#دكتور_حاتم_البيطار #دحاتم_البيطار #timodentist 📞01005684344 💬 واتس 01202389028 Dr Hatem ElBitar د حاتم البيطار أستشاري وجراح أسنان زميل الزمالة المصرية محاضر ادارة المستشفيات ومكافحة العدوى 01005684344 #دحاتم_البيطار http://bit.ly/2xzMIlo

1. Journal of Infection and Public Health 14 (2021) 533–542
Contents lists available at ScienceDirect
Journal of Infection and Public Health
journal homepage: http://www.elsevier.com/locate/jiph
Antimicrobial and cytotoxic activities of isoniazid connected
menthone derivatives and their investigation of clinical pathogens
causing infectious disease
Fatimah S. Al-Khattafa
, Arunadevi Manib
, Ashraf Atef Hatamleha
, Idhayadhulla Akbarb,∗
a
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
b
Research Department of Chemistry, Nehru Memorial College (Affiliated with the Bharathidasan University), Puthanampatti-621007, Tiruchirappalli
District, Tamil Nadu, India
a r t i c l e i n f o
Article history:
Received 16 November 2020
Received in revised form
20 December 2020
Accepted 26 December 2020
Keywords:
Isoniazid
Menthone
Mannich base
Grindstone Chemistry
Antibacterial
Antifungal
Cytotoxic activities
SAR (structure-activity relationships)
Minimum inhibitory concentration
Pathogens
a b s t r a c t
Background: This work is development of new molecules of isoniazid derivatives as dealing with potential
of antimicrobial activity against clinical pathogens causing infectious disease. Antimicrobial of novel
Mannich base derivatives can be achieved via one-pot synthesis in green chemistry approach. This method
offers efficient, mild reaction conditions and high yields. In this study, totally 12 compounds (1a–l) was
prepared and screened for cytotoxic and antimicrobial activities.
Materials and methods: Newly synthesised compounds were conformed via FT- IR, 1
H, and 13
C NMR
(Nuclear Magnetic Resonance), and mass spectra analysis. All compounds were checked antibacterial
activity against gram-positive bacteria of Enterococcus faecalis, Staphylococcus aureus and gram-negative
bacteria of Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli. All compounds were
checked against antifungal activity against Aspergillus fumigatus, Candida albicans, Cryptococcus neofor-
mans, Aspergillus niger, and Microsporum audouinii. All compounds were screened for cytotoxic activity
against the MCF-7 (Michigan Cancer Foundation-7) cancer cell line.
Result: The compound 1g was highly (MIC: 0.25 ␮g/mL) active against gram-negative bacterial of P.
aeruginosa, whereas other compounds 1e and 1h were more active (MIC: 2 ␮g/mL) in K. pneumoniae and
also 1g (MIC: 2 ␮g/mL) was more active in E. faecalis than standard ciprofloxacin. Antifungal screening,
the compound 1b was highly active (MIC: 0.25 ␮g/mL) against C. albicance, 1g (MIC: 2 ␮g/mL) and 1h
(MIC: 4 ␮g/mL) was significant of active against A. fumigatus, and the compound 1c (MIC: 4 ␮g/mL) was
extremely active in M. audouinii than clotrimazole. Compound 1g (GI50 = 0.01 ␮M) exhibited high activity
against the MCF-7 cell line, while 1b (GI50 = 0.02 ␮M) was equipotent active compared with standard
doxorubicin.
Conclusion: A novel set of isoniazid derivatives (1a–l) and 1h were synthesized and screened for antimi-
crobial and cytotoxic activities. We found some highly active molecules, which are evidencing to be a
potential treatment of bacterial and fungal infection candidates.
© 2021 The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for
Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).
Introduction
Infectious diseases caused by bacterial pathogens have become
a main public health problem due to the extensive occurrence of
drug resistance. Morbidity and major health problem produced
all around the world due to the involvement of bacterial and
fungal infections [1,2]. Every year, millions of people were affected
∗ Corresponding author.
E-mail addresses: a.idhayadhulla@gmail.com, idhayadhulla@nmc.ac.in
(I. Akbar).
because of bacterial infections [3]. So, there is an urgent need for
identification of novel lead structure for designing of new, potent
and less toxic agents and effective against the resistant strain [4].
Drug development is one of the high-risk process, which need
for synthesis, modern drug repositioning [5]. Conversely, drug
repositioning also describes that utilized as a template for the
synthesis of new analogues [6,7]. Several bacterial strains causing
infectious which appeared to be in control are once again causing
death every year due to the absence of suitable antibiotic drug [8].
Thus, there is a serious global healthcare emergency, which needs
the urgent development of more effective of multidrug-resistant
pathogens [9].
https://doi.org/10.1016/j.jiph.2020.12.033
1876-0341/© 2021 The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

2. F.S.Al-Khattafetal. Journal of Infection and Public Health 14 (2021) 533–542
Fig. 1. Biological active Isoniazid and menthone derivatives.
The first study regarding the mechanism of action of iso-
niazid (INH) was published in 1970 by Winder and Collins
[10], the isoniazid derivatives are potential of bacterial strains
resistant [11], and isoniazid hybrids also numerous efforts of
anti-microbial agents [12–16]. Basically, hydrazide-hydrazone
derivatives have more attention because of many biologi-
cal applications [17–20], and discussed the structure-activity
relationships (SAR) of antimicrobial activity [21]. Moreover,
isoniazid-related hydrazones showed enhanced production of
infection [22].
Isonicotinoyl hydrazone derivatives were also a significant
response in anti-mycobacterial agents [23–25]. Schiff bases deriva-
tives of thiosemicarbazone and semicarbazone derivatives of
(±)-3-menthone of were found to show signs of protection in max-
imal electroshock seizure screen [26], anti-HIV activity [27,28], and
some Schiff’s bases antimicrobial agents [29].
Fig. 1 indicated that isoniazid is one of the best effect of anti-
tuberculosis drugs [30], which main scaffold for the synthesis of
medicinally important anti-mycobacterial [31], and other exam-
ples such as LL-3858 and isoniazid derivatives for anti-tubercular
activities [32], menthone also the best performance of antimi-
crobial activity and their relative compounds such as pulegons,
humulone and abscisic acid is well known antimicrobial activity
for reported in previous literatures [33–36].
The Mannich base of isonicotinoyl hydrazone has better biologi-
cal activity [37–39], and increases the lipophilicity of parent amines
and amides [40]. The lipophilicity of mannich bases empowers
them to cross bacterial and fungal membranes. Similarly, isoniazid
has the greatest bactericidal activity and is used almost from the
outset of tuberculosis chemotherapy [41,42], anti-inflammatory
[43,44], antimicrobial activities [45], antituberculosis drug [46],
and also acts as infections and development of antimycobacterial
drug [47,48].
With this concept in mind, we selected isoniazid and menthone
due to its multitasking properties, current study the development
of new molecules and overcome the above drugs, we develop effec-
tive and economical synthesis of new isoniazid hybrids menthone
as new anti-bacterial and anti fungal agents.
534

3. F.S.Al-Khattafetal. Journal of Infection and Public Health 14 (2021) 533–542
Materials and methods
Chemicals and spectroscopic analyses
All chemicals were obtained from Sigma–Aldrich. Fourier-
transform infrared spectroscopy (FT-IR) (4000–400 cm−1) was
recorded Shimadzu 8201pc (Shimadzu, Tokyo, Japan). The 1H & 13C
NMR recording via JEOL- (300 and 75 MHz, respectively) in DMSO-
d6 (Jeol, Tokyo, Japan). The elemental analyzer model Varian EL III
(Varian, Inc., Karlsruhe, Germany) was used for analysis of elemen-
tal presences. Silica gel plates (Merck precoated 1057210001) and
fluorescent indicator (UV Lamp Model UV GL-58) were used for
analysis of Thin layer chromotography.
General procedure for the synthesis of compound (1a)
A reaction mixture, menthone (0.01 mol, 1.54 g), isoniazid (0.01
mol, 1.37 g), benzaldehyde (0.01 mol, 1.06 g) was mixed in a mor-
tar with ground up to 15 min at 32 ◦C. After that the powdered
material was washed with water. The final solid material was sep-
arated from column chromatography using 40% ethyl acetate and
40% hexane solvents. The same method was used for the synthesis
of compounds (1b–1l).
N’-((3-isopropyl-6-methyl-2-oxocyclohexyl)
(phenyl)methyl)isonicotinohydrazide (1a)
A pale yellow solid, yield 92%; MF = C23H29N3O2; MW = 379;
m.p. = 141–143 ◦C; Rf = 0.33; IR (KBr) ␯max: 3345, 3000, 2850, 1725,
1640, 1600, 1400, 1080 cm−1; 1H NMR (DMSO-d6) ␦: 8.86 (2H, d, J
= 9.25 Hz), 8.05(1H, s), 7.82(2H, d, J. N-((3-isopropyl-6-meth = 9.25
Hz), 7.39(2H, dd, J = 10.25 Hz, J = 10.21 Hz,), 7.29 (2H, d, J = 10.22
Hz, J = 10.21 Hz), 7.26 (1H, d, J = 10.25 Hz), 4.18 (1H, s), 3.10 (1H,
s), 2.83 (1H, s), 2.20 (1H, s), 2.05 (1H, s), 1.84 (2H, s), 1.58 (2H, s),
1.97 (1H, s), 0.96(6H, s), 0.92(6H, s); 13C NMR(75 MHz) ␦: 214.1,
167.1, 149.6, 140.8, 140.5, 128.5, 128.1, 125.9, 121.7, 59.3, 54.3,
50.9, 32.6, 29.8, 27.5, 26.2, 20.5, 18.3; EI–MS: m/z 379 [M]+(39), 303
(100); HRMS: m/z: calcd for C23H29N3O2: 379.23, found 379.20;
Anal. calcd C23H29N3O2: C, 72.79; H, 7.70; N, 11.07; Found: C, 72.81;
H, 7.72; N, 11.05;
N’-((4-chlorophenyl)(3-isopropyl-6-methyl-2-oxocyclohexyl)
methyl)isonicotinohydra zide (1b)
A pale yellow solid, yield 90%; MF = C23H28ClN3O2; MW =
413.94; m.p. = 154–156 ◦C; Rf = 0.32; IR (KBr) ␯max: 3348, 3018,
2855, 1742, 1661, 1620, 1422, 1088; 1H NMR (DMSO-d6) ␦: 8.83
(2H, d, J = 9.25 Hz), 8.06(1H, s), 7.83 (2H, d, J = 9.25 Hz), 7.46(2H,
dd, J = 10.25 Hz, J = 10.21 Hz), 7.48(2H, d, J = 10.25 Hz, J = 10.21
Hz), 4.19 (1H, s), 3.29 (1H, s), 2.81 (1H, s), 2.32 (1H, s), 2.05 (1H,
s), 1.81 (2H, s), 1.58 (2H, s), 1.99 (1H, s), 0.95(6H, s), 0.95(6H, s);
13C NMR(75 MHz) ␦: 213.2, 167.7, 148.6, 141.8, 140.1, 137.4, 128.3,
127.5, 131.6, 127.5, 126.1, 124.9, 120.7, 58.3, 53.3, 51.9, 33.6, 28.8,
26.5, 25.2, 21.5, 17.3; EI–MS: m/z 413 [M]+(31), 303 (100); HRMS:
m/z: calcd for C23H28ClN3O2: 413.94, found 413.92; Anal. calcd
C23H28ClN3O2: C, 66.74; H, 6.82; Cl, 8.56; N, 10.15; Found: C, 66.76;
H, 6.80; Cl, 8.54; N, 10.13;
N’-((4-hydroxyphenyl)(3-isopropyl-6-methyl-2-
oxocyclohexyl)methyl)isonicotinohydra
zide (1c)
A pale yellow solid, yield 90%; MF = C23H29N3O3; MW = 395.49;
m.p. = 122–125 ◦C; Rf = 0.29; IR (KBr) ␯max: 3350, 3021, 2852, 1729,
1667, 1603, 1405, 1090; 1H NMR (300 MHz) ␦: H NMR (300 MHz)
␦: 8.86 (2H, d, J = 9.25 Hz), 8.05(1H, s), 7.85 (2H, d, J = 9.25 Hz),
5.36(1H, s, OH), 7.16(2H, d, J = 10.25 Hz), 6.72(2H, d, J = 10.25 Hz),
4.18 (1H, s), 3.20 (1H, s), 2.85 (1H, s), 2.26 (1H, s), 2.05 (1H, s), 1.84
(2H, s), 1.58 (2H, s), 1.97 (1H, s), 0.98(6H, s), 0.92(6H, s); 13C NMR(75
MHz) ␦: 213.6, 168.2, 156.8, 149.1, 141.1, 140.5, 133.6, 128.5, 128.4,
128.1, 125.9, 121.8, 116.6, 59.3, 54.1, 50.1, 32.6, 29.8, 27.5, 26.2,
20.1, 18.0; EI–MS: m/z 395 [M]+(18), 303 (100); HRMS: m/z: calcd
for C23H29N3O3: 395.49, found 395.47; Anal. calcd C23H29N3O3: C,
69.85; H, 7.39; N, 10.62; Found: C, 69.87; H, 7.37; N, 10.60.
N’-((3-isopropyl-6-methyl-2-oxocyclohexyl)(4-
nitrophenyl)methyl)isonicotinohydrazide (1d)
A pale yellow solid, yield 92%; MF = C23H28N4O4; MW = 424.22;
m.p. = 150–152 ◦C; Rf = 0.29; IR (KBr) ␯max: 3349, 3021, 2853, 1728,
1646, 1612, 1430, 1083; 1H NMR (DMSO-d6) ␦: 8.86 (2H, d, J = 9.25
Hz), 8.07(1H, s), 7.84 (2H, d, J = 9.24 Hz), 7.57(2H, d, J = 10.25 Hz),
8.20(2H, d, J = 10.25 Hz), 4.18 (1H, s), 3.21 (1H, s), 2.84 (1H, s),
2.27 (1H, s), 2.05 (1H, s), 1.84 (2H, s), 1.58 (2H, s), 1.97 (1H, s),
0.98(6H, s), 0.91(6H, s); 13C NMR(75 MHz) ␦: 214.5, 167.1, 149.6,
146.7, 144.9, 140.6, 140.5, 128.5, 128.1, 126.7, 125.9, 124.6, 121.1,
59.3, 54.2, 50.2, 32.6, 29.8, 27.5, 26.2, 20.3, 18.3; EI–MS: m/z 424
[M]+(36), 303 (100); HRMS: m/z: calcd for C23H28N4O4: 424.49,
found 424.51; Anal. calcd C23H28N4O4: C, 65.08; H, 6.65; N, 13.20;
Found: C, 65.09; H, 6.64; N, 13.22.
N’-((3-isopropyl-6-methyl-2-oxocyclohexyl)(4-
methoxyphenyl)methyl)isonicotino
hydrazide (1e)
A pale yellow solid, yield 92 %; MF = C24H31N3O3; MW = 409.24;
m.p. = 139–141 ◦C; Rf = 0.29; IR (KBr) ␯max: 3347, 3016, 2871, 1742,
1667, 1617, 1427, 1082; 1H NMR (DMSO-d6) ␦ : 8.86 (2H, d, J =
9.25 Hz), 8.03(1H, s), 7.80 (2H, d, J = 9.25 Hz), 7.16(2H, d, J = 10.25
Hz), 6.92 (2H, d, J = 10.25 Hz), 3.80(3H, s), 7.10(1H, s), 3.26(1H, s),
2.85(1H, s), 2.21(1H, s), 2.05 (1H, s), 1.84(2H, s), 1.58(2H, s), 1.97(1H,
s), 0.96(6H, s), 0.93(6H, s); 13C NMR(75 MHz) ␦: 213.6, 167.2, 157.4,
149.6, 140.8, 140.5, 133.4, 128.4, 128.5, 128.1, 125.9, 121.7, 115.7,
59.2, 54.3, 50.9, 32.6, 29.8, 27.5, 26.2, 20.5, 18.6; EI–MS: m/z 409
[M]+(42), 303 (100); HRMS: m/z: calcd for C24H31N3O3: 409.52
found 409.50; Anal. calcd C24H31N3O3: 70.39; H, 7.63; N, 10.26;
Found, 70.40; H, 7.61; N, 10.24.
N’-((4-(dimethylamino)phenyl)(3-isopropyl-6-methyl-2-
oxocyclohexyl)methyl)
isonicotinohydrazide (1f)
A pale yellow solid, yield 92%; MF = C25H34N4O2; MW = 422.56;
m.p. = 141–143 ◦C; Rf = 0.29; IR (KBr) ␯max: 3349, 3020, 2865, 1746,
1661, 1618, 1429, 1086; 1H NMR (DMSO-d6) ␦: 8.86 (2H, d, J = 9.25
Hz), 8.09(1H, s), 5.56(1H,s), 4.19 (1H, s), 3.18 (1H, s), 7.80 (2H, d,
J = 9.25 Hz), 7.11 (2H, d, J = 10.25 Hz), 6.72 (2H, d, J = 10.25 Hz),
3.10 (6H,s), 7.15(1H, s), 2.89(1H, s), 2.21(1H, s), 2.0 (1H, s), 1.84(2H,
s), 1.58(2H, s), 1.97(1H, s), 0.96(6H, s), 0.92(6H, s); 13C NMR(75
MHz) ␦: 213.1, 168.0, 149.7, 147.8, 142.8 140.9, 140.5, 129.4, 128.5,
128.1, 125.9, 121.9, 111.5, 58.2, 54.2, 50.8, 32.6, 29.8, 27.5, 26.2,
20.7, 18.6; EI–MS: m/z 422 [M]+(11), 303 (100); HRMS: m/z: calcd
for C25H34N4O2: 422.56, found 422.61; Anal. calcd C25H34N4O2: C,
71.06; H, 8.11; N, 13.26; Found: C, 71.09; H, 8.13; N, 13.24.
(E)-N’-(1-(3-isopropyl-6-methyl-2-oxocyclohexyl)-3,7-
dimethylocta-2,6-dien-1-yl)
isonicotinohydrazide (1g)
A pale yellow solid, yield 92%; MF = C26H39N3O2; MW = 425.61;
m.p. = 149–151 ◦C; Rf = 0.65; IR (KBr) ␯max: 3347, 3019, 2856, 1746,
1652, 1613, 1424, 1086; 1H NMR (DMSO-d6) ␦: 8.86 (2H, d, J = 9.25
535

4. F.S.Al-Khattafetal. Journal of Infection and Public Health 14 (2021) 533–542
Hz), 8.05(1H, s), 7.82 (2H, d, J = 9.25 Hz), 5.56(1H,s), 4.19 (1H, s), 3.20
(1H, s), 5.27 (1H, s), 3.23 (1H, s), 2.89 (1H, s), 2.27 (1H, s), 2.12(2H,
s), 2.09 (2H, s), 2.05 (1H, s), 1.70 (6H,s), 1.86 (3H, s), 1.84 (2H, s),
1.58 (2H, s), 1.98 (1H, s), 0.96 (6H, s), 0.93 (6H, s); 13C NMR(75 MHz)
␦: 212.9, 167.3, 149.8, 140.9, 140.5, 134.6, 132.7, 137.4, 39.1, 26.7,
128.4, 18.9, 24.7, 128.5, 128.1, 125.9, 121.6, 59.0, 54.6, 50.8, 32.6,
29.8, 27.5, 26.2, 20.4, 18.6, 16.6; EI–MS: m/z 425[M]+(19), 303(100);
HRMS: m/z: calcd for C26H39N3O2: 425.61, found 425.45; Anal.
calcd C26H39N3O2: C, 73.37; H, 9.24; N, 9.87; Found: C, 73.35; H,
9.23; N, 9.86.
N’-((1H-indol-3-yl)(3-isopropyl-6-methyl-2-
oxocyclohexyl)methyl)isonicotinohydrazide (1h)
A pale yellow solid, yield 92%; MF = C25H30N4O2; MW = 418.24;
m.p. = 169–172 ◦C; Rf = 0.48; IR (KBr) ␯max: 3351, 3017, 2867, 1730,
1661, 1614, 1419, 1089; 1H NMR (DMSO-d6) ␦: 10.25(1H,s), 8.86
(2H, d, J = 9.25 Hz), 8.08 (1H, s), 7.80 (2H, d, J = 9.25 Hz), 7.11 (2H, d,
J = 10.20 Hz), 7.34 (2H, d, J = 10.20 Hz), 4.20 (1H, s), 3.20 (1H, s), 2.87
(1H, s), 2.23 (1H, s), 2.05 (1H, s), 1.84 (2H, s), 1.58 (2H, s), 1.97 (1H, s),
0.96 (6H, s), 0.92 (6H, s); 13C NMR (75 MHz) ␦: 213.3, 167.5, 149.8,
140.9, 140.5, 121.9, 118.3, 11.7, 116.3, 136.5, 128.5, 117.9, 125.4
128.5, 128.1, 125.9, 121.8, 58.9, 54.0, 50.3, 32.6, 29.8, 27.5, 26.2,
20.6, 18.4; EI–MS: m/z 418 [M]+(28), 303 (100); HRMS: m/z: calcd
for C17H25N3O2: 303.40, found 303.42; Anal. calcd C17H25N3O2: C,
67.30; H, 8.31; N, 13.85; Found: C, 67.33; H, 8.30; N, 13.82.
N’-(furan-3-yl(3-isopropyl-6-methyl-2-
oxocyclohexyl)methyl)isonicotinohydrazide (1i)
A pale yellow solid, yield 92 %; MF = C21H27N3O3; MW = 369.21;
m.p. = 168–170 ◦C; Rf = 0.69; IR (KBr) ␯max: 3350, 3020, 2885, 1729,
1642, 1615, 1419, 1083; 1H NMR (DMSO-d6) ␦: 8.86 (2H, d, J = 9.25
Hz), 8.03(1H, s), 7.83 (2H, d, J = 9.25 Hz), 7.65 (2H, d, J = 10.21
Hz), 6.44 (2H, d, J = 10.21 Hzl), 6.42 (2H, d, J = 10.21 Hz), 4.18 (1H,
s), 3.23 (1H, s), 2.84 (1H, s), 2.22 (1H, s), 2.05 (1H, s), 1.84 (2H,
s), 1.58 (2H, s), 1.97 (1H, s), 0.98 (6H, s), 0.91(6H, s); 13C NMR(75
MHz) ␦: 212.9, 167.6, 151.6, 149.2, 140.7, 141.7, 140.5, 128.5, 128.1,
125.9, 121.6, 110.5, 108.4, 58.8, 54.2, 50.8, 32.6, 29.8, 27.5, 26.2,
20.9, 18.1; EI–MS: m/z 369[M]+(32), 303 (100); HRMS: m/z: calcd
for C21H27N3O3: 303.40, found 303.42; Anal. calcd C21H27N3O3: C,
67.30; H, 8.31; N, 13.85; Found: C, 67.32; H, 8.30; N, 13.82.
N’-((3-isopropyl-6-methyl-2-oxocyclohexyl)(pyridin-2-
yl)methyl)isonicotinohydrazide (1j)
A pale yellow solid, yield 86%; MF = C22H28N4O2; MW = 380.48;
m.p. = 143–146 ◦C; Rf = 0.49; IR (KBr) ␯max: 3347, 3014, 2867, 1729,
1648, 1625, 1413, 1083; 1H NMR (DMSO-d6) ␦: 8.86 (2H, d, J = 9.25
Hz), 8.15(1H, s), 7.80 (2H, d, J = 9.25 Hz), 7.49 (1H, d, J = 10.25
Hz), 7.73 (1H, d, J = 10.25 Hz), 8.43 (1H, d, J = 10.25 Hz), 7.31(1H,
d, J = 10.24 Hz), 4.21 (1H, s), 3.23 (1H, s), 2.85 (1H, s), 2.23 (1H,
s), 2.05 (1H, s), 1.84 (2H, s), 1.58 (2H, s), 1.97 (1H, s), 0.98 (6H, s),
0.94 (6H, s); 13C NMR (75 MHz) ␦: 215.6, 167.7, 157.4, 149.4, 144.2,
140.7, 140.5, 129.4, 129.0, 122.8 128.5, 128.1, 125.9, 121.8, 59.1,
54.1, 50.7, 32.6, 29.8, 27.5, 26.2, 20.6, 18.4; EI–MS: m/z 380 [M]+(36),
303(100); HRMS: m/z: calcd for C22H28N4O2: 380.48, found 380.21;
Anal. calcd C22H28N4O2: C, 69.45; H, 7.42; N, 14.73; Found: C, 69.42;
H, 7.41; N, 14.72.
N’-((3-isopropyl-6-methyl-2-oxocyclohexyl)(thiazol-5-
yl)methyl)isonicotinohydrazide (1k)
A pale yellow solid, yield 92%; MF = C20H26N4O2S; MW = 386;
MP = 165–168 ◦C; Rf = 0.58; IR (KBr) ␯max: 3351, 3022, 2862, 1738,
1652, 1621, 1430, 1088; 1H NMR (DMSO-d6) ␦ H NMR (300 MHz)
␦: 8.86 (2H, d, J = 9.25 Hz), 8.05(1H, s), 7.85 (2H, d, J = 9.25 Hz),
7.19(1H, s), 8.80(1H, s), 4.20 (1H, s), 3.19 (1H, s), 2.87 (1H, s), 2.21
(1H, s), 2.05 (1H, s), 1.84 (2H, s), 1.58 (2H, s), 1.97 (1H, s), 0.97 (6H,
s), 0.93(6H, s); 13C NMR (75 MHz) ␦: 215.2, 168.2, 157.5, 149.7,
143.5,140.6, 140.5, 133.7, 128.5, 128.1, 125.9, 121.6, 58.8, 54.4, 50.7,
32.6, 29.8, 27.5, 26.2, 20.8, 18.1; EI–MS: m/z 386 [M]+(17), 303.40
(100); HRMS: m/z: calcd for C20H26N4O2S: 386.51, found 386.50;
Anal. calcd C20H26N4O2S: C, 62.15; H, 6.78; N, 14.50; S, 8.30; Found:
C, 62.14; H, 6.79; N, 14.51; S, 8.32.
N’-(benzo[d][1,3]dioxol-5-yl(3-isopropyl-6-methyl-2-
oxocyclohexyl)methyl)isonicotino
hydrazide (1l)
A pale yellow solid, yield 84%; MF = C24H29N3O4; MW = 423.78;
m.p. = 112–119 ◦C; Rf = 0.40; IR (KBr) ␯max: 3348, 3010, 2865, 1728,
1660, 1617, 1410, 1091; 1H NMR (DMSO-d6) ␦: 8.86 (2H, d, J = 9.25
Hz), 8.05(1H, s), 7.83 (2H, d, J = 9.25 Hz), 6.74(1H, d, J = 9.21 Hz), 6.83
(1H, d, J = 9.21 Hz), 6.95(1H, s, J = 9.21 Hz), 4.18 (1H, s), 3.28 (1H, s),
2.84(1H, s), 2.21 (1H, s), 2.05 (1H, s), 1.84 (2H, s), 1.58 (2H, s), 1.97
(1H, s), 0.96 (6H, s), 0.92(6H, s); 13C NMR(75 MHz) ␦: 212.2, 167.7,
149.1, 140.3, 140.5, 133.8, 120.4, 111.6, 112.8, 148.2, 148.0, 102.3,
128.5, 128.1, 125.9, 121.1, 59.0, 54.2, 50.7, 32.6, 29.8, 27.5, 26.2,
20.5, 18.2; EI–MS: m/z 423 [M]+(18), 303(100); HRMS: m/z: calcd
for C24H29N3O4: 423.50, found 421.32; Anal. calcd C24H29N3O4: C,
68.06; H, 6.90; N, 9.92; Found: C, 68.08; H, 6.91; N, 9.90.
Antimicrobial activity
The compounds (1a–l) were screened for antibacterial activity
against gram-positive of Staphylococcus aureus (ATCC-25923), Ente-
rococcus faecalis (ATCC- 29212) and gram-negative of Escherichia
coli (ATCC-25922), Pseudomonas aeruginosae (ATCC-27853), Kleb-
siella pneumoniae (ATCC-13883) were evaluated by disc diffusion
method [49].
The compounds (1a–l) were estimated for antifungal activity
against Cryptococcus neoformans (ATCC 24067), Candida albicans
(ATCC 32552), Aspergillus niger (ATCC -201572), Microsporum
audouinii (ATCC -9079), and Aspergillus fumigatus (ATCC-13073)
using a disc diffusion method [49].
Minimum inhibitory concentration (MIC) was evaluated for all
compounds (1a–l), the compounds were prepared by twofold dilu-
tions such as 64, 32, 16, 8, 4, 2, 1, 0.5, and 0.25 ␮g/mL, respectively.
Detailed experimental procedure was available in Supplementary
information (SI) section.
Cytotoxic activity
The MCF-7 cell line was achieved from the American Type Cell
Collection (ATCC; Manassas, VA, USA). All synthesized compounds
(1a–l) were tested for cytotoxic activity, according to the procedure
recommended in pervious literature [49]. Detailed experimental
procedure was available in Supporting information (SI) section.
Results and discussion
Materials and characterization
The one-pot multicomponent of derivatives were synthesized
via solvent-free green chemistry. The final solid material was re-
crystallized using suitable alcohol to get pure product, as per
Scheme 1. The proposed synthesis is solvent and catalyst free syn-
thesis. Target compounds were analysis via FT-IR, 1H 13C NMR
spectrum.
The spectral values of all compounds (1a–l) was compared with
previous literature values [50]. In FT-IR spectra, compounds (1a–l)
536

5. F.S.Al-Khattafetal. Journal of Infection and Public Health 14 (2021) 533–542
Scheme 1. Synthetic route of Isoniazid derivatives (1a–l).
Table 1
Antibacterial activity measured by the zone of inhibition (mm).
Comp. No. Zone of inhibition(mm), 100 ␮g/mL concentration
Gram-positive Gram-negative
S. aureus E. faecalis E. coli P. aeruginosa K. pneumoniae
1a 6 0 6 0 12
1b 6 20 20 12 22
1c 22 15 12 6 0
1d 6 6 2 12 0
1e 0 2 2 27 27
1f 6 2 6 6 20
1g 27 27 30 34 22
1h 2 20 6 27 27
1i 2 22 6 0 0
1j 2 0 0 0 2
1k 2 0 6 2 2
1l 0 2 2 2 2
Ciprofloxacin 32 22 32 30 27
Table 2
Antibacterial activity of compound (1a–l).
Comp. No. Minimum Inhibitory Concentration (MIC, ␮g/mL)
Gram-positive Gram-negative
S. aureus E. faecalis E. coli P. aeruginosa K. pneumoniae
1a 64 100 64 100 32
1b 64 8 8 32 4
1c 4 16 32 64 100
1d 64 64 100 32 100
1e 100 100 100 2 2
1f 64 100 64 64 8
1g 2 2 1 0.25 4
1h 100 8 64 2 2
1i 100 4 64 100 100
1j 100 100 100 100 100
1k 100 100 64 100 100
1l 100 100 100 100 100
Ciprofloxacin 0.5 4 0.5 1 2
exhibited characteristic absorption bands range of 3345–3351,
1640–1667 and 2850–2885, cm−1 for –NH, –CO stretching and
–CO–NH group, respectively, the values were compared with pre-
vious publications [51].
The 1H NMR spectra of compounds (1a–l), the sharp singlet peak
of proton –CO–NH appeared around ␦ 8.12–8.05 ppm. The singlet
around ␦ 4.21–4.18 for –CH moiety in the structures, the signals at
␦ 0.99–0.96 and 0.95–0.91 ppm for six protons(–2CH3) and three
protons (–CH3) methyl group presents, singlet signal at ␦ 2.89–2.83
(s, 1H, CH adjacent to C O), ␦ 2.27–2.20 (m, 1H, CH adjacent to
C O). The signals at ␦ 3.29–3.10 corresponding to –NH protons,
8.86 (2H), 7.82 (2H) corresponding to pyridine moiety, the spectral
values was matched with previous publications [52].
In 13C NMR spectra (1a–l), the signals around ␦ 167.1–168.9,
59.3–58.2, and 212.2–2.15 were arise for the –OC–NH–, CH, and
–C O carbon presence. The carbon signals at ␦ 149.6–148.6 (C4,
Pyridine), 141.8–140.8 (C1, Pyridine), 123.5–121.7 (C2, Pyridine),
51.9–50.9 (CH adjacent to C O), 54.3–53.3 (CH adjacent to C O),
21.5–20.5(2CH3), 18.3–17.3(–CH3), respectively. HRMS spectrum
and elemental analysis results are also satisfied with the confor-
mation all compounds.
Biological activity
The in vitro antibacterial activities of compounds (1a–l) were
estimated against a set of human pathogenic bacteria, namely
gram-positive of S. aureus, E. faecalis and gram-negative of E. coli,
P. aeruginosa, and K. pneumoniae. The in vitro antifungal activities
were evaluated against A. niger, C. albicans, Cr. neoformans, and M.
audouinii. Ciprofloxacin and clotrimazole used as a standard. The
537

6. F.S.Al-Khattafetal. Journal of Infection and Public Health 14 (2021) 533–542
Table 3
The zone of inhibition (mm) of antifungal activity.
Comp. No. Zone of inhibition(mm), 100 ␮g/mL concentration
Cr. neoformans C. albicans A. niger M. audouinii A. fumigatus
1a 6 0 2 0 0
1b 0 34 0 2 12
1c 2 6 6 22 0
1d 2 12 12 12 6
1e 2 22 22 20 0
1f 12 2 0 0 20
1g 6 6 6 6 27
1h 0 0 0 2 22
1i 2 6 6 6 2
1j 2 2 2 0 0
1k 0 0 2 2 2
1l 0 6 6 6 0
Clotrimazole 27 32 27 20 22
Table 4
Antifungal activity of compound (1a–l).
Comp. No. Minimum Inhibitory Concentration(MIC, ␮g/mL)
Cr. neoformans C. albicans A. niger M. audouinii A. fumigatus
1a 64 100 100 100 100
1b 100 0.25 100 100 32
1c 100 64 64 4 100
1d 100 32 32 32 64
1e 100 4 4 8 100
1f 32 100 100 100 8
1g 64 64 64 64 2
1h 100 100 100 100 4
1i 100 64 64 64 100
1j 100 100 100 100 100
1k 100 100 100 100 100
1l 100 64 64 64 100
Clotrimazole 2 0.5 2 8 4
Fig. 2. Structure activity relationship of active compounds.
zone of inhibition (mm) are denoted in Tables 1 and 3. The zone
of inhibition was measured by each compounds at 100 ␮g/mL in
DMSO (Dimethyl sulfaoxide) concentration. The value of MIC repre-
sented in Tables 2 and 4. Gram positive bacterial strain, S. aureus as a
reference, all compounds were not significant of activity compared
with ciprofloxacin, this result compared with previous reports of
isoniazid against S. aureus (MIC: 500 ␮g/mL) [53], and also com-
pared with menthone was activity of 20 mm zone of inhibition was
observed with previous study [54], whereas the compound 1g was
moderate activity (27 mm; MIC = 2 ␮g/mL) compared with other
compounds.
If E. faecalis is used for assessment, 1g (27 mm; MIC = 2 ␮g/mL)
was highly active than standard ciprofloxacin (27 mm; MIC = 4
␮g/mL), when compared with the isoniazid previous study report
E. faecalis (125 ␮g/mL) [53], and compared with menthone was
observed 20 mm zone of inhibition in a previous study [54],
whereas other compounds 1i shows that equipotent activity (22
mm; MIC = 4 ␮g/mL) compared with standard. Fig. 3 shows that
538

7. F.S.Al-Khattafetal. Journal of Infection and Public Health 14 (2021) 533–542
Fig. 3. Compounds (1a–l) compared with E. faecalis Vs cytotoxic activity with ␮g/mL
concentration.
Fig. 4. Compounds (1a–l) compared with P. aeruginosa Vs cytotoxic activity with
␮g/mL concentration.
compound compared with E. faecalis and cytotoxic in ␮g/mL con-
centration.
All compounds were low activity against gram negative bacteria
of E. coli strain, the activity was compared with isoniated for E. coli
(MIC: 500 ␮g/mL) [53], compared with menthone was observed 15
mm zone of inhibition in apervious study [54].
If considered P. aeruginosa, the compound 1g (MIC = 0.25 ␮g/mL)
was extremely active associated with standard and other com-
pounds 1e and 1h shows moderate active (27 mm; MIC = 2 ␮g/mL)
than other compounds, the activity was compared with isoniated
for P. aeruginosa (MIC: 500 ␮g/mL) [53], compared with menthone
was observed no inhibition in the previous study [54]. Fig. 4 shows
that compound compared P. aeruginosa with cytotoxic activity in
␮g/mL concentration.
Comparison of K. pneumonia, the compounds 1e and 1h (27
mm; MIC = 2 ␮g/mL) displayed equipotent activity compared with
standard (27 mm; MIC = 2 ␮g/mL), compared with menthone was
observed of 10 mm zone of inhibition [54], whereas the compound
1g was moderately active (22 mm; MIC = 4 ␮g/mL) than other
compounds.
Antifungal activity outlines demonstration that the all com-
pounds were not significant compared with standard clotrimazole
against Cr. Neoformans, compared with isoniazid (MIC: 252.29
␮g/mL) of activity [55], compared with menthone was observed
zone of inhibition (5 mm) in a previous study [56].
The compound 1b (34 mm; MIC = 0.25 ␮g/mL) was highly active
against C. albicans compared with the standard, compared with
menthone was observed zone of inhibition 20 mm in the previous
study [52], the compound 1e showed moderated active (22 mm;
MIC = 4 ␮g/mL) against A. niger than other compound whereas
low active than standard. Fig. 5 shows that compound compared
C. albicans with cytotoxic activity in ␮g/mL concentration
Fig. 5. Compounds (1a–l) compared with Candida albicans Vs cytotoxic activity with
␮g/mL concentration.
Fig. 6. Compounds (1a–l) compared with M. audouinii Vc MCF-7 cell line with ␮g/mL
concentration.
Table 5
Cytotoxic activity of compounds (1a–l).
Compounds MCF-7 Cell cline
GI50 (␮M) TGI (␮M) LC50 (␮M)/(␮g/mL)
1a 0.90 ± 0.05 1.82 ± 0.19 3.62 ± 0.26/(1.37)
1b 0.02 ± 0.00 0.34 ± 0.01 0.68 ± 0.15/(0.28)
1c 1.90 ± 0.21 2.00 ± 0.11 4.60 ± 0.16/(1.81)
1d 7.20 ± 0.19 15.10 ± 0.10 36.20 ± 0.14/(15.35)
1e 10.50 ± 0.13 26.60 ± 0.12 56.20 ± 0.17/(22.99)
1f 48.30 ± 0.15 86.20 ± 0.19 100/(42.25)
1g 0.01 ± 0.00 0.11 ± 0.01 0.35 ± 0.05/(0.14)
1h 1.00 ± 0.21 3.60 ± 0.02 9.70 ± 0.12/(4.05)
1i 5.20 ± 0.11 13.10 ± 0.12 31.20 ± 0.12/(11.51)
1j 11.5 ± 0.13 26.40 ± 0.12 51.30 ± 0.02/(19.51)
1k 8.20 ± 0.60 16.10 ± 0.69 31.20 ± 0.01/(12.51)
1l 1.20 ± 0.05 2.20 ± 0.19 6.30 ± 0.02/(12.04)
Doxorubicin 0.02 ± 0.00 0.21 ± 0. 09 0.74 ± 0. 01/(0.40)
a
The values of mean ± SD (n = 3).
If taking M. audouinii, the compound 1c (22 mm; MIC = 4 ␮g/mL)
presence extremely active related to the standard, whereas the
compound 1e was equipotent (20 mm; MIC = 8 ␮g/mL) than the
standard (20 mm; MIC = 8 ␮g/mL). Fig. 6 shows that compound
compared M. audouinii with MCF-7 cell line in ␮g/mL concentra-
tion.
Consider the A. fumigatus fungal strain the compound 1g (27
mm; MIC = 2 ␮g/mL) showed highly active than standard whereas
the compound 1h (22 mm; MIC = 4 ␮g/mL) was equipotent than the
standard (22 mm; MIC = 4 ␮g/mL), compared with the menthone
was observed 26 mm (MIC, 88.0 ␮g/mL) zone of inhibition in the
previous study [57].
The cytotoxic activity, the compounds (1a–l) were estimated for
cytotoxic activity against MCF-7 cell lines, at assay used 100 ␮M
for 48 h (MTT anticancer assay). The MCF-7(breast) cell line used in
the present investigation. The results are represented in Table 5. The
results were communicated in terms of the GI50 (growth inhibitor),
TGI (total growth of inhibition), and LC50 (lethal concentration). The
539

8. F.S.Al-Khattafetal. Journal of Infection and Public Health 14 (2021) 533–542
Fig. 7. Compounds (1a–l) of cytotoxicity activity comparison of concentration with
activities.
compound 1g (GI50 = 0.01 ␮M) was high, while 1b (GI50 = 0.02 ␮m)
showed equipotent activity, and other compounds (GI50 0.90 to
48.3 ␮M) displayed reasonable active against the MCF-7 cell line
associated with doxorubicin.
Fig. 7 shows that chat for mean ± SD cytotoxity values of
GI50, TGI50 and LC50 in ␮M concentration of compounds (1a–l).
In conclusion, new derivatives (1a–l) were investigated by bio-
logical activity, the compound 1g (MIC = 0.25 ␮g/mL) showed
strong antibacterial activity in contradiction of the gram negative
bacterial strain of P. aeruginosa related to the reference standard
ciprofloxacin, while 1c (MIC = 0.02 ␮g/mL) displayed strange anti-
fungal activity against C. albicans than clotrimazole. Compound 1g
(GI50 = 0.01 ␮M) exhibited high active against the MCF-7 cell line,
while 1b (GI50 = 0.02 ␮M) was equipotent active compared with
standard doxorubicin.
Structure activity relationship
The structure activity relationship (SAR) is represented in Fig. 2.
The SAR exhibited the association of electron with drawing and
electron-releasing groups in the C-4 position of phenyl ring with
isoniazid analogs 1a–l were intensely potential for gram-positive
and gram negative microorganisms than standard ciprofloxacin
[58].
The compounds 1b, 1c, 1e, and 1g were significant of activity in
all bacterial and fungal species. The SAR exposed strong electron-
withdrawing groups, for example, –Cl, and electron releasing
groups –OH is indicating better antimicrobial action [59]. The SAR
showing that lipophilicity supposed a crucial role in attractive
antibacterial activity [60].
The compound 1g was highly active against E. faecalis (27 mm;
MIC:2 ␮g/mL) and P. aeruginosa (34 mm; MIC: 0.25 ␮g/mL) com-
pared than ciprofloxacin whereas low active in S. aureus, E. coli, and
K. pneumoniae species, and also high potential against A. fumiga-
tus (27 mm; MIC 2 ␮g/mL) in antifungal, due to the compound 1g
having citiral act as lipophilicity with 3-isonicotinohydrazide and
menthone, whereas low active other spices.
The compound 1c was highly active (22 mm; MIC: 4 ␮g/mL)
against M. audouinii compared than ciprofloxacin and compound 1c
having 4-OH phenyl group connected with 3-isonicotinohydrazide
with a menthone better performance of other compounds.
Compound 1b was not significant of active against all bacterial
strain but highly active (34 mm; MIC: 0.25 ␮g/mL) in contradiction
of C. albicans. Substitution of electron-withdrawing group of –Cl at
the C-4 position as in compound 1b displayed nearly active than
clotrimazole (32 mm; MIC: 0.5 ␮g/mL).
The compounds 1e was equipotent active against K. pneumoniae
(27 mm; MIC: 2 ␮g/mL) and equipotent active against M. audouinii
(20 mm; MIC: 8 ␮g/mL) compared with clotrimazole, the com-
pound 1e have electron donating groups (4-OCH3) group connected
with isonicotino hydrazide, which equipotent activity compared to
other compounds.
The compounds 1j, 1k, and 1l were very low response against all
bacterial species, which due to have heterocyclic ring substitution
with no para substituted aromatic groups presences.
Therefore, SAR demonstrated that 3-isonicotinohydrazide with
citral of lipophilicity of compound 1g, the compound 1b electron-
withdrawing groups (–Cl), and electron releasing groups (–OH)
were significant of antimicrobial activity and also cytotoxic active
for all compounds, the compounds 1b, 1c, and 1g were highly toxic
compared with other compounds.
Conclusion
In conclusion, an efficient synthesis of multi-drug resistant
pathogens of derivatives, namely, (1a–l), via the grindstone method
to yield 88–96%. The results showed that some excellent active
against gram-positive, gram-negative bacteria and fungus infec-
tion, which results have been achieved with the scaffold. The
compound 1g (MIC = 2 ␮g/mL) and compound 1g (MIC = 0.25
␮g/mL) showed significant antibacterial activity against gram pos-
itive bacterial of E. faecalis, and gram negative bacterial of P.
aeruginosa than standard ciprofloxacin. The alkyl chain length of
the heterocyclic unit was found to be crucial for good activity. Gen-
erating such hybrid compounds can be a promising approach to
develop good desired biological activities. The compound 1c (MIC
= 4 ␮g/mL) exhibited in height antifungal activity in contradiction
of M. audouinii and compound 1b (MIC = 0.25 ␮g/mL) exhibited
in height antifungal activity in contradiction of C. albicans com-
pared to the clotrimazole. The compounds 1b and 1c was significant
of antifungal activities. To study the SAR, electron donating (OH)
groups and electron withdrawing (Cl) groups on the phenyl ring are
most favour the least antifungal activities. The highly active antimi-
crobial compounds 1b, 1c, and 1g were compared with cytotoxic
activity against the MCF-7 cell line, while 1g (LC50 = 0.14 ␮g/mL),
1b (LC50 = 0.28 ␮g/mL), and 1c (LC50 = 1.81 ␮g/mL) were highly
cytotoxic activity compared with other compounds. The results
indicates, we trust the compounds 1b, 1c, and 1g could serve as
a novel class of antimicrobial agents. In the future, a variety of
analogues are probable to appear as first line antibiotic agents.
Funding
No funding sources.
Competing interests
None declared.
Ethical approval
Not required.
Acknowledgement
The authors extend their appreciation to the Researchers Sup-
porting Project number (RSP-2020/224), King Saud University,
Riyadh, Saudi Arabia.
Appendix A. Supplementary data
Supplementary material related to this article can be found,
in the online version, at doi:https://doi.org/10.1016/j.jiph.2020.12.
033.
540

9. F.S.Al-Khattafetal. Journal of Infection and Public Health 14 (2021) 533–542
References
[1] Qadri F, Svennerholm AM, Faruque ASG, Sack RB. Enterotoxigenic,
Escherichia coli in developing countries:epidemiology, microbiology, clinical
features, treatment, and prevention. Clin Microbiol Rev 2005;18:465–83,
http://dx.doi.org/10.1128/CMR.18.3.465-483.2005.
[2] Devasia RA, Jones TF, Ward J, Stanfford L, Hardin H, Bopp C, et al. Endemi-
cally acquired foodborne outbreak of enterotoxin-producing Escherichia coli
serotype O169:H41. Am J Med 2006;119:7–10, http://dx.doi.org/10.1016/j.
amjmed. 2005.07.063.
[3] Datta DV, Chhutani SSA. Treatment of amebic liver abscess with emetine
hydrochloride, niridazole, and metronidazole A controlled clinical trial. Am J
Trop Med Hyg 1947;23:586–9.
[4] Murphy ST, Case HL, Ellsworth E, Hagen S, Husband M, Jonnides T, et al. The
synthesis and biological evaluation of novel series of nitrile-containing fluo-
roquinolones as antibacterial agents. Bioorg Med Chem Lett 2007;17:2150–5,
http://dx.doi.org/10.1016/j.bmcl.2007.01.090.
[5] Li Xiang, Li Haitao, Li Shengqing, Zhu Feng, Dong JK, Xie H, et al. Ceftriaxone, an
FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by tar-
geting Aurora B. Carcinogenesis 2012;33:2548–57, http://dx.doi.org/10.1093/
carcin/bgs283.
[6] Kigondu E, Wasuna M, Warner A, Chibale DFK. Pharmacologically active
metabolites, combination screening and target identification-driven drug
repositioning in anti-tuberculosis drug discovery. Bioorg Med Chem
2014;22:4453–61, http://dx.doi.org/10.1016/j.bmc.2014.06.012.
[7] Sun P, Guo J, Winnenburg R, Baumbach J. Drug repurposing by inte-
grateddfcd mining and drug–gene–disease triangulation. Drug Discov Today
2017;22:615–9, http://dx.doi.org/10.1016/j.drudis.2016.10.008.
[8] Verma SK, Verma R, Xue F, Thakur PK, Girish YR, Rakesh KP. Antibacterial
activities of sulfonyl or sulfonamide containing heterocyclic derivatives and its
structure-activity relationships (SAR) studies: a critical review. Bioorg Chem
2020;105:104400, http://dx.doi.org/10.1016/j.bioorg.2020.104400.
[9] Qin Hua-Li, Zhang Zai-Wei, Ravindar L, Rakesh KP. Antibacterial activities with
the structure-activity relationship of coumarin derivatives, antibacterial activ-
ities with the structure-activity relationship of coumarin derivatives. Eur J Med
Chem 2020;207:11283, http://dx.doi.org/10.1016/j.ejmech.2020.112832.
[10] Filomena M, Susana S, Cristina V, Ruben E-L, Lídia S, Susana V, et al. Design,
synthesis and biological evaluation of novel isoniazid derivatives with potent
antitubercular activity. Eur J Med Chem 2014;81:119–38, http://dx.doi.org/10.
1016/j.ejmech.2014.04.077.
[11] Beena DSR. Antituberculosis drug research: a critical overview. Med Res Rev
2013;33:693–764, http://dx.doi.org/10.1002/med.21262.
[12] Gao C, Feng LS, Lv ZS, Xu Z, Wu X. Isoniazid derivatives and their anti-
tubercular activity. Eur J Med Chem 2017;133:255–67, http://dx.doi.org/10.
1016/j.ejmech.2017.04.002.
[13] Kumar D, Khare G, Beena, Kidwai S, Tyagi AK, Singh R, et al. Novel isoniazid–
amidoether derivatives: synthesis, characterization and antimycobacterial
activity evaluation. Med Chem Commun 2015;6:131–7, http://dx.doi.org/10.
1039/C4MD00288A.
[14] Kumar D, Beena, Khare G, Kidwai S, Tyagi AK, Singh R, et al. Synthesis of novel
1,2,3-triazole derivatives of isoniazid and their in vitro and in vivo antimycobac-
terial activity evaluation. Eur J Med Chem 2014;81:301–31, http://dx.doi.org/
10.1016/j.ejmech.2014.05.005.
[15] Judge V, Narasimhan B, Ahuja M, et al. Synthesis, antimycobacterial,
antiviral, antimicrobial activities, and QSAR studies of isonicotinic acid-1-
(substituted phenyl)- ethylidene/cyclohepty lidene hydrazides. Med Chem Res
2012;21:1935–52, http://dx.doi.org/10.1007/s00044-011-9705-2.
[16] Zhang S, Xu Z, Gao C, Ren QC, Chang L, Lv ZS, et al. Triazole derivatives and their
anti-tubercular activity. Eur J Med Chem 2017;138:501–13, http://dx.doi.org/
10.1016/j. ejmech. 2017.06.051.
[17] Rollas S, Küçükgüzel SG. Biological activities of hydrazone derivatives.
Molecules 2007;12:1910–39, http://dx.doi.org/10.3390/12081910.
[18] Rasras AJM, Al-Tel TH, Al-Aboudi AF, Al-Qawasmeh RA. Synthesis and
antimicrobial activity of cholic acid hydrazone analogues. Eur J Med Chem
2010;45:2307–13, http://dx.doi.org/10.1016/j.ejmech.2010.02.006.
[19] Mohareb RM, Fleita DH, Sakka OK. Novel synthesis of hydrazide-hydrazone
derivatives and their utilization in the synthesis of coumarin, pyridine, thiazole
and thiophene derivatives with antitumor activity. Molecules 2011;16:16–27,
http://dx.doi.org/10.3390/molecules16010016.
[20] Asif M. Pharmacologically potentials of hydrazonone containing compounds A
promising scaffold. Int J Adv Chem 2014;2:85–103, http://dx.doi.org/10.14419/
ijac.v2i2.2301.
[21] Liu H, Long S, Rakesh KP, Zha Gao-Feng. Structure-activity relationships (SAR)
of triazine derivatives: promising antimicrobial agents. Eur J Med Chem
2020;185:111804, http://dx.doi.org/10.1016/j.ejmech.2019.111804.
[22] Maccari R, Ottanà R, Vigorita MG. In vitro advanced antimycobacterial screening
of isoniazid- related hydrazones, hydrazides and cyanoboranes: part 14. Bioorg
Med Chem Lett 2005;15:2509–13, http://dx.doi.org/10.1016/j.bmcl.2005.03.
065.
[23] Tatiane SC, Jessica BC, Marcelle LFB, Raoni SBG, Camilo HSL, Pedro EA, et al.
In vitro anti-mycobacterial activity of (E)-N’-(monosubstituted-benzylidene)
isonicotino hydrazide derivatives against isoniazid-resistant strains. Infect Dis
Rep 2012;4(1):e13, http://dx.doi.org/10.4081/idr.2012.e13.
[24] Naveen Kumar HS, Parumasivam T, Jumaat F, et al. Synthesis and evaluation
of isonicotinoyl hydrazone derivatives as antimycobacterial and anticancer
agents. Med Chem Res 2014;23:269–79, http://dx.doi.org/10.1007/s00044-
013-0632-2.
[25] Vavříková E, Polanc S, Kočevar M, Košmrlj J, Horváti K, B
osze S, et al. New series
of isoniazid hydrazones linked with electron-withdrawing substituents. Eur J
Med Chem 2011;46:5902–9, http://dx.doi.org/10.1016/j.ejmech.2011.09.054.
[26] Jain JS, Srivastava RS, Aggrawal N, Sinha R. Synthesis and evaluation
of Schiff bases for anticonvulsant and behavioral depressant properties.
Cent Nerv Syst Agents Med Chem 2007;7:200–4, http://dx.doi.org/10.2174/
187152407781669143.
[27] Mishra V, Pandeya SN. Analgesic activity and hypnosis potentiation effect of (±)
3-menthone semicarbazone and thiosemicarbazone derivatives. Acta Pharm
2001;51:83–8.
[28] Mishra V, Pandeya SN, Pannecouque C, Witvrouw M, De Clercq E. Anti HIV activ-
ity of thiosemicarbazone and semicarbazone derivatives of (±) 3-menthone.
Arch Pharm Pharm Med Chem 2002;5:183–6, http://dx.doi.org/10.1002/1521-
4184(200205)335:5183::AID- ARDP1833.0.CO;2-U.
[29] Rakesha KP, Kumarab HK, Ullasa BJ, Shivakumaraa J, Channe Gowdaa D.
Amino acids conjugated quinazolinone-Schiff’s bases as potential antimi-
crobial agents: synthesis, SAR and molecular docking studies. Bioorg Chem
2019;90:103093, http://dx.doi.org/10.1016/j.bioorg.2019.103093.
[30] Bass Jr JB, Farer LS, Hopewell PC, O’Brien R, Jacobs RF, Ruben F, et al. Treatment
of tuberculosis and tuberculosis infection in adults and children. American Tho-
racic Society and The Centers for Disease Control and Prevention. Am J Respir
Crit Care Med 1994;149:1359–74.
[31] Rodrigues MO, Cantos JB, D’Oca CRM, Soares KL, Coelho TS, Piovesan LA, et al.
Synthesis and anti-mycobacterial activity of isoniazid derivatives from renew-
able fatty acids. Bioorg Med Chem 2013;21:6910–4, http://dx.doi.org/10.1016/
j.bmc.2013.09.034.
[32] Galyna PV, Michail AT, Volodymyr GB, Nataliia MD, Mykola IG, Sergiy ST, et al.
Novel isoniazid derivative as promising antituberculosis agent. Future Micro-
biology 2020;15:869–79, http://dx.doi.org/10.2217/fmb-2019-0085.
[33] Judge V, Narasimhan B, Ahuja M, et al. Synthesis, antimycobacterial,
antiviral, antimicrobial activities, and QSAR studies of isonicotinic acid-1-
(substituted phenyl)-ethylidene/cyclo heptylidene hydrazides. Med Chem Res
2012;21:1935–52, http://dx.doi.org/10.1007/s00044-011-9705-2.
[34] Gon Çalves MJ, Vicente AM, Cavaleiro C, Salgueiro L. Composition and antifungal
activity of the essential oil of Mentha cervina from Portugal, Natural Product
Research Formerly. Nat Prod Lett 2007;21:867–71, http://dx.doi.org/10.1080/
14786410701482244.
[35] Bogdanova K, Röderova M, Kolar M, Langova K, Dusek M, Jost P, et al.
Antibiofilm activity of bioactive hop compounds humulone, lupulone and
xanthohumol toward susceptible and resistant staphylococci. Res Microbiol
2018;169:127–34, http://dx.doi.org/10.1016/j.resmic.2017.12.005.
[36] Khedr MA, Alberto Massarotti A, Maged E. Mohamed rational discovery of (+)
(S) abscisic acid as a potential antifungal agent: a repurposing approach. Sci
Rep 2018;8:8565, http://dx.doi.org/10.1038/s41598-018-26998-x.
[37] Joshi C, Khosla N, Tiwari P. In vitro study of some medicinally impor-
tant Mannich bases derived from antitubercular agent. Bioorg Med Chem
2004;14:571–6, http://dx.doi.org/10.1016/j.bmc.2003.11.001.
[38] Sujith KV, Jyothi NR, Prashanth S, Balakrishna K. Regioselective reaction:
synthesis and pharmacological study of Mannich bases containing ibupro-
fen moiety. Eur J Med Chem 2009;44:3697–702, http://dx.doi.org/10.1016/j.
ejmech.2009.03.044.
[39] Gamal El-Din AR, Hatem AS, Gamal MG. Design, synthesis, antibacterial activity
and physicochemical parameters of novel N-4-piperazinyl derivatives of nor-
floxacin. Bioorg Med Chem 2009;17:3879–86, http://dx.doi.org/10.1016/j.bmc.
2009.04.027.
[40] Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T,
et al. inhA, a Gene encoding a target for isoniazid and ethionamide in
Mycobacterium tuberculosis. Science 1994;263:227–30, http://dx.doi.org/10.
1126/science.8284673.
[41] Deretic V, Pagan-Ramos E, Zhang Y, Dhandayuthapani S, Via LE. The extreme
sensitivity of Mycobacterium tuberculosis to the front-line antituberculosis
drug isoniazid. Nat Biotechnol 1994;14:1557–61, http://dx.doi.org/10.1038/
nbt1196-1557.
[42] Rozwarski DA, Grant GA, Barton DH, Jacobs Jr WR, Sacchettini JC. Modification
of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis.
Science 1998;279:98–102, http://dx.doi.org/10.1126/science.279.5347.98.
[43] Meshram J. Design, synthesis, and evaluation of isoniazid derivatives act-
ing as potent anti- inflammatory and anthelmintic agents via Betti reaction
Ipsita Mohanram. Med Chem Res 2014;23:939–47, http://dx.doi.org/10.1007/
s00044-013-0693-2.
[44] Malhotra M, Sharma S, Deep A. Synthesis, characterization and antimicrobial
evaluation of novel derivatives of isoniazid. Med Chem Res 2012;21:1237–44,
http://dx.doi.org/10.1007/s00044-011-9634-0.
[45] Patil PS, Kasare SL, Haval NB, Khedkar VM, Dixit PP, Rekha ME, et al. Novel
isoniazid embedded triazole derivatives: synthesis, antitubercular and antimi-
crobial activity evaluation. Bioorg Med Chem Lett 2020;30:127434, http://dx.
doi.org/10.1016/j.bmcl.2020.127434.
[46] Zeng S, Soetaert K, Ravon F, Vandeput M, Bald D, Kauffmann JM, et al.
Bactericidal I. Activity involves electron transport chain perturbation. Antimi-
crob Agents Chemother 2019;63, http://dx.doi.org/10.1128/AAC.01841-18,
1841–18.
[47] Sinha N, Jain S, Tilekar A, Upadhayaya RS, Kishore N, Jana GH, et al. Synthesis
of isonicotinic acid N
-arylidene-N-[2-oxo-2-(4-aryl-piperazin-1-yl)-ethyl]-
541

10. F.S.Al-Khattafetal. Journal of Infection and Public Health 14 (2021) 533–542
hydrazides as antitubercul osisagents. Bioorg Med Chem Lett 2005;15:1573,
http://dx.doi.org/10.1016/j.bmcl.2005.01.073.
[48] Sriram D, Yogeeswari P, Madhu K. Synthesis and in vitro and in vivo
antimycobacterial activity of isonicotinoyl hydrazones. Bioorg Med Chem Lett
2005;15:4502, http://dx.doi.org/10.1016/j.bmcl.2005.07.011.
[49] Hatamleh AA, Al Farraj D, Salah Al-Saif S, Chidambaram S, Radhakrishnan
S, Akbar I. Synthesis, cytotoxic analysis, and molecular docking studies of
tetrazole derivatives via N- Mannich base condensation as potential antimicro-
bials. Drug Des Devel Ther 2020;14:4477–92, http://dx.doi.org/10.2147/DDDT.
S270896.
[50] Jardosh Hardik H, Patel Manish P. Design and synthesis of biquinoloneeisoni-
azid hybrids as a new class of antitubercular and antimicrobial agents. Eur J
Med Chem 2013;65:348–59, http://dx.doi.org/10.1016/j.ejmech.2013.05.003.
[51] Judge V, Narasimhan B, Ahuja M, et al. Isonicotinic acid hydrazide deriva-
tives: synthesis, antimicrobial activity, and QSAR studies. Med Chem Res
2012;21:1451–70, http://dx.doi.org/10.1007/s00044-011-9662-9.
[52] Jain J, Kumar Y, Sinha R, Kumar R, Stables J. Menthone aryl acid hydrazones:
a new class of anticonvulsants. Med Chem 2011;7:56–61, http://dx.doi.org/10.
2174/157340611794072689.
[53] Zargarnezhad S, Gholami A, Khoshneviszadeh M, Abootalebi SN, Ghasemi
Y. Antimicrobial activity of isoniazid in conjugation with surface- modified
magnetic nanoparticle against Mycobacterium tuberculosis and nonmycobacte-
rial microorganisms. J Nanomater 2020;9:7372531, http://dx.doi.org/10.1155/
2020/7372531.
[54] Jirovetz L, Buchbauer G, Bail S, Denkova Z, Slavchev A, Stoyanova A, et al. Antimi-
crobial activities of essential oils of mint and peppermint as well as some of
their main compounds. J Essent Oil Res 2009;21(4):363–4366, http://dx.doi.
org/10.1080/10412905.2009.9700193.
[55] Rossana de AC, Rosana S, Francisca Je de FM, et al. Inhibitory activity of
isoniazide and ethionamide against Cryptococcus biofilms. Can J Microbiol
2015;11:827–36, http://dx.doi.org/10.1139/cjm-2015-0230.
[56] Kumar A, Singh SP, Chhokar SS. Antimicrobial activity of the major isolates of
mentha oil and derivatives of menthol. Anal Chem Lett 2011;1:70–85, http://
dx.doi.org/10.1080/22297928.2011.10648206.
[57] Hussain AI, Anwar F, Nigam PS, Ashraf M, Gilani Anwarul H. Seasonal variation
in content, chemical composition and antimicrobial and cytotoxic activities
of essential oils from four Mentha species. J Sci Food Agric 2010;90:1827–36,
http://dx.doi.org/10.1002/jsfa.4021.
[58] Holiyachi M, Shastri SL, Chougala BM, Shastri LA, Joshi SD, Dixit SR, et al.
Design, synthesis, and structure-activity relationship study of coumarin ben-
zimidazole hybrid as potent antibacterial and anticancer agents. Chem Select
2016;1:4638–44, http://dx.doi.org/10.1002/slct.201600665.
[59] Patel P, Pillai J, Darji N, Patel P, Patel B. Design, synthesis and characterization
of novel molecules comprising benzothiazole and sulphonamide linked to sub-
stituted aryl group via azo link as potent antimicrobial agents. Int J Drug Res
Tech 2012;2:289–96.
[60] Turkmen H, Zengin G, Buyukkircali B. Synthesis of sulfanilamide derivatives
and investigation of in vitro inhibitory activities and antimicrobial and physical
properties. Bioorg Chem 2011;39:114–9, http://dx.doi.org/10.1016/j.bioorg.
2011.02.004.
542