Novel series of dehydrozingerone inspired potential antimycobacterial agents: design, synthesis, spectral studies and in vitro biological evaluation.
Hampannavar, Girish Appasaheb.
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Tuberculosis (TB) is a key health burden globally. With the emergence of resistance issue, the antitubercular research has been challenging. Novel effective drugs are immediately required to treat this serious epidemic disease. Innovative potential antitubercular drug candidates are momentously required to combat the disadvantages linked with existing drugs or line of treatments. Synthetic manipulations of natural sources are being extensively investigated worldwide for developing potent and efficient drugs. Besides, these manipulations also offer effective leads for further optimization. Therefore, this project is an effort in identifying a novel and effective antitubercular leads based on natural product model dehydrozingerone (DZG), a curcumin degradant. In this project we have performed an extensive literature survey of DZG for its known biological activities. And further, we have synthesized some novel series of DZG fused heterocyclic compounds with three different 5 membered heterocyclic scaffolds namely, thiazole, thiazolidon- 4-one and pyrazole. A total of 53 compounds comprising of styryl hydrazine thiazole hybrids (6ao, Chapter 3), styryl hydrazine thiazolidin-4-one hybrids (7a-d, 10a-l and 13a-b, Chapter 4) and lastly styryl fused pyrazole derivatives of acid hydrazides, semicarbazone and thiosemicarbazones (8a-i, 11a-h and 14a-c, Chapter 5) have been synthesized by versatile synthetic routes as outlined in schemes of respective chapters. The completion of reaction and the purity of synthesized compounds were established by chromatographic analysis. All the newly synthesized compounds displayed acceptable analysis for their anticipated structures, which were established based on physicochemical and spectral data (IR, 1H NMR, 13C NMR and HRMS). These newly synthesized compounds were primarily evaluated for their in vitro antimycobacterial activities at Infectious Disease Research Institute (IDRI) within the National Institute of Allergy and Infectious Diseases (NIAID) screening program, Bethesda, USA or Department of Microbiology, Inkosi Albert Luthuli Hospital, Durban, South Africa. From the systematic analysis of antimycobacterial activity results obtained following key observations were made. i. Degradants of curcumin have been looked upon for molecular variations in developing diverse scaffolds. DZG is an imperative scaffold and its numerous analogs have emerged as a promising leads in the design and development of some novel medicinally active compounds with improved metabolic, pharmacokinetic and pharmacological profiles, indicating that there is much scope for considering DZG as a structural framework for developing effective leads. ii. Chapter 3: Of the fifteen novel styryl hydrazine thiazole derivatives synthesized and tested, compound 6o exhibited significant antimycobacterial activity (H37Rv; MIC = 1.5 μM; IC50 = 0.48 μM) along with bactericidal (MBC = 12 μM) and intracellular antimycobacterial activities (IC50 = < 0.098 μM). Furthermore, 6o displayed prominent antimycobacterial activity under hypoxic (MIC = 46 μM) and normal oxygen (MIC = 0.28 μM) conditions along with anti-mycobacterial efficiency against isoniazid (MIC = 3.2 μM for INH-R1; 1.5 μM for INH-R2) and rifampicin (MIC = 2.2 μM for RIF-R1; 6.3 μM for RIF-R2) resistant strains of Mycobacterium tuberculosis. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for antimycobacterial activity. iii. Chapter 4: From the eighteen novel styryl hydrazine thiazolidin-4-one hybrids derivatives synthesized and tested, Compounds 7a (MIC = 110 μM; IC50 = 67 μM), 7c (MIC = 120 μM; IC50 = 66 μM) and 10g (MIC = 100 μM; IC50 = 100 μM) exhibited noteworthy antimycobacterial activity. Further, the title compounds displayed least cytotoxic effects against a mammalian Vero cell determined using MTT assay. iv. Chapter 5: Among the twenty novel styryl pyrazolo carbazone derivatives synthesized and tested, Compounds 8a, 8c, 8d, 8g, 8h, 8i and 11f showed reasonable antibacterial activity (MIC = 50 μg/mL) against B. subtilis, compound 11a demonstrated noteworthy activity towards P. aeruginosa (MIC = 25 μg/mL). Further, compounds 8a, 8d, 8e, 8f, 8i, and 11h showed good to moderate antifungal activity ranging from 25 to 50 μg/mL towards C. neoformans (MIC = 25 μg/mL) and C. albicans (MIC = 50 μg/mL). Besides, compound 8a, comprising of isonicotinoyl hydrazide portion displayed remarkable antitubercular activity (MIC = 0.78 μg/mL) against H37Rv. Substituted urea derivatives, 14a-c and 11d also exhibited encouraging activity (MIC = 12.5 and 25 μg/mL, respectively) whereas, derivative with carbothioamide portion 11a, (MIC = 0.78 μg/mL) illustrated significant activity against H37Rv. Moreover, some of the tested compounds showed reasonable activity against MDR (multi drug resistant) and MOTT (mycobacteria other that tuberculosis) strains.