Herein we describe design and synthesis of different series of novel small molecules featuring 3-methylthiazolo[3,2-a]benzimidazole moiety (as a tail) connected to the zinc anchoring benzenesulfonamide moiety via ureido (7), enaminone (12), hydrazone (14), or hydrazide (15) linkers. The newly prepared conjugates have been screened for their inhibitory activities toward four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms: hCA I, II, IX and XII. Thereafter, the urea and enaminone linkers were elongated by one- or two-atoms spacers to afford the elongated counterparts 9 and 13, respectively. Finally, the zinc anchoring sulfonamide group was replaced by the carboxylic acid group to afford acids 17. Compounds 12d, 13b and 15 displayed single-digit nanomolar CA IX inhibitory activities (KIs = 6.2, 9.7 and 5.5 nM, respectively), along with good selectivity towards hCA IX over hCA I and II. Subsequently, they were screened for their growth inhibitory actions against breast cancer MCF-7 and MDA-MB-231 cell lines, and for their impact on cell cycle progression and induction of apoptosis. Moreover, a molecular docking study was conducted to gain insights for the plausible binding interactions of target sulfonamides within hCA isoforms II, IX and XII binding sites.

3-Methylthiazolo[3,2-a]benzimidazole-benzenesulfonamide conjugates as novel carbonic anhydrase inhibitors endowed with anticancer activity: Design, synthesis, biological and molecular modeling studies / Alkhaldi A.A.M.; Al-Sanea M.M.; Nocentini A.; Eldehna W.M.; Elsayed Z.M.; Bonardi A.; Abo-Ashour M.F.; El-Damasy A.K.; Abdel-Maksoud M.S.; Al-Warhi T.; Gratteri P.; Abdel-Aziz H.A.; Supuran C.T.; El-Haggar R.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - ELETTRONICO. - 207:(2020), pp. 0-0. [10.1016/j.ejmech.2020.112745]

3-Methylthiazolo[3,2-a]benzimidazole-benzenesulfonamide conjugates as novel carbonic anhydrase inhibitors endowed with anticancer activity: Design, synthesis, biological and molecular modeling studies

Nocentini A.;Bonardi A.;Gratteri P.;Supuran C. T.
;
2020

Abstract

Herein we describe design and synthesis of different series of novel small molecules featuring 3-methylthiazolo[3,2-a]benzimidazole moiety (as a tail) connected to the zinc anchoring benzenesulfonamide moiety via ureido (7), enaminone (12), hydrazone (14), or hydrazide (15) linkers. The newly prepared conjugates have been screened for their inhibitory activities toward four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms: hCA I, II, IX and XII. Thereafter, the urea and enaminone linkers were elongated by one- or two-atoms spacers to afford the elongated counterparts 9 and 13, respectively. Finally, the zinc anchoring sulfonamide group was replaced by the carboxylic acid group to afford acids 17. Compounds 12d, 13b and 15 displayed single-digit nanomolar CA IX inhibitory activities (KIs = 6.2, 9.7 and 5.5 nM, respectively), along with good selectivity towards hCA IX over hCA I and II. Subsequently, they were screened for their growth inhibitory actions against breast cancer MCF-7 and MDA-MB-231 cell lines, and for their impact on cell cycle progression and induction of apoptosis. Moreover, a molecular docking study was conducted to gain insights for the plausible binding interactions of target sulfonamides within hCA isoforms II, IX and XII binding sites.
2020
207
0
0
Goal 3: Good health and well-being for people
Alkhaldi A.A.M.; Al-Sanea M.M.; Nocentini A.; Eldehna W.M.; Elsayed Z.M.; Bonardi A.; Abo-Ashour M.F.; El-Damasy A.K.; Abdel-Maksoud M.S.; Al-Warhi T....espandi
File in questo prodotto:
File Dimensione Formato  
121-Alkhaldi_EJMC20.pdf

Accesso chiuso

Tipologia: Pdf editoriale (Version of record)
Licenza: Tutti i diritti riservati
Dimensione 2.19 MB
Formato Adobe PDF
2.19 MB Adobe PDF   Richiedi una copia

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1218484
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 53
  • ???jsp.display-item.citation.isi??? 45
social impact