Publications by authors named "Shahinda S R Alsayed"

7 Publications

  • Page 1 of 1

Facile synthesis and antimycobacterial activity of isoniazid, pyrazinamide and ciprofloxacin derivatives.

Chem Biol Drug Des 2021 Feb 26. Epub 2021 Feb 26.

School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.

Several rationally designed isoniazid (INH), pyrazinamide (PZA) and ciprofloxacin (CPF) derivatives were conveniently synthesized and evaluated in vitro against H37Rv Mycobacterium tuberculosis (M. tb) strain. CPF derivative 16 displayed a modest activity (MIC = 16 µg/ml) and was docked into the M. tb DNA gyrase. Isoniazid-pyrazinoic acid (INH-POA) hybrid 21a showed the highest potency in our study (MIC = 2 µg/ml). It also retained its high activity against the other tested M. tb drug-sensitive strain (DS) V4207 (MIC = 4 µg/ml) and demonstrated negligible cytotoxicity against Vero cells (IC  ≥ 64 µg/ml). Four tested drug-resistant (DR) M. tb strains were refractory to 21a, similar to INH, whilst being sensitive to CPF. Compound 21a was also inactive against two non-tuberculous mycobacterial (NTM) strains, suggesting its selective activity against M. tb. The noteworthy activity of 21a against DS strains and its low cytotoxicity highlights its potential to treat DS M. tb.
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http://dx.doi.org/10.1111/cbdd.13836DOI Listing
February 2021

Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis.

Bioorg Chem 2021 Jan 19;106:104486. Epub 2020 Nov 19.

School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia. Electronic address:

The treacherous nature of tuberculosis (TB) combined with the ubiquitous presence of the drug-resistant (DR) forms pose this disease as a growing public health menace. Therefore, it is imperative to develop new chemotherapeutic agents with a novel mechanism of action to circumvent the cross-resistance problems. The unique architecture of the Mycobacterium tuberculosis (M. tb) outer envelope plays a predominant role in its pathogenesis, contributing to its intrinsic resistance against available therapeutic agents. The mycobacterial membrane protein large 3 (MmpL3), which is a key player in forging the M. tb rigid cell wall, represents an emerging target for TB drug development. Several indole-2-carboxamides were previously identified in our group as potent anti-TB agents that act as inhibitor of MmpL3 transporter protein. Despite their highly potent in vitro activities, the lingering Achilles heel of these indoleamides can be ascribed to their high lipophilicity as well as low water solubility. In this study, we report our attempt to improve the aqueous solubility of these indole-2-carboxamides while maintaining an adequate lipophilicity to allow effective M. tb cell wall penetration. A more polar adamantanol moiety was incorporated into the framework of several indole-2-carboxamides, whereupon the corresponding analogues were tested for their anti-TB activity against drug-sensitive (DS) M. tb H37Rv strain. Three adamantanol derivatives 8i, 8j and 8l showed nearly 2- and 4-fold higher activity (MIC = 1.32 - 2.89 µM) than ethambutol (MIC = 4.89 µM). Remarkably, the most potent adamantanol analogue 8j demonstrated high selectivity towards DS and DR M. tb strains over mammalian cells [IC (Vero cells) ≥ 169 µM], evincing its lack of cytotoxicity. The top eight active compounds 8b, 8d, 8f, 8i, 8j, 8k, 8l and 10a retained their in vitro potency against DR M. tb strains and were docked into the MmpL3 active site. The most potent adamantanol/adamantane-based indoleamides 8j/8k displayed a two-fold surge in potency against extensively DR (XDR) M. tb strains with MIC values of 0.66 and 0.012 µM, respectively. The adamantanol-containing indole-2-carboxamides exhibited improved water solubility both in silico and experimentally, relative to the adamantane counterparts. Overall, the observed antimycobacterial and physicochemical profiles support the notion that adamantanol moiety is a suitable replacement to the adamantane scaffold within the series of indole-2-carboxamide-based MmpL3 inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2020.104486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775894PMC
January 2021

Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents.

RSC Adv 2020 Feb 19;10(13):7523-7540. Epub 2020 Feb 19.

School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia. Email:

Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) () strain. Naphthamide derivatives and were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds and had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. It is worth noting that the two most active compounds and also exhibited the highest selective activity towards DS, MDR and XDR strains over mammalian cells [IC (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five.
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http://dx.doi.org/10.1039/c9ra10663dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497412PMC
February 2020

Kinase Targets for Mycolic Acid Biosynthesis in Mycobacterium tuberculosis.

Curr Mol Pharmacol 2019 ;12(1):27-49

School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia.

Background: Mycolic acids (MAs) are the characteristic, integral building blocks for the mycomembrane belonging to the insidious bacterial pathogen Mycobacterium tuberculosis (M.tb). These C60-C90 long α-alkyl-β-hydroxylated fatty acids provide protection to the tubercle bacilli against the outside threats, thus allowing its survival, virulence and resistance to the current antibacterial agents. In the post-genomic era, progress has been made towards understanding the crucial enzymatic machineries involved in the biosynthesis of MAs in M.tb. However, gaps still remain in the exact role of the phosphorylation and dephosphorylation of regulatory mechanisms within these systems. To date, a total of 11 serine-threonine protein kinases (STPKs) are found in M.tb. Most enzymes implicated in the MAs synthesis were found to be phosphorylated in vitro and/or in vivo. For instance, phosphorylation of KasA, KasB, mtFabH, InhA, MabA, and FadD32 downregulated their enzymatic activity, while phosphorylation of VirS increased its enzymatic activity. These observations suggest that the kinases and phosphatases system could play a role in M.tb adaptive responses and survival mechanisms in the human host. As the mycobacterial STPKs do not share a high sequence homology to the human's, there have been some early drug discovery efforts towards developing potent and selective inhibitors.

Objective: Recent updates to the kinases and phosphatases involved in the regulation of MAs biosynthesis will be presented in this mini-review, including their known small molecule inhibitors.

Conclusion: Mycobacterial kinases and phosphatases involved in the MAs regulation may serve as a useful avenue for antitubercular therapy.
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http://dx.doi.org/10.2174/1874467211666181025141114DOI Listing
June 2019

Design, synthesis and biological screening of some novel celecoxib and etoricoxib analogs with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile.

Bioorg Chem 2017 02 26;70:173-183. Epub 2016 Dec 26.

Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni Suef University, Beni Suef 62514, Egypt; Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah 21418, Kingdom of Saudi Arabia.

Two new series of 4,6-diaryl-3-cyanopyridine 4a-r and 1,3,5-triaryl-2-pyrazolines 6a-f and were prepared. The new compounds were evaluated for their in vitro COX-2 selectivity and in vivo anti-inflammatory activity. Compounds 4o,r and 6d,f had moderate to high selectivity index (S.I.) compared to celecoxib (selectivity indexes of 4.5, 3.14, 4.79 and 3.21, respectively) and also, showed in vivo anti-inflammatory activity approximately equal to or higher than celecoxib (edema inhibition %=60.5, 64.5, 59.3 and 59.3, after 3h, respectively) and the effective anti-inflammatory doses were (ED=10.1, 7.8, 8.46 and 10.7mg/kg respectively, celecoxib ED=10.8mg/kg) and ulcerogenic liability were determined for these compounds which showed promising activity by being more potent than celecoxib with nearly negligible ulcerogenic liability compared to celecoxib (reduction in ulcerogenic liability versus celecoxib=85, 82, 74 and 67%, respectively).
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http://dx.doi.org/10.1016/j.bioorg.2016.12.008DOI Listing
February 2017

Design, synthesis and biological screening of new 4-thiazolidinone derivatives with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile.

Bioorg Chem 2016 Feb 6;64:1-12. Epub 2015 Nov 6.

Department of Pharmaceutical Organic Chemistry, Beni Suef University, Beni Suef 62514, Egypt.

Two series of new thiazolidin-4-one derivatives 4a-c and 8a-e were designed and prepared. All the synthesized compounds were evaluated for their in vitro COX-2 selectivity and anti-inflammatory activity in vivo. Compounds 8c and 8d showed the best overall in vitro COX-2 selectivity (selectivity indexes of 4.56 and 5.68 respectively) and in vivo activities (edema inhibition %=61.8 and 67 after 3h, respectively) in comparison with the reference drug celecoxib (S.I.=7.29, edema inhibition %=60 after 3h). In addition, 8c and 8d were evaluated for their mean effective anti-inflammatory doses (ED50=27.7 and 18.1 μmol/kg respectively, celecoxib ED50=28.2 μmol/kg) and ulcerogenic liability (reduction in ulcerogenic potential versus celecoxib=85%, 92% respectively. Molecular docking studies were performed and the results were in agreement with that obtained from the in vitro COX inhibition assays.
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http://dx.doi.org/10.1016/j.bioorg.2015.11.001DOI Listing
February 2016

Synthesis and anti-inflammatory evaluation of new 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives possessing an aminosulphonyl pharmacophore.

Arch Pharm Res 2015 Nov 23;38(11):1932-42. Epub 2015 Apr 23.

Department of Pharmacology, Faculty of Veterinary, Cairo University, Cairo, Egypt.

A novel series of 2-pyrazoline derivatives 13a-l was synthesized via aldol condensation of 4-substituted acetophenones with appropriately substituted aldehydes followed by cyclization of the formed chalcones with 4-hydrazinobenzenesulfonamide hydrochloride. The chemical structures of the target pyrazoline derivatives were proved by means of IR, (1)H NMR, (13)C NMR, mass spectroscopy and elemental analyses data. All the synthesized compounds were evaluated for their cyclooxygenase selectivity, anti-inflammatory and ulcerogenic liability. While compounds 13e, 13h and 13i showed moderate COX-2 selectivity in vitro and good anti-inflammatory activity in vivo, compound 13i showed the highest anti-inflammatory activity that is very close in potency to the reference drug (celecoxib) with better gastric profile than celecoxib.
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http://dx.doi.org/10.1007/s12272-015-0606-7DOI Listing
November 2015