay confirmed effective early apoptosis induction by treatment with compound 6g. Loss of mitochondrial membrane potential and enhanced ROS generation were confirmed with JC-1 and DCFDA staining method, respectively by treatment with compound 6g, suggesting a possible mechanism for inducing apoptosis. Moreover, flow cytometric analysis revealed that compound 6g blocked G0/G1 phase of the cell cycle in a dose-dependent manner. Compound 6g effectively reduced the levels of Gal-1 protein in a dose-dependent manner. The binding constant (Ka) of 6g with Gal-1 was calculated from the intercept value which was observed as 1.9 x 107 M-1 by Fluorescence spectroscopy. Molecular docking studies showed strong interactions of compound 6g with Gal-1 protein. CONCLUSION: Our studies demonstrate the anticancer potential and Gal-1 inhibition of heterocyclic imines linked coumarin-thiazole hybrids.

Antimicrobial Peptides: A Promising Therapeutic Strategy in Tackling Antimicrobial Resistance.

BACKGROUND: Antimicrobial resistance (AMR) has posed a serious threat to global public health and it requires immediate action, preferably long term. Current drug therapies have failed to curb this menace due to the ability of microbes to circumvent the mechanisms through which the drugs act. From the drug discovery point of view, the majority of drugs currently employed for antimicrobial therapy are small molecules. Recent trends reveal a surge in the use of peptides as drug candidates as they offer remarkable advantages over small molecules. METHODS: Newer synthetic strategies like organometalic complexes, Peptide-polymer conjugates, solid phase, liquid phase and recombinant DNA technology encouraging the use of peptides as therapeutic agents with a host of chemical functions, and tailored for specific applications. In the last decade, many peptide based drugs have been successfully approved by the Food and Drug Administration (FDA). This success can be attributed to their high specificity, selectivity and efficacy, high penetrability into the tissues, less immunogenicity and less tissue accumulation. Considering the enormity of AMR, the use of Antimicrobial Peptides (AMPs) can be a viable alternative to current therapeutics strategies. AMPs are naturally abundant allowing synthetic chemists to develop semi-synthetics peptide molecules. AMPs have a broad spectrum of activity towards microbes and they possess the ability to bypass the resistance induction mechanisms of microbes. RESULT: The present review focuses on the potential applications of AMPs against various microbial disorders and their future prospects. Several resistance mechanisms and their strategies have also been discussed to highlight the importance in the current scenario. CONCLUSION: Breakthroughs in AMP designing, peptide synthesis and biotechnology have shown promise in tackling this challenge and has revived the interest of using AMPs as an important weapon in fighting AMR.