molecules Article Synthesis, Characterization, and Biological Evaluation of Some Novel Pyrazolo[5,1-b]thiazole Derivatives as Potential Antimicrobial and Anticancer Agents Abdulrhman Alsayari 1 , Abdullatif Bin Muhsinah 1 , Yahya I. Asiri 2, Faiz A. Al-aizari 3,4, Nabila A. Kheder 5, Zainab M. Almarhoon 3 , Hazem A. Ghabbour 6 and Yahia N. Mabkhot 7,* 1 Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia; [email protected] (A.A.); [email protected] (A.B.M.) 2 Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia; [email protected] 3 Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; [email protected] (F.A.A.-a.); [email protected] (Z.M.A.) 4 Department of Chemistry, Faculty of Science, Al-Baydha University, Albaydah 38018, Yemen 5 Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt; [email protected] 6 Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt; [email protected] 7 Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia Citation: Alsayari, A.; Muhsinah, * Correspondence: [email protected]; Tel.: +966-1724-19734 A.B.; Asiri, Y.I.; Al-aizari, F.A.; Kheder, N.A.; Almarhoon, Z.M.; Abstract: The pharmacological activities of thiazole and pyrazole moieties as antimicrobial and Ghabbour, H.A.; Mabkhot, Y.N. anticancer agents have been thoroughly described in many literature reviews. In this study, a conve- Synthesis, Characterization, and Biological Evaluation of Some Novel nient synthesis of novel pyrazolo[5,1-b]thiazole-based heterocycles was carried out. The synthesized 1 13 Pyrazolo[5,1-b]thiazole Derivatives as compounds were characterized by IR, H and C NMR spectroscopy and mass spectrometry. Some Potential Antimicrobial and selected examples were screened and evaluated for their antimicrobial and anticancer activities and Anticancer Agents. Molecules 2021, 26, showed promising results. These products could serve as leading compounds in the future design of 5383. https://doi.org/10.3390/ new drug molecules. molecules26175383 Keywords: pyrazolo[5,1-b]thiazole; X-ray crystallography; antibacterial activity; antifungal activity; Academic Editors: Vera L. M. Silva anticancer activity and Artur M. S. Silva Received: 29 July 2021 Accepted: 31 August 2021 1. Introduction Published: 4 September 2021 Antibiotics saved millions of lives during the twentieth century by eliminating the Publisher’s Note: MDPI stays neutral deadly threat of infection. In recent years, the overuse of antimicrobial agents has played a with regard to jurisdictional claims in significant role in creating more resistant strains of bacteria [1], thus causing an increase published maps and institutional affil- in morbidity and mortality [2]. Therefore, safer, cheaper, and more effective antimicrobial iations. agents with a new mode of action are needed [3]. Although cancer is considered the second leading cause of death, taking the lives of 9.6 million people every year [4,5], many cancers are curable if detected early and treated promptly [6]. Chemotherapy is a treatment that uses medications to destroy cancer cells. It typically works by preventing cancer cells from developing, dividing, or proliferating. However, chemotherapy has several disadvantages, Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. one of which is a lack of selectivity leading to extreme side effects and minimal efficacy. This article is an open access article Another is the emergence of drug resistance [7]. Therefore, there is an urgent need to distributed under the terms and design and synthesize potent and highly selective anticancer molecules that offer little-to- conditions of the Creative Commons zero toxicity to normal cells [8]. Thiazole derivatives demonstrate many pharmacological Attribution (CC BY) license (https:// activities [9–17]. The thiazole ring can be traced in several well-established drugs such creativecommons.org/licenses/by/ as the non-steroidal anti-inflammatory drug meloxicam, the anti-ulcer drug famotidine, 4.0/). the antibacterial sulfathiazole, the antiviral ritonavir, the antiparasitic thiabendazole, and Molecules 2021, 26, 5383. https://doi.org/10.3390/molecules26175383 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 14 little-to-zero toxicity to normal cells [8]. Thiazole derivatives demonstrate many pharma- Molecules 2021, 26, 5383 2 of 13 cological activities [9–17]. The thiazole ring can be traced in several well-established drugs such as the non-steroidal anti-inflammatory drug meloxicam, the anti-ulcer drug fa- motidine, the antibacterial sulfathiazole, the antiviral ritonavir, the antiparasitic thia- manybendazole, anticancer and many medicines anticanc includinger medicines dasatinib, including dabrafenib, dasatinib, dabrafenib, and epothilones. and epothi- Figure1 showslones. Figure some 1 of shows the most some effective of the most drugs effective containing drugs acontaining thiazole ring a thiazole [18]. ring [18]. O OH HN N O H2N N H NSS NH O S S 2 S H NH2 S N O N N S O N N O O NH2 Meloxicam Famotidine Sulfathiazole N S S N O HN O N O OH OH N HN O H S H H N N N N N S H Cl N N N NN O Ritonavir Tiabendazole Dasatinib R O N S H F N H OH N F O N S S NH2 O O N O F O OH Dabrafenib Epothilones A (R =H) and B (R = CH3) Figure 1. 1. CommercialCommercial drugs drugs containing containing a thiazole a thiazole ring. ring. Pyrazole derivatives derivatives have have been been reported reported as antimicrobial as antimicrobial [19], [analgesic19], analgesic [20], anti- [20], anti- inflammatoryinflammatory [21], [21], and and anticancer anticancer agents agents [22]. [22]. Additionally, Additionally, many many pharmaceutical pharmaceutical drugs drugs con- taincontain the the pyrazole pyrazole moiety, moiety, such such as theas the antidepressant antidepressant fezolamine fezolamine and and the the anti-inflammatories anti-inflam- celecoxib,matories celecoxib, mepirizole, mepirizole, and lonazolac. and lonazolac. Moreover, Moreover, the pyrazole the pyrazole derivative derivative pyrazofurin pyrazo- has Molecules 2021, 26, x FOR PEER REVIEWbeenfurin has reported been reported to have to antiviral have antiviral [23,24 ][23,24] and anticancer and anticancer activities activities [24, [24,25].25]. Figure Figure3 of2 14depicts 2 somedepicts of some the most of the potent most potent drugs drugs containing containing a pyrazole a pyrazole ring. ring. F3C H C CH 3 N 3 N CH N N 3 N N N N CH3 S O H3C H3C O N NH2 H3C Mepirizole Fezolamine Celecoxib O Cl O NH2 HO OH NH HO O N N N OH HO Pyrazofurin Lonazolac FigureFigure 2. CommercialCommercial drug drug molecules molecules containing containing pyrazole pyrazole rings. rings. Many literature reviews suggest that the pharmacophore hybrids may have en- hanced efficacy, fewer drug–drug interactions, and less potential to induce drug re- sistance [26]. In light of the significance of pyrazoles and thiazoles, numerous studies have been conducted on the synthesis and biological evaluations of new hybrid pharmaco- phores containing pyrazole and thiazole moieties [27–30]. Figure 3 presents three examples of pharmacologically active pyrazolo[5,1-b]thiazole derivatives: pyrazolo[5,1-b]thiazole derivative (A) (a protein kinase inhibitor for treating cancer and other diseases) [31], pyrazolothiazole (B) (a potent corticotropin-releasing fac- tor 1(CRF1) receptor antagonists) [32], and pyrazolo[5,1-b]thiazole derivative (C) (pos- sessing a strong suppressant function against the H37Ra strain) [33] (Figure 3). N O O O F NH N F NH N S O N F N S N O A O B N N S NH O NO F F F C Figure 3. Pharmacologically active pyrazolo[5,1-b]thiazole derivatives. Hydrazides are an important class of biologically active compounds [34–38]. Hydra- zides and their condensation products have been reported to possess a wide range of pharmacological and biological activities, including antibacterial [34], tuberculostatic [35], HIV inhibitory [36], pesticidal [37], and antifungal [38] activities. Some of them are used as monoamine oxidase (MAO) inhibitors and serotonin antagonists in psychopharmacol- ogy [39]. Furthermore, isonicotinoyl hydrazide (isoniazid) is an excellent antituberculosis Molecules 2021, 26, x FOR PEER REVIEW 3 of 14 F3C H C CH 3 N 3 N CH N N 3 N N N N CH3 S O H3C H3C O N NH2 H3C Mepirizole Fezolamine Celecoxib O Cl O NH2 HO OH NH HO O N N N OH HO Molecules 2021, 26, 5383 Pyrazofurin 3 of 13 Lonazolac Figure 2. Commercial drug molecules containing pyrazole rings. Many literatureliterature reviews reviews suggest suggest that that the the pharmacophore pharmacophore hybrids hybrids may havemay enhancedhave en- efficacy,hanced fewerefficacy, drug–drug fewer drug–d interactions,rug interactions, and less potential and less to inducepotential drug to resistanceinduce drug [26]. re- In lightsistance of the [26]. significance In light of ofthe pyrazoles significance and of thiazoles, pyrazoles numerous and thiazoles, studies numerous have been studies conducted have onbeen the conducted synthesis on and the biological synthesis evaluations and biolog ofical new evaluations hybrid pharmacophores of new hybrid containingpharmaco- pyrazolephores containing and thiazole pyrazole moieties and [27 thiazole–30]. moieties [27–30]. Figure3 3 presents presents three three examples examples